How I Survived Melanoma Skin Cancer

How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

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How I Survived Malignant Melanom

By The Time You've Finished Reading How I Survived Melanoma Skin Cancer Seven Survivors Tell Their Stories. You'll Feel Like A New Person, with A New, More Positive Outlook! You will learn: 1. How do I know if I have melanoma? What are the signs and symptoms? I wanted to know why the doctor was so concerned when she looked at that little mole on my forearm. What was it that looked so sinister? How worried should I be? Was the doctor over-reacting? 2. What tests will the doctor carry out to see if I have melanoma? Will they be able to tell me on the spot if there is a problem? Or will I have to wait for days, fretting about whats going on? 3. How curable is melanoma? If they do tell me its melanoma, what exactly does that mean? Is it a death sentence? Will they tell me You have 12 months to live. Get your life in order and prepare for the worst.? 4. What are the stages of the disease? The reading Id done said that there were different stages of melanoma. What are the symptoms of each stage? What are the survival rates of each stage? If I had a later stage melanoma, wouldnt I know about it? Wouldnt I actually feel like I was sick? 5. How quickly does the disease progress or spread? Should I have gone to the doctor sooner? Id noticed the mole changing over about 3 months. Was this delay critical? 6. How is melanoma normally treated? Would I have to go through chemotherapy and radiation treatment? If so, for how long? What are the odds of curing the disease using these treatments? How extensive is any surgery likely to be? How big will the scars be? 7. What are the common side effects of the treatments? Would I lose my hair? Would I become sterile? What else could I expect? 8. What alternative treatments are available? Id heard of people going on special macro-biotic diets. Id seen lots of herbal remedies on the internet. Which of these are proven and documented, and which ones are snake oil? Is it possible to combine alternative treatments with surgical other western treatments? How do I find a doctor that is open to using both alternative and western treatments? 9. What are the latest treatments being developed, and who is carrying out clinical trials of these new treatments?

How I Survived Malignant Melanom Summary


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Cav1 Is Down or Upregulated in Melanoma Cells

Focusing on the role of Cav-1 in malignant melanoma emerges once again as a complex picture. The overall data on Cav-1 show that it possesses dual functions within the same cancer, either as a pro- or anti-metastatic protein. Historically, the murine B16 melanoma cell system, especially through its subclone B16F, was chosen as a model for studying tumor cell and host properties in association with metastases 21 . More recently, B16F cells were utilized to explore the function of Cav-1 in melanoma development and dissemination 31 . Since this work is the last of a list of papers based on B16 melanoma cell lines, studies on the role of the Cav-1 gene on metastasis formation in this system deserve a closer examination. The low Cav-1 expressing B16F10 cells, a B16-derived murine melanoma cell line, were selected for their uniqueness to colonize lung and, as an experimental system, to assess the effects of Cav-1 re-introduction in these tumor cells 31 . Specifically, Trimmer and coworkers...

Phosphorylated Cav1 Is Implicated in Melanoma Progression

The role of the phosphorylation status of Cav-1 was demonstrated in melanoma where we transfected the wild-type Cav-1 and a non-phosphorylatable mutant (Cav-1-Y14A) into a Cav-1-negative primary melanoma cell line 9 . The role of Cav-1 on the different levels of malignancy was then analyzed through in vitro migration assays. The effects observed in Cav-1-expressing cells were strictly related to its phosphorylation levels as demonstrated by the abrogation of tumorigenicity in the presence of the Cav-1-Y14A non-phosphorylatable mutant. The functional involvement of ph-Cav-1 was also confirmed by treatment with the Src-family kinase inhibitor PP1, which strongly reduced the chemotactic ability of melanoma cells 9 ,

Cav1Containing Exosomes Are Secreted by Melanoma Cells

Metastatic Melanoma Primary Melanoma Metastatic Melanoma Primary Melanoma Fig. 5.1 Schematic representation of exosome-mediated cell to cell communication. Exosomes, abundantly released by metastatic melanoma cells, are taken up through a fusion mechanism by primary melanoma recipients. The induction of a more malignant phenotype is associated with the transfer of metastases-related molecules, including Cav-1 Ph-Cav-1, MMP-9 and miR-221 -222 Fig. 5.1 Schematic representation of exosome-mediated cell to cell communication. Exosomes, abundantly released by metastatic melanoma cells, are taken up through a fusion mechanism by primary melanoma recipients. The induction of a more malignant phenotype is associated with the transfer of metastases-related molecules, including Cav-1 Ph-Cav-1, MMP-9 and miR-221 -222 Because of their ability to circulate and transport a broad spectrum of proteins deriving from different compartments of the producing cell, exosomes can be considered important...

Influence Melanoma Tumor Progression

In addition to the effects of C-X-C chemokines on leukocyte chemotaxis, the C-X-C chemokines MGSA GRO-a and IL-8 are reported to enhance the growth of normal melanocytes, nevocytes, and melanoma cells (4,5,7,15,44a). The expression of MGSA GRO or IL-8 in immortalized melanocytes is also associated with an enhanced ability to form colonies in soft agar and tumors in nude mice (5,16,47,48). IL-8 expression has also been correlated with an enhanced metastatic capacity for melanoma tumors (52). Antibodies to MGSA GRO-a, IL-8, or CXCR2 can block this autocrine loop, slow the growth of the cells in vitro, and reduce formation of colonies in soft agar (24,37,48). Thus, the deregulation of expression of these chemokines can have important effects on melanocyte tumor progression. An essential component of the autocrine loop for C-X-C chemokines in melanoma is the expression of receptors for MGSA GRO proteins in melanocytes and malignant melanoma cells. Moser et al. (54) examined the expression...

Melanoma Exosomes Are Highly Released in Acidic Microenvironment and in Patients Plasma

Among the recognized and well-described exosome biological functions, several studies indicated exosomes as instruments used by cancer cells to prepare distal sites for metastatic dissemination. A good example of this is given by glioma exosomes bearing an oncogenic EGF receptor variant (EGFRvIII), which once released from normal endothelial cells can trigger a cascade pathway, leading to increased tumorigenic properties of target cells 1 . Parallel studies also reported a dramatic action of melanoma exosomes on endothelial regulation, as evidenced by spheroid growth and the formation of early vasculature precursor 10 . Studies on the molecular mechanisms of exosomes trafficking have been lacking, and it is only recently that several hypotheses have emerged either in normal or tumor cells. It has been proposed that the interaction of exosomes with recipient cells may occur through lipids 19 or ligand-receptor bindings 26 . Alternatively, exosomes may enter through endocytic...

Melanoma of the Conjunctiva

Malignant melanomata can occur on the conjunctiva (Figure 15.10) but they should not be confused with the relatively common benign conjunctival naevus. The latter is a slightly raised pigment-stippled lesion often seen at the limbus on the temporal side. Closer examination with the hand lens or microscope reveals one or two minute cysts. It is generally accepted that these benign lesions should be excised and biopsied if they become irritable or sometimes simply on cosmetic grounds, but they rarely become malignant. The treatment of conjunctival malignant melanoma involves wide surgical excision with adjuvant cryother-apy or radiotherapy. The five-year survival rate is approximately 85 . Figure 15.10. Melanoma of conjunctiva. 03 Figure 15.10. Melanoma of conjunctiva. 03

Classification of Melanoma

Clark et al. (1) defined four major histogenetic types of melanoma based largely on the growth pattern of their intraepithelial portions. These include superficial spreading melanoma (SSM), nodular melanoma (NM), lentigo maligna melanoma (LMM), and acral lentiginous melanoma (ALM). This classification has been challenged on the grounds that these types of melanoma have a similar prognosis when matched for sex, thickness, and site and that many of the characteristics of each type are, in fact, secondary to the site of the neoplasm or caused by secondary changes such as solar elastosis (2). Although there is general agreement that the Clark classification has neither independent prognostic value nor diagnostic relevance, the Clark nomenclature continues to be widely used in clinical practice. It also is entrenched in the medical literature regarding melanoma and correlates with the epidemiology of the disease. The histopathologic presentations of the four major histogenetic types of...

Histologic Evolution of Melanoma

A number of histologic features are common to melanoma in most locations and correspond to its evolution. The earliest lesions of most melanomas in situ, small macules clinically, appear microscopically as proliferations of solitary melano-cytes at or slightly above the dermal-epidermal junction spaced at irregular intervals (Fig. 6). The nuclei of the mela-nocytes in these early neoplasms may or may not be cyto-logically atypical but are almost always larger than those of the non-neoplastic basal melanocytes. As lesions of the melanoma in situ evolve, melanocytes can aggregate to form nests and spread to the upper spinous, granular, and cornified layers. Poor circumscription is a characteristic feature (Fig. 7). Often single neoplastic melanocytes will be visible beyond the last nest on either side of the lesion, and some of these cells may be situated above the basal layer. Melanoma in situ typically involves follicular infundibula with melanocytes distributed in the same pattern as...

Nevoid Melanoma Definition

The term nevoid melanoma has been used to describe papular, predominantly intradermal proliferations of deceptively banal-appearing atypical melanocytes that are small and fairly symmetric thus resembling the architecture of a benign nevus. The concept is in evolution and is not universally accepted. Nevoid melanomas are rare and often are diagnosed retrospectively after metastases have occurred. It is likely that many so-called nevoid melanomas represent early NMs (6). Others are made up of large epithelioid mel-anocytes that resemble the cells of a Spitz's nevus. Since only a minority of such lesions actually behave in a malignant fashion, it is likely that many such lesions actually are Spitz's nevi that have been misdiagnosed.

Clinical Evolution of Melanoma

Malignant melanomas may arise de novo, that is, in apparently normal skin or in association with a pre-existing melanocytic nevus. When malignant melanomas arise de novo, they begin as a small, lightly pigmented macule that in time is characterized by asymmetry, scalloped borders, poor circumscription, and variations in color of predominantly tan to brown (Fig. 1A). Some such macular lesions become patches that are increasingly asymmetrical, poorly circumscribed, and varied in color (Fig. 1B). Other macular lesions of melanoma eventually become papular or nodular. Some other macular lesions may simply enlarge to become patches, others plaques, and still others combinations of papules or nodules upon patches or plaques (Figs. 2A-C 3A and B). Some nodules and tumors ulcerate. Some melanomas may undergo partial or complete regression (Fig. 4). The clinical features of malignant melanomas just described apply to malignant melanomas at all anatomic sites of the skin and mucous membranes....

Cav1 in Skin Cancer

Skin cancer is the most common form of neoplasia in the United States. The two most common, but likely highly curable types, are basal cell cancer and squamous cell carcinomas. Conversely, melanoma is rare, but very aggressive. In the last decades, its incidence is steadily increasing in most countries, while not paralleled by the development of new therapeutic agents with a significant impact on survival. At present, early detected melanomas can be cured by surgical excision, while more advanced stages are difficult to control. Once melanomas metastasize, the median 5-year survival rate is less than 5 18 . At present, few data exist on Cav-1 expression and function in non-melanoma skin cancers. A microarray-based gene profiling showed increased Cav-1 expression in human basal cell carcinomas (BCC) as compared to normal skin, suggesting that it may play a dynamic role in controlling the slow progression of these tumors through both decreased cellular motility and tumor promotion 25 We...

Familial Melanoma

A family history of melanoma in first- or second-degree relatives of patients with melanoma can be elicited in up to 10 of cases. Germ-line inactivating mutations of the CDKN2A gene have been documented in 25-40 of families with three or more affected individuals, and in up to 15 of individuals with multiple primary melanomas 22, 23 . CDKN2A encodes two tumor-suppressor proteins p16 and ARF, which are known to negatively regulate the retinoblas-toma and p53 pathways, respectively. Their loss has been documented to predispose to the development of melanoma. Mutations of the CDKN2A gene that affect p16 are much more common than those that affect the p14 gene. The estimated frequency of a mutated p16 gene in the general population is 0.01 , and the incidence of mutations in sporadic melanoma cases is only 0.2 22, 24 . Similarly, the incidence of germ-line CDKN2A mutations in patients with early-onset disease, a population that would resemble a familial cancer syndrome, is also...

Melanoma of the Iris

This rare iris tumour usually presents as a solitary iris nodule, which might or might not be pigmented. It can cause distortion of the pupil, which can be an early warning sign. Other features that can point to the diagnosis are localised lens opacity, iris neovascularisation and elevation of intraocular pressure. Melanoma of the iris is extremely slow growing and probably much less malignant than choroidal melanoma,

Genes In Melanoma

The expression of chemokines is normally tightly regulated and is only transiently induced in response to mediators of the inflammatory response such as IL-1, tumor necrosis factor-a (TNF-a), and a variety of other agents (3). Interestingly, during tumor progression and chronic inflammation, this tight regulation of chemokine expression is disturbed such that numerous tumor lesions and chronically inflammed tissues have been reported to express chemokines continuously (2,6,44,46,50,63,66). For example, in the absence of cytokine stimulation, the expression of MGSA GRO is very low in normal melanocytes and normal retinal pigment epithelial cells, but is quite high in malignant melanoma (7,10,47,63,64). In normal skin keratinocytes, MGSA GRO expression appears to coincide with differentiation, as noted by the presence of immu-noreactive MGSA GRO in suprabasal keratinocytes and in the hair follicles, sebaceous glands, and sweat ducts. By contrast, lesional tissue from 7 7 squamous cell...


The prognosis of metastatic melanoma is dismal. Research of HDC for this disease dates back more than 40 years.47 Early trials with high-dose single agents with BCNU,48 melphalan,49 or thiotepa50 achieved higher response rates than those expected with conventional-dose chemotherapy, but of brief duration. Disease confined to skin or lymph nodes was more likely to respond. High-dose combinations of melphalan BCNU,51 cyclophosphamide cisplatin BCNU,52 or DTIC (dacarbazine) melphalan ifosfamide53 showed higher activity than did single-agent therapy, but no improvement in outcome. In summary, the use of HDC in melanoma remains experimental. While HDC may provide a favorable setting for testing of immunotherapy against minimal residual melanoma,54 it is unlikely that HDC and ASCT will play a meaningful role in the management of this disease in the foreseeable future.

CAIs And Skin Cancer

These compounds showed tumor growth inhibitory properties. Typically, they showed GI50 values in the low micromolar range (10 to 42 nM) against a wide number of tumors and melanoma (Supuran and Scozzafava 2000b, 2000c) and are considered among the most potent tumor cell growth inhibitors belonging to the sulfonamide CAIs to date (Table 11.2). The mechanism of tumor growth inhibition with these sulfonamide CAIs is not known at present, but several hypotheses have been proposed. Thus, as suggested by Chegwidden and Spencer (1995), these compounds, similarly to the classical inhibitors acetazolamide, methazolamide or ethoxzolamide, might reduce the provision of bicarbonate for the synthesis of nucleotides (mediated by carbamoyl phosphate synthetase II) and other cell components such as membrane lipids (mediated by pyruvate carboxylase). Such a mechanism would likely involve CA II and CA V. An alternative, or additional, mechanism might involve acidification of the intracellular milieu as...

Metastatic Melanoma

Melanocytic neoplasms constitute a spectrum of benign and malignant skin tumors that have distinct clinical, morphological, and molecular genetic profiles. Melanomas are neoplasms of melanocytes that have the potential to metastasize or are on an evolutionary pathway in which the acquisition of that potential is likely. Melanomas may develop within a pre-existing benign melanocytic nevus, but the great majority develop de novo. Intermittent high dose UV radiation is the major environmental risk factor for melanoma, but genetic factors undoubtedly play an important role. Melanomas are the most important group of cutaneous malignancies because of their inherent capability for metastasis. The most commonly affected anatomic sites are the face in both sexes, the ear, head, neck, back, and shoulders in men, and the legs in women. Melanomas begin as macules that may progress to plaques and tumors. Most begin as faintly uniform brown macules with slightly irregular borders. Over time, they...

Choroidal Melanoma

The most common primary intraocular tumour is the malignant melanoma of the choroid. In white people,the tumour has an incidence of one in 2500 and the average age at presentation is 50 years. The incidence rises with age with a peak at 70 years. However, it is important to appreciate that no age is exempt because choroidal melanomas have been reported in children as young as three years. It is extremely rare in black people. It differs from melanoma of the skin in that it grows more slowly and metastasises late. Most choroidal melanomas are thought to originate from choroidal nevi, which are present in up to 10 of the population. At first, it is seen as a raised pigmented oval area, which can be anywhere in the fundus (Figure 15.1). It is usually brown in colour although it can be amelanotic (or greyish). As the tumour enlarges there might be an associated exudative retinal detachment or, less often, secondary glaucoma. Other associated features might include choroidal haemorrhage...

Classification System

Invasive cancer refers to any malignancy except non-melanoma skin cancer (squamous and basal cell carcinoma), in situ cancer of the breast or uterine cervix, or ovarian cancers of borderline significance. It does include low-grade brain tumors (e.g., benign astrocytoma and juvenile pilocytic astrocytoma) with low metastatic potential since these tumors can be fatal because of local growth. There are two basic systems of classification the International Classification of Diseases for Oncology (ICD-O) and the International Classification of Childhood Cancers (ICCC). The ICD evolved first, and has been through several iterations

Clinical studies head and neck cancer

Early clinical studies clearly demonstrated that cisplatin could be administered safely and concurrently with radiation therapy (73-75). Early clinical trials that demonstrated the promise of the combination of cisplatin and radiation therapy included the treatment of brain tumors (76,77), head and neck tumors (78), malignant melanoma (79), and bladder cancer (80). Early clinical trial integrating carboplatin administration with radiation therapy was carried out in patients with locally advanced nonsmall cell lung cancer (NSCLC) (81). A hypothesis put forth by Coughlin and colleagues (81) was that the best clinical outcomes would be achieved with the combination of cisplatin and radiation therapy in tumors that were responsive to cisplatin.

The Supergene Family Of Chemotactic Cytokines

The genes encoding many of the C-X-C chemokines map to human chromosome 4(q12-q21) and their proteins possess 20-50 amino acid homology with one another (3,35). Several C-X-C chemokines have been identified, including platelet factor 4 (PF4), IL-8, growth-related oncogene-a, -p, and -y (GRO-a, -p, -y), epithelial cell-derived neutrophil-activating factor-78 (ENA-78), granulocyte chemotactic protein-2 (GCP-2), interferon-y-inducible protein-10 (IP-10), monokine induced by interferon (MIG), and the amino terminal processed forms of platelet basic protein connective tissue-activating protein III, p-thromboglobulin, and neutrophil-activating peptide-2 (NAP-2) (15,20,29,37,48,52) (Table 1). PF4 was the first member of the C-X-C chemokine family to be described and was identified as a heparin-binding protein that could block the anticoagulation property of heparin. Many of the C-X-C chemokines were originally discovered based on their biologic activity or their ability to be expressed based...

Cellbased Cancer Vaccines

However, as the science of determining how an effective APC initiates an immune response advance, these strategies are being used to alter tumor cells and render them as loci of immune stimulation. The most general method for cell-based immunotherapy is to use a single representative cancer cell as a universal vaccine for all patients with that same type of cancer. Some investigators consider this approach as suboptimal as it is allogeneic, where the MHC type of the vaccine and the patient do not match, and the immune system may be distracted from generating a tumor-antigen-specific to an allospecific response. Others argue that an allogeneic vaccine will be effective for just this reason, and that the alloimmune response will serve to amplify the cancer-antigen-specific response. This issue will be addressed in Chapter 10, where Copier and Dalgleish discuss the use of whole tumor cells as vaccines in this unique approach to cancer therapy, as tumor-specific...

Future Directions And Application Of Nscs In Brain Tumors

NSCs offer a way to deliver a broad range of therapeutic molecules to intracranial glioma cells in a specific fashion. Immunomodulatory factors hold promise. Ehtesham et al. have already shown the successful and efficacious delivery of IL-12 and TRAIL to implanted brain tumors (80,81). Other cytokines with demonstrated promise in the treatment of glioma could be similarly delivered by NSCs (84). For example, IL-24 or melanoma differ-entiation-associated-7 induces the expression of the proapoptotic protein BAX and suppresses the growth of glioma cells (85). Aoki et al. showed that IL-7 reduced the tumorigenicity of glioma cells in vivo via a T-cell-medi-

Subversion of Innate Immunity Receptors Stimulation of Toll Like Receptors on Lung Carcinoma Cells Modulates Cell

TLR are pattern recognition receptors for pathogen-associated molecular patterns (PAMP) and endogeneous molecules released from injured and necrotic cells (DAMP) (Kumar et al. 2009). Lungs are frequently exposed to viruses such as influenza or respiratory syncitia virus, that are mainly recognized by endogenous TLR3, 7 and 8 (Kumar et al. 2009). Among the 11 different TLR described to date, we thus focused our study on TLR7 and TLR8, receptors for ssRNA (Diebold et al. 2004 Heil et al. 2004) and to a minor extent on TLR3, receptor for dsRNA (Liu et al. 2008). The stimulation of TLR7, TLR8, and TLR3 that are commonly expressed by cells of the immune system leads to the activation of NFKB and the production of proinflammatory cytokines (Napolitani et al. 2005 Hart et al. 2005 Larange et al. 2009). It induces a rapid antiviral response via the induction of type I and type II IFN which in turn enhance the adaptive immune response. Imiquimod, a TLR7 agonist is currently...

Use in Prevention and Therapy

Vitamin A is one of nature's primary anticancer substances, particularly in the skin and mucous membranes. Ample intakes of vitamin A have been shown to protect against cancers of the lung, bladder, prostate, larynx, esophagus, stomach, and colon. Vitamin A can prevent precancerous lesions, such as oral leukoplakia (white patches on the lips and mouth often found in smokers) and cervical dysplasia, from developing and may produce regression and disappearance of these disorders.15 As a cancer treatment, large doses of retinoic acid may reduce growth and recurrence of certain forms of skin cancer.16 As an antioxidant, beta-carotene helps provide protection against damage from many xenobiotics (such as polychlorinated biphenyls PCBs ). It may also reduce the risk of skin cancer associated with exposure to sunlight6 and radiation.2

Etiology and Risk Factors

Given that the duration of exposure to potential environmental carcinogens is directly proportional to age, it is not surprising that tobacco-, sunlight-, or diet-related cancers are more likely to occur in older adolescents than in younger persons. With the probable exception of melanoma, cancers known to have been related to environmental exposures in older adults have not been implicated with any certainty to environmental agents in 15- to 30-year-olds. In most people, it appears to take considerably longer than one or two decades for these environmentally related cancers to become manifest. The logical hypothesis is that adolescents who develop cancer after a carcinogenic exposure have a predisposing genotype. For example, melanoma is more common among Australian adolescents than among those elsewhere in the world, as described above. The Australia data does suggest that solar exposure may be able to induce skin cancer before the end of the second decade of life, at least in that...

The Immune Reaction in a Tumor Developing in an Immuno Priviledged Site The Case of Primary Intraocular Lymphoma

Some tumors can develop in the eye, among which are retinoblastoma, choroid ocular melanoma, and primary intraocular lymphoma (PIOL). PIOL is a rare disease from the group of Diffuse Large B-cell Lymphoma (DLCBL) and is usually called uveitis masquerade syndrome as it frequently displays misleading symptoms with forms of infectious uveitis. PIOL is genetically very similar to central nervous system lymphoma of other locations such as intra-cerebral, spinal cord, and lepto-meningeal lymphomas. Like other tumors developing in immune-privileged sites or in immune-compromised individuals, PIOLs are very aggressive with a 5-year survival rate of less than 5 . In addition, PIOLs have very peculiar invading characteristics with 85 developing cerebral lymphoma and 80 metastasing to the controlateral eye (Nussenblatt et al. 2006). The question therefore arose to the existence of immune surveillance toward PIOL in the eye. The presence of T cells in tumoral eyes has been reported and we...

Cell Assays on RGD Peptide Amphiphiles

We demonstrated that the supported monolayers of looped RGD support adhesion and spreading of M14 5 human melanoma cells and RHE-1A rat heart endothelial cells in a dose-dependent and specific manner (48). An equimolar mixture of looped RGD and looped RGE yielded the highest degree of cell spreading (Fig. 9a). Control surfaces of 100 looped RGE surfaces resulted in minimal cell adhesion and spreading (Fig. 9b). Inhibition assays using integrin-blocking antibodies identified a3b as the primary receptor-mediating melanoma cell adhesion to the looped RGD construct. Cells did not spread on monolayers containing the amino-coupled RGD amphiphiles, whereas cells spread in a nonspecific manner on monolayers of the carboxy-coupled RGD amphiphiles. In both linear Figure 9a Spreading of M14 5 human melanoma cells (spreading increases as the shape factor gets smaller) on mixtures of looped RGD and RGE peptide amphiphiles. Figure 9a Spreading of M14 5 human melanoma cells (spreading increases as...

Regulation of p53 Stability by ARF and MDM2

Functions, because it associates with many of the same proteins to which cyclin G1 binds, including p53, PP2A, MDM2, and ARF (137). This p53-stabilizing effect of PP2A cyclin G complexes may also influence the malignancy of cancer cells, considering that enhanced expression of a truncated form of PP2A was observed in highly metastatic melanoma cells (140). Cells overexpressed with this truncated form of PP2A show irradiation-induced checkpoint defects and appear to elevate genetic instability, which may promote tumor progression (141). These data suggest that cyclin G1 is a positive feedback regulator of p53, since it downregulates the activity of MDM2, which would otherwise restrain the accumulation of p53 (142).

Antigenic Specificity of Induced Regulatory T Cells

Other evidence for the existence of adaptive regulatory T cells specific for self-antigens and their significant biological role comes from studies of tumor immunity. Initial observations suggested that the presence of CD25+ regulatory T cells can diminish anti-tumor responses, but it was not clear whether this effect was antigen-specific (Shimizu et al. 1999). Several recent studies have suggested that adaptive CD25+ T cells may suppress tumor immunity by recognizing self-antigens. For example, CD25+ T cells with suppressor ability can be elicited by gene gun immunization with autoantigens identified in the SEREX screen (Nishikawa et al. 2003). In another example, human T cell clones with a phenotype resembling regulatory T cells were isolated from tumor-infiltrating lymphocytes of melanoma patients (Wang et al. 2004). Some of these clones were identified to be reactive to the self-protein LAGE1. However, it also remains unclear in these experiments whether these cells arose from...

FSee 708 Kinase Inhibitors for Cancer

A deeper understanding of the molecular events leading to tumor formation, invasion, angiogenesis, and metastasis has provided a new mechanistic basis for oncology drug discovery targeted anticancer therapy.79 The rationale behind this approach is relatively simple specific inhibitors of proteins involved in aberrant signaling mechanisms would interfere with cancer progression, altering the natural course of the disease while sparing normal tissues. Although numerous disappointments have been harvested, we start to see how a new generation of targeted cancer agents - both low-molecular-mass inhibitors (e.g., imatinib, gefitinib, erlotinib)80 and humanized monoclonal antibodies (e.g., trastuzumab, cetuximab, becacizumab)77,81,82 - can provide incremental improvements over existing drug treatments. In addition to the identification of more effective anticancer agents, other areas under development include gene therapy (administration of tumor suppressor genes), immunotherapy (to boost...

Processing of MHC Class IRestricted Peptide Antigens

Clear as another cap, the 19 S cap, is normally attached to the 20 S core and contains subunits capable of binding and unfolding ubiquitylated substrates. Irrespective of the exact biochemical function of PA28 in vivo, PA28 expression has been shown to be important for the processing of some antigenic peptides in cells, as the generation of the melanoma-associated peptide antigen TRP2360-368 depends solely on the expression of PA28 (23). It was recently shown that the N-terminal region flanking the antigenic peptide TRP2360-368 conferred sensitivity to PA28 by promoting coordinated cleavages at the N- and C-termini of that peptide antigen (24).

Synthetic Carbohydratebased Vaccines

The Globo-H-KLH vaccine performed well in immunologic investigations 10 . Preliminary studies conducted on mice revealed this vaccine construct to be capable of producing strong IgM and weaker IgG responses, as determined by ELISA screening. Importantly, the antibodies thus obtained were found to be specific to Globo-H, reacting only with Globo-H-positive (MCF-7) cell lines, as determined by flow cytometry analysis, and not with Globo-H-negative (B78.2 melanoma) cells. Furthermore, the antibodies raised were very effective at inducing complement-mediated cytotoxicity of MCF-7 cells.

Processing of MHC Class IIRestricted Peptide Antigens

Because tumor antigen-specific CD4+ T cells and Treg play a critical role in the priming of antitumor T-cell responses and the activity of antitumor T cells in situ, respectively, the presentation of tumor-associated peptide antigens by MHC class II molecules has gained more importance over the last few years. Unlike MHC class I, MHC class II molecules bind peptides of widely different length, ranging from 15 to 30 amino acids. Several molecules are involved in the processing and editing of MHC class II-restricted peptide antigens, in particular endo lysosomal enzymes, MHC class II accessory molecules (DM and DO), and the invariant chain. It is commonly viewed that the major source of peptide antigens presented by MHC class II molecules is provided by the endo lysosomal degradation of endocytosed or cell surface proteins. However, accumulating evidence suggests that cytoplasmic and nuclear antigens may also gain access to MHC class II by intracellular autophagy or chaperone-mediated...

Incidence Rates by Age and Diagnostic Group

Mias, with lymphomas second highest, then CNS tumors and bone tumors. In this age group, STS, germ cell tumors, melanoma, and carcinomas were relatively uncommon. In comparison with younger adolescents, the most striking difference in the 15- to 19-year-olds was a doubling of the incidence rates for lymphomas, which were the most common malignancies in this age group. Rates for leukemias, CNS tumors, and bone tumors were a little lower than those observed in the 13- to 14-year age group, but increases in rates relative to the younger age group were observed in STS, germ cell tumors, melanoma, and carcinomas. However, rates for these malignancies were still markedly lower than rates for leukemia and lymphoma. Table 3.8 Incidence of germ cell tumors, melanoma and other miscellaneous tumors per adolescents and young adults, England and Wales, 1979-2000 Melanoma mias was approximately 1 1 in 13- to 14-year olds, but in 20- to 24-year olds this had increased to more than 3 1. However, the...

Classification Of Human Cancers

Although the terminology applied to neoplasms can be confusing for a number ofreasons, certain generalizations can be made. The suffix oma, applied by itself to a tissue type, usually indicates a benign tumor. Some malignant neoplasms, however, may be designated by the oma suffix alone these include lymphoma, melanoma, and thymoma. Rarely, the oma suffix is used to describe a nonneoplastic condition such as granuloma, which is often not a true tumor, but a mass of granulation tissue resulting from chronic inflammation or abscess. Malignant tumors are indicted by the terms carcinoma (epithelial in origin) or sarcoma (mesenchymal in origin) preceded by the histologic type and followed by the tissue of origin. Examples of these include adenocarcinoma of the breast, squamous cell carcinoma of the lung, basal cell carcinoma of skin, and leiomyosarcoma of the uterus. Most human malignancies arise from epithelial tissue. Those arising from stratified squamous epithelium are designated...

All cancers154118231980

Table 3.8 includes incidence rates for germ cell tumors, melanoma, and certain tumors that are seen typically in younger children. The most dramatic increase in rates with age among the adolescent and young adult group occurs in the gonadal germ cell tumors, for which the rate increases from 0.33 per 100,000 in 13- to 14-year-olds to 1.25 in 15- to 19-year-olds, and to 3.76 in 20- to 24-year-olds, representing more than an 11-fold increase in rates over the age range. This is entirely due to testicular germ cell tumors. Nongonadal germ cell tumors are much less frequent than gonadal, and although rates increase across the age groups, the trends with age are less dramatic. There is a small decrease in rates with increasing age for intracranial germ cell tumors. Wilms tumor, neuroblastoma, hepatoblastoma, and retinoblastoma have peak incidences in children aged less than 5 years, but a small number of cases have been registered in the adolescent and young adult age range. Cases of...

Temporal Trends in incidence

Marked increases in incidence were also seen for gonadal germ cell tumors (accounted for primarily by testicular tumors), melanoma, and carcinoma of the thyroid (in all cases p< 0.0001) (Fig 3.6). There was no corresponding significant increase in ovarian germ cell tumors. Colorectal carcinomas showed a significant trend, which was accounted for by an increase between the second and third time periods (p< 0.001) (Fig 3.6).

Etiology and Pathogenesis 361 Etiology

Not surprising that tobacco-, sunlight-, or diet-related cancers are more likely to occur in older adolescents and young adults than in younger persons. Nonetheless, these environmental agents known to be carcinogens in older adults have not been demonstrated to cause cancer with any significant frequency in adolescents. It appears to take considerably longer than one or two decades in most persons for these environmentally related cancers to become manifest. The logical hypothesis is that adolescents who develop cancer after a carcinogenic exposure have a predisposing genotype. For example, melanoma is more common among Australian adolescents than elsewhere in the world, as described above. This suggests that solar exposure may be able to induce skin cancer before the end of the second decade of life, at least in that part of the world. That melanomas during adolescence usually occur in nonexposed areas of the body mitigates against this explanation, and may suggest that the...

Genetic Predisposition and genetic Susceptibility

Skin cancer, lymphoma, sarcoma, and hepatic cancers also occur at higher frequency in persons with inherited conditions such as neurofibromatosis, ataxia telangiectasia, Li-Fraumeni syndrome, xeroderma pigmentosa, Fanconi pancytopenia, hereditary dys-plastic nevus syndrome, nevoid basal cell carcinoma syndrome, multiple endocrine neoplasia syndromes, and Turner syndrome. In the aggregate, however, the cancers that are known to be due to these conditions account thus far for only a small proportion of the can

Surgery as a Cancer Therapy

The ultimate in untested, unscientific practice involved the treatment of malignant melanoma. For much of this century, Moffat and Ketchum of the University of Miami School of Medicine wrote in 1994, the surgical management of primary cutaneous malignant melanoma was based on a detailed clinicopathological description of a single case by William Sampson Handley in 1907 . . . Surprisingly, with no other supporting evidence, Han-dley's principles became established in surgical teaching and practice and defined the surgical standard of care for melanoma for many decades (47, 49).

Cadherins and epithelialmesenchymal transition EMT

Changes in expression of other cadherins accompanies downregulation of E-cadherin, in a situation reminiscent of the epithelial-mesenchymal transition that occurs during embryonic development. This transition is characterized by a loss of epithelial cell polarity and cell-cell contact, gain of mesenchymal markers such as N-cadherin, and an increased migratory phenotype.154 Increased levels of N-cadherin, normally expressed in neuronal cells and fibroblasts in adults, are observed in breast and prostate cancer and invasive melanoma.155 N-cadherin is thought to mediate a less stable and more dynamic form of cell-cell adhesion, and its overexpression enhances invasion and formation of metastasis. These changes occurred despite the presence of E-cadherin, suggesting that N-cadherin may play a dominant role. N-cadherin invasive activity occurs, at least partly, via association with the fibroblast growth factor receptor-1 (FGFR-1). Interaction results in stabilization of FGFR-1 leading to...

Integrins and Downstream Signaling Pathways

Multiple signaling components are activated by FAK and SFKs including ETK, an intracellular tyrosine kinase found at high levels in metastatic carcinoma cells and the ERK MAPK and JUN kinase cascades, which, in addition to modifying gene expression, can affect motility by direct phosphorylation of cytoskeletal components.166 Activated SFKs phosphorylate and initiate signaling from paxillin and p130CAS.165 Modulation of motility and the actin cytoskeleton occurs principally via the consequent activation of the Rho GTPase family members Rho, Rac, and cdc42. Both Rac and Cdc42 are required for carcinoma motility and invasion, promoting actin polymerization at the leading edge of migrating cells.167 RhoA and RhoC are upregulated in metastatic carcinomas, and RhoC overexpression favors colonization of the lung in an experimental melanoma metastasis model. Rho, acting via two effectors, ROCK and mDIA, regulates actomyosin fiber assembly and contraction, contributing toward pulling forward...

Bcg In Bladder Cancer

It was with this background that studies of BCG in bladder cancer began. Studies by Coe and Feldman in 1966 5 demonstrated that the bladder responded to BCG with a delayed-type hypersensitivity reaction such as that observed in the skin, and in 1974 Silverstein reported response of melanoma metastatic to the bladder treated with intralesional BCG 6 . The success in melanoma led us in 1973, at the suggestion of David McCullough, to evaluate BCG in an animal model of bladder cancer 7 . At the same time Morales independently began clinical studies, and published the results of the first successful clinical trial of BCG in nine patients with recurrent bladder cancer in 1976 8 . In that study six weekly intravesical plus percutaneous administrations of 120 mg of Armand Frappier BCG resulted in a 12-fold reduction in bladder tumor recurrence. This success prompted the NCI to request proposals for controlled clinical trial of Morales' technique, and contracts were given to Lamm at the...

Inflammatory Control at the Tumor Site

Adoptive transfer of tumor specific Th17 into mice harboring primary irradiated tumors or experimental lung nodules of B16 melanoma cells reduced their tumor burden. The anti-tumor effects appeared to depend on the presence of host IFN-gR, but antibody mediated depletion of IFN-g did not change the outcome (Martin-Orozco et al. 2009 Muranski et al. 2008). It is therefore not clear if in the antitumor function of proinflammatory Th17 induced anti-tumor effects by attracting myeloid cells, or if the transferred cells reverted to a Th1 profile in vivo.

Historical Perspectives

Later in the eighteenth century, the first direct observation associating chemicals was made by John Hill, who in 1761 noted that nasal cancer occurred in people who used snuff excessively. In 1775, Percival Pott reported a high incidence of scrotal skin cancer among men who had spent their childhood as chimney sweeps. One hundred years later, von Volkman, in Germany, and Bell, in Scotland, observed skin cancer in workers whose skin was in continuous contact with tar and paraffin oils, which we now know contain polycyclic aromatic hydrocarbons. In 1895, Rehn

Why the lack of Progress in Older Adolescents and Young adults with cancer

The initiative includes several strategies. In all of the pediatric group protocols for malignancies that sub-stantively overlap young adult patients, such as leukemia, Hodgkin lymphoma and the sarcomas, the upper age limit has been raised to 30, 40, or 50 years, depending on the disease. The pediatric group has also opened adult cooperative group trials in melanoma. Reciprocally, an adult cooperative group has opened the pedi-atric cooperative group trial in Ewing sarcoma. Plans are underway for the pediatric and adult groups to develop and open trials together in other sarcomas.

Altered Peptide Ligands

Second, the T-cell repertoire against the peptide antigens may be partially tolerized or have low-intermediate avidity. Third, the peptide may be rapidly modified or degraded. To circumvent these limitations, altered peptide ligands have been developed. However, careful biochemical analyses of the impact of such modification on processing are rarely performed. All too often, it is assumed that the processing of antigens containing modified amino acids will be similar to those containing the natural sequences. One category of altered antigens includes peptides with modified anchor residues to increase affinity to MHC molecules. The natural sequence of these peptides is characterized by the presence of suboptimal anchor residues. Substitution of these residues by canonical MHC class I anchor residues dramatically increases the stability of the peptide-MHC complexes and converts most of these peptide antigens into highly immunogenic peptides. Typical...

Tumor Necrosis Family Apoptosis and Immune Surveillance

KiSS-1 encodes a neuropeptide ligand for a GPCR hGPR54(AXOR12), identified as a gatekeeper of the reproductive cascade.223 KiSS-1 and hGPR54 display complementary expression patterns in the brain and in the placenta where they have been identified as regulators of trophoblast invasion, inducing migration and protease expression.224 KiSS-1 appears to play a similar role in tumor invasion and metastasis. Forced expression of KiSS-1 suppresses metastasis of melanomas and human breast carcinomas without affecting tumorigenicity.225-227 Although the action of Kiss-1 may depend on tumor type, loss of KiSS-1 expression was correlated with tumor recurrence in gastric cancer and venous invasion and distant metastasis in invasive bladder cancer patients. Additionally, loss of KiSS-1 and or hGPR54 gene expression was found to be a significant predictor of lymph node metastasis in esophageal squamous cell carcinoma (ESCC).217 Upon entering the vasculature, mechanical forces contribute to the...

Fibroblast Growth Factor and Angiogenesis

Multiple studies have documented expression of FGF ligands, particularly FGF2, within tumors. Abrogation of FGF signaling has been shown to inhibit neovascularization and growth of experimental tumors, while a synergistic effect on tumor vessel density is observed upon administration of VEGF-A and FGF.266,267 However, whereas a consistent correlation between tumor microvessel density and VEGF-A expression has been documented, there appears to be marked heterogeneity when FGF levels are examined. One notable exception is melanoma, in which FGF2 levels and microvessel density are clearly correlated.268

Conclusion And Prospects

Anticancer T-cell vaccines have to fulfill at least two conditions First, they have to stimulate cytolytic CD8+ T cells and, second, they have to activate CD8+ T cells capable of recognizing tumor cells. These two conditions are constrained by the available T-cell repertoire into which the vaccines will have to tap, by the efficacy of the vaccine at mobilizing this repertoire and by factors influencing antigen processing and presentation. As discussed in this chapter, antigen processing regulates the selection of thymocytes in the thymus and the T-cell repertoire in the periphery. It also controls the presentation of tumor-associated peptides by MHC molecules and, consequently, regulates both CD4+ and CD8+ T-cell responses. Antigen processing may produce largely different peptides depending on the environment of the tumor. Finally, induction of effective T-cell responses against peptide tumor antigens may favor the selection of antigen-negative tumor cell populations. On the basis of...

D CD44Hyaluronan Interactions in Tumor Invasion and Metastasis

There is long standing evidence that many solid tumors are enriched in hyaluronan (163). As far back as the beginning of the 20th century there was the description of a 'mucinous substance' associated with malignant breast carcinoma, analogous in nature to that found in umbilical cord (164). Higher levels of hyaluronan are associated with poor prognoses in many cancers including human ovarian, breast and prostate carcinomas (165-168). Coincident with this is the finding that CD44 is often upregulated in several of the same tumor tissues (36,169,170). Given the close association of extracellular matrix receptors participating in adhesion and migration, a predicted facilitatory role for CD44 during invasion and metastasis is well warranted. A necessary question is whether binding to hyaluronan is a necessary component of CD44's positive function in invasion and or metastasis. Bartolazzi et al. (171) demonstrated that stable transfectants of CD44H in human melanoma cell line MC acquired...

Platelet Derived Growth Factor

Whereas VEGF-A is predominantly required during the initial steps of angiogenesis (formation of the endothelial plexus) subsequent steps, involving recruitment and vessel coverage by pericytes and smooth muscle cells, appear to be dependent on other soluble factors, e.g., PDGF PDGF-B acts as a pericyte and smooth muscle cell chemoattractant whereas TGF-b has been implicated in vessel stabilization.269,270 Microscopic examination indicates that tumor capillaries possess mural cells however, unlike normal vessels in which pericytes are well organized and closely associated with the endothelial compartment, tumor pericytes were present at a lower density and appeared more loosely attached.271 Positive immunohistochemical staining for PDGFR-B, originating from associated pericytes, was observed in tumors.194 Experimental manipulation of PDGF levels has demonstrated that release of PDGF from both endothelial and tumor cells can impinge on pericyte recruitment to tumor vessels.272...

Deregulated Cytosolic Signaling Pathways

Different growth factors and cytokines transduce their growth-promoting signals through the activation of the small G protein Ras (Figure 4). This leads to activation of members of the Raf family of serine threonine kinases (c-Raf, A-Raf, and B-Raf) and its downstream effector, the mitogen-activated protein kinase (MAPK) kinase (MEK). This protein then phosphorylates and activates MAPK, the so-called extracellular signal-regulated kinase (ERK). The Ras-Raf-MEK-MAPK pathway controls the growth and survival of a broad spectrum of cancers. Thus, it has been shown by the expression of dominant negative or activated forms of MEK that the expression of cyclin D1, which leads to transition from G1 to S phase, is controlled by MEK signaling.287 Activating mutations in Ras and Raf are present in a large percentage of solid tumors. For example, the Ras oncogene is found mutated in its oncogenic form in 15 of human cancers, with subsequent activation of the MAPK pathway.288 The MEK and ERK...

Tumor Derived Heat Shock Protein Peptide Complexes

Melanoma GM-CSF-transduced tumor cells including fibrosarcoma, leukemia, melanoma, and lung, colon, prostate, and breast cancers (9,23-28). Across these studies, HSPs have been shown to significantly slow tumor growth, elicit complete tumor regression, and or prolong survival.

Hereditary Metabolic Diseases

Bleeding within neoplasm mimicking a stroke. A 59-year-old man, in good health, suddenly collapsed. A few hours later, he was lethargic, his left side was paralyzed, a mild right ptosis was present, and the right pupil was slightly larger than the left, indicating incipient transtentorial uncal herniation. Three days later, he died. His medical history was significant for excision of a cutaneous melanoma 9 years earlier. A noncontrast CT scan of the head shows (A) a large right frontal and (B) a small right occipital hyperdense lesion surrounded by hypodense edema with mass effect. The brain shows (C) circumscribed hemor-rhagic lesions corresponding to the large frontal and the small occipital lesions shown on the CT scan, and also a third small parietal lesion histologically, all melanomas.

B7Expressing Tumor Cells

In animal studies of this approach, complete regression of established tumors and or prolongation of survival have been demonstrated in models of myeloma, hepatoma, glioma, fibrosarcoma, lymphoma, mesothelioma, masto-cytoma, melanoma, and breast and colon cancers (16-18,52-58).

Novel chemotherapeutic agents

Temozolomide, a novel oral, second-generation alkylating agent, has shown significant promise as a cytotoxic agent in the treatment of a variety of solid tumors including melanoma, glioma, mycosis fungoides. Temozolomide is a prodrug of the active alkylating agent (MTIC) that is spontaneously converted to the active form under physiologic conditions. The drug demonstrates 100 oral bioavailability and excellent tissue distribution including penetration of the blood-brain barrier and into cerebrospinal fluid (51). Phase I II studies have shown significant antineoplastic effect in patients with recurrent malignant glioma (52,53). A randomized phase II trial comparing PCV to temozolomide in patients with supraten-torial GBM at first relapse demonstrated improved progression free survival, overall survival, tumor response, and quality of life among the patients treated with temozolomide compared to those treated with PCV (54). In a study of 33 patients with newly diagnosed GBM or AA,...

Irradiation Carcinogenesis

Heavy exposure to sunlight induces similar changes in human skin, and the degree of exposure to sunlight is closely related to the incidence of skin cancer (see Chapter 3). Whether continuing exposure to UV rays in sunlight is the promoting agent in skin cancer or additional promoting events are required is not clear, but it seems that UV irradiation is a complete carcinogen, just as some chemicals are that is, it has both initiating and promoting activities. Patients who cannot efficiently repair UV-induced damage, such as those with xeroderma pigmento-sum, have a much higher risk of developing malignant skin tumors.

Ultraviolet Radiation

Ultraviolet radiation-induced lesions, generated by UV-B (280-320 nm wavelength) or UV-A (320-400 nm wavelength), result from DNA damage, which is converted to mutations during cellular repair processes. UB-B and UV-A generate different types of DNA damage and DNA repair mechanisms (reviewed in Reference 113). Irradiation with UV-B produces cyclobutane pyrimidine dimers that are repaired by nucleotide excision repair. If left unrepaired, C T and CC TT base transitions occur. UV-A-induced DNA damage produces mostly oxi-dative lesions via photosensitization mechanisms and is repaired by base excision repair. UV-B and UV-A also produce different effects on the immune system and elicit different tran-scriptional and inflammatory responses. While the specific mechanisms by which UV radiation induces basal cell or squamous cell carcinomas or melanoma are not clear, a number of signal transduction pathways are affected that can either lead to apoptosis or to increased cell proliferation...

Do The Preclinical Studies Predict Outcomes In Human Trials

In the clinical setting, a number of studies have tested many of the same personalized vaccine approaches described above in patients with melanoma, colon cancer, non-small cell lung cancer, and lymphoma (Table 2). Among these were two randomized, controlled trials where efficacy findings can be interpreted Vitespen) melanoma arm (626 vs. 383 days, P .177). melanoma melanoma

The Ambiguous Role of Caveolin1 in Cancer

The expression of caveolin-1 in colon tissue and cancer cell lines (see previous section). Furthermore, caveolin-1 is known to promote tumor formation and its presence is correlated with poor prognosis and survival in prostate cancer. Indeed, the expression of caveolin-1 reportedly increases in primary tumors from prostate 154 and certain leukemia-derived cell lines 52 , Also, in prostate cancer cells, caveolin-1 presence increases tumor growth and the incidence of metastasis 7, 67, 88, 136 . Increased caveolin-1 expression in tumor samples is not restricted to cases, like the prostate, where normal tissues have low relative caveolin-1 levels, since increased expression was also reported in tumor models where initial caveolin-1 loss is observed, such as colon 11 and breast cancer 38,42,123 . In most of these cases, the available data argue for a strong positive correlation between expression of caveolin-1, metastasis, and MDR ,42, 80, 81 , Moreover, studies in samples derived from...

Chemokines And Nk Cell Effector Functions

Supported by the fact that NK-mediated lysis of K562 cells and degranulation in the presence of MIP-1a was enhanced in the presence of fibronectin and VCAM-1, suggesting that enhancement of cell adhesion and adhesion molecule presentation by chemokines may facilitate or potentiate NK cell cytotoxic activity (64). In addition, I have recently found, using an adherent NK-sensitive melanoma line, that C-C chemokines and IP-10 facilitate NK cell adhesion to tumor cell monolayers within 15 min, suggesting that the chemokines are promoting NK target cell conjugation (Taub, D., unpublished data). Another possible mechanism for chemokine-induced modulation of tumor cell lysis is provided by data demonstrating that chemokines induce NK cell degranulation (45,64). Granule exocytosis is an important mechanism in NK cellmediated killing (9-12). Serine esterases, granzymes, and perforins have been shown to be present in NK cell granules and to play an essential role in tumor cell killing in vitro....

Analysis of Cytotoxic Agents in Xenograft Models

The data include several examples of cytotoxic agents that show significant xenograft activity that is reflective of clinical activity irinotecan is highly active in several models of colon cancer, temozolomide is efficacious in a model of glioma and one of two models of melanoma, paclitaxel is active in models of bladder, breast, lung, and prostate cancer, rituximab is highly active in two models of B-cell lymphoma, and gemcitabine is active in a model of pancreatic cancer. Note, however, that this activity can be quite dependent on the dose and schedule employed (note irinotecan in colon cancer models). Correlating dose and schedule with PK (e.g., efficacy driven by Cmax, area under the curve (AUC), time over threshold, etc.) is a vital aspect of preclinical evaluation in order to help define the optimum clinical schedule (once- versus twice-daily administration, continuous versus intermittent therapy, etc.). Table 1 also highlights some of the differences in activity that can be...

Nk Cell Trafficking And Cancer Any Relevance

Since the early 1980s, the adoptive transfer of LAK cells or tumor-infiltrating lymphocytes (TILs) has been performed in a series of cancer patients, resulting in a low but significant proportion of clinical responses, especially in those with renal cell carcinoma and melanoma (35). Critical to the activity of these systemically transferred effector cells is their localization to tumor sites. However, for the most part, the proportion of LAK and TIL cells capable of penetrating tumor tissues is quite small, consistent with several early lymphocyte trafficking studies demonstrating that highly activated T- and mononuclear cells migrate poorly into peripheral tissues and tend to localize in various organs and lymphatic tissues (35).

Innate Immune Cells

NKT cells produce both T helper 1 (Th1) and T helper 2 (Th2) cytokines, depending on their mode of activation, underscoring key regulatory roles for the cytokine milieu and glycolipid antigen repertoire present in the tumor microenvironment. Indeed, NKT cells can undermine tumor rejection in some tumor models through a mechanism that involves transforming growth factor P (TGF-P) production by Gr-1+ myeloid suppressor cells (Terabe et al., 2003). Studies have indicated that the CD4- NKT cells effectuate tumor rejection in the MCA-induced fibrosarcoma and B16F10 melanoma models, whereas CD4 + NKT cells contribute to the pathogenesis of inflammatory diseases (e.g., asthma) by the secretion of IL-4, IL-5, and IL-13 (Akbari et al, 2006 Crowe et al, 2005). A deeper understanding of the factors determining the induction of NKT cell subsets during tumor development is an important goal of further investigation.

Chemotherapy Plus Active Immunotherapy

Chemotherapeutic agents have been tested with cancer vaccines and have demonstrated synergy in several models. For instance, docetaxel administered two days prior to each of the three vaccinations of GM-CSF-secreting B16 melanoma cells results in 50 long-term survival of B16 tumor-bearing mice compared to 10 survival with either agent alone (76). While docetaxel was shown to induce neutropenia and lymphopenia, the expansion and survival of antigen-specific T cells (examined in OT-1 TCR transgenic mice using OVA-transfected B16 cells) was not impaired. In another study using neu transgenic mice, three different chemotherapeutic drugs (cyclophosphamide, doxorubicin, and paclitaxel) were tested in combination with a HER-2 neu expressing tumor vaccine and showed enhanced activity in a therapeutic setting (77). Whether drug was administered before or after vaccination affected the outcome and the optimal order of administration was found to vary from one drug to the next.

Adaptive Antitumor Responses

IgG subclasses to bind the array of activating and inhibitory Fcy receptors expressed on DCs, which influences the balance of effector versus tolerizing function (Nimmerjahn and Ravetch, 2005). In this regard, IgG2a and IgG2b display higher affinity than IgG1 and IgG3 for the activating Fcy IV receptor and are more potent for antibody-dependent cellular cytotoxicity. Together, these properties resulted in superior suppression of B16 melanoma growth in vivo. These findings should advance the development of therapeutic monoclonal antibodies and provide a framework for clarifying the roles of endogenously produced antitumor antibodies. The principal mechanism involved in the priming of antitumor T cells appears to be cross-presentation of tumor-associated antigens by professional antigen presenting cells, particularly DCs. This pathway allows processing of exogenously acquired tumor antigens into the MHC class I pathway, whereas proteins captured through endo-cytosis or autophagy are...

Nonspecific Immune Modulation Plus Active Immunotherapy

Striking synergy between anti-CTLA-4 antibody and autologous GM-CSF-secreting B16 melanoma and SM1 breast tumor vaccines against established disease in mice has been observed, and the antibody has also been tested in combination with an off-the-shelf GM-CSF-secreting prostate cancer vaccine, with promising results in preclinical studies (84-86). In a preliminary study in human cancer patients previously treated with either autologous or off-the-shelf cancer vaccines who went on to receive infusion with anti-CTLA-4 antibody, only those patients who received the autologous vaccine demonstrated signals of clinical activity (87). Many additional clinical trials are underway testing anti-CTLA-4 antibody either as monotherapy or in combination with off-the-shelf peptide vaccines, GM-CSF, and off-the-shelf whole cell vaccines (88,89 and http ). Unfortunately, there are no clinical trials currently underway testing anti-CTLA-4 antibody with personalized cancer vaccines...

History Of Mononuclear Cell Infiltration In Cancer

Mononuclear cell infiltration is a common feature of many types of human cancers. In fact, its occurrence is considered so unremarkable that there are no systematic studies describing the prevalence or intensity of infiltrates by tumor type or stage. Instead, it is generally asserted that intense infiltrates are associated with certain tumor types, such as medullary carcinoma of the breast and malignant melanoma (1,2), and that most other cancers are also infiltrated to differing extents. Even without an epidemiology of tumor-related inflammatory infiltrates, tumor biologists have extensively focused on this phenomenon for more than 100 yr.

Infiltrates And Their Function

Infiltrates varied with tumor type and were most common in renal cell carcinoma, melanoma, and colorectal carcinomas, although CD167CD11c+ cells of similar appearance were also very common in breast and lung carcinomas. Expression of CD16 may be related to the activation or maturation status of the monocytes and may explain why other investigators see lower proportions of CD16+ cells in tumor infiltrates (although technical differences may also account for the discrepancy) (17). This suggests that some straightforward immunohistochemical analyses may also underestimate the true proportion of macrophages in tumors. These contradictory results could be a reflection of the dual role played by infiltrating cells, in particular macrophages. On the one hand, their cytocidal capacity immediately suggests a mechanism for direct antitumor activity, and a variety of experimental models have generated evidence consistent with this idea. For example, Fidler (26)...

Adoptive immune therapy

In these early studies, LAK cells were derived from peripheral blood mononuclear cells and activated ex vivo with high-dose IL-2. Ex vivo activated LAK cells were capable of lysing tumor cells in a process unrelated to major histocompatibility proteins (25). After initial preclinical success, clinical efforts focused on the use of LAK cells and IL-2 in the treatment of solid tumors such as renal cell carcinoma and melanoma. Unfortunately, no advantage has been clearly demonstrated for the administration of LAK cells and IL-2 over administration of IL-2 alone in metastatic cancer (26). Recent studies have offered an explanation for the limited therapeutic efficacy of LAK cells, given their inability to home exclusively to the tumor (27,28). A search for more potent killer cells has led to the discovery of tumor-infiltrating lymphocytes (TILs) (29). With the phenotype of cytotoxic lymphocytes, these cells kill in a major histocompatability complex (MHC)-restricted...

Disclaimer Not for patient use To be used as a research guide only

PD markers have long been used in phase I studies to determine the optimal dose by assessing serum plasma levels of the drug in conjunction with safety and toxicology parameters. Other analytes in either blood or urine associated with disease can also be evaluated if the pathogenesis of disease is understood and it is in this context where discovery of novel biomarkers of disease may be greatly aided by genomic, proteomics and metabolomics.67,86 Functional biomark-ers, an extension of a pharmacodynamic type of biomarker, are biochemical measures that indicate the drug is reaching its target and affecting its proposed mechanism of action. Evaluating cell death in cancer therapies may soon be possible using an enzyme-linked immunosorbent assay (ELISA)-based assay measuring caspase 3-mediated apoptosis in solid tumors (Cyclacel, UK),75 but it will be limited to accessible tumor types. Recently, functional biomarker assays for PARP inhibition were demonstrated in metastatic melanoma from...

Strategies to Modulate Treg Number and Function

In light of the expression of CD25 by Tregs, this molecule has been an early target for both pre-clinical and clinical studies of Treg depletion. The administration of anti-CD25 mAbs in mouse models of cancer leads to CD4+CD25+ Treg depletion and a significant enhancement of anti-tumor activity, and the clinical utility of this approach has recently been described by Rech and Vonderheide (Rech and Vonderheide 2009). Tregs in mouse and human may also be targeted by CD25 fusion proteins such as LMB-2 which consists of a single-chain Fv fragment of a CD25-specific mAb linked to a 38 kDa fragment of Pseudomonas exotoxin A. Preclinical in vitro studies of human PBMCs successfully depleted CD4+CD25+ Tregs following incubation with LMB-2 (Attia et al. 2006). Administration of LMB-2 followed by peptide vaccination in patients with melanoma resulted in a profound fall of Foxp3+CD4+CD25+ Tregs, although this did not result in clinical responses (Powell et al. 2007b). CD25-directed depletion of...

Attenuating Treg Function

Blockade of the suppressive molecule CTLA-4, which is expressed at high concentration on Tregs, may also attenuate Treg function. Gvax when used in combination with anti-CTLA-4 mAbs can mediate tumor rejection in a number of mouse tumor models, including the poorly immunogenic B16 melanoma (Peggs et al. 2009 Quezada et al. 2006, 2008). The latest study is the first to demonstrate the critical importance of synergy between the independent contributions of CTLA-4 blockade in cis and in trans to anti-tumor activity, illustrating that both Teff and Tregs are relevant targets for the therapeutic efficacy of anti-CTLA-4 mAbs (Peggs et al. 2009). This neutralizing mAb therapy has now reached clinical trials in many cancers with two humanized anti-CTLA-4 mAbs, MDX-010 (Ipili-mumab) and CP-675 206 (Tremelimumab). In a phase I trial treating metastatic melanoma, 36 of patients showing grade III IV autoimmune toxicity had tumor regression compared with 5 in patients without autoimmune symptoms...

Antitumor Effects Of Mcp1 In Vivo

These results suggest that MCP-1-mediated macrophage infiltration into tumors occurs in immunocompetent animals as well as in athymic mice. This was demonstrated directly by engineering MCP-1 expression in a B16 murine melanoma-derived cell line that does not ordinarily express MCP-1 (65). A clone expressing MCP-1 formed a tumor with double the proportion of macrophages and a slower growth rate compared to nonexpressing tumors. Again, this difference occurred despite identical growth rates in vitro for expressing and nonexpressing clones. Interestingly, however, despite forming slower-growing tumors, the MCP-1-expressing cells actually had a higher tumor-forming efficiency at low inocula (i.e., 102 cells site). This phenomenon is considered to be supportive evidence for the tumor-promoting role of macrophages. As in the work of Prehn (52), at low inocula, the growth factors provided by infiltrating macrophages can promote the clonogenic growth of individual tumor cells. However, with...

Mechanisms Of Mcp1 Antitumor Effects

In an early study, the addition of MCP-1 to purified human monocytes in tissue culture enhanced their ability to inhibit DNA synthesis in six malignant human cell lines (37). These included colon and breast carcinoma lines as well as melanoma, rhab-domyosarcoma, and leiomyosarcoma lines. The effect was clearly cytostatic and occurred with an ED50 of approx 0.3 nM, consistent with MCP-1's Kd for its receptor on monocytes. By contrast, the ability of MCP-1 to enhance the tumoricidal effects of monocytes in vitro has been documented (71). Elicited peritoneal macrophages from C3H mice were incubated with radiolabeled syngeneic murine melanoma cells (K-1735) at an effector target ratio of 10 1. In the presence of 1 g mL of LPS, macrophages were able to lyse melanoma cells engineered to express human MCP-1, but not parental or control cells. (LPS plus interferon induced lysis regardless of MCP-1 expression status.) The addition of LPS and human MCP-1 to cultures of macrophages induced lysis...

Allogeneic Whole Tumor Cells

Some of the earliest attempts at inducing an antitumor response were in melanoma, where intact allogeneic cell lines were used as a vaccine (11). Canvaxin is a whole, multicell polyvalent vaccine consisting of a mixture of three sub-lethally irradiated allogeneic melanoma lines that are of different HLA haplotypes CanvaxinTM was extensively tested in phase 1 and 2 clinical trials with the results indicating a statistically significant increase in median and five-year survival of stage III and IV surgically resected patients with melanoma when compared with matched historical controls (13,14). The promising clinical benefit was correlated with vaccine-induced immune responses (11,15-18). Early phase 2 nonrandomized clinical trial results indicated a strong cellular delayed type hypersensitivity (DTH) along with high anti-TA99 IgM and anti-GD2, -GD3, -GM2, and -GM3 ganglioside IgM titers in patients with resected melanoma (19). Serum complement-dependent cytotoxicity for melanoma cell...

Use of interleukin2 in other malignancies

Melanoma and renal cell cancer induced CR in 1 to 5 and partial remission with shrinkage of tumor metastases in 5 to 15 of patients (73). Even more encouraging were the initial reports of IL-2 use in combination with LAK cells in renal cell carcinoma, with CR rates in up to 30 of patients (74-76). Larger multicenter studies show, however, a more modest response independent of the use of LAK cells (77).

Rheb Modulation of Survival and Host Tumor Interactions

Cells are grown as monolayer cultures. However, FTIs can produce significant apoptotic events in more complex growth environments and in tumor-bearing hosts. FTIs induce apoptosis, or more specifically anoikis, when cells are denied substrate 98 . A similar profound induction of apoptosis was reported for C32 melanoma cells when grown as subcutaneous tumors in nude mice 43 . When the same C32 melanoma cell line was grown as monolayer cultures, only an antiproliferative effect was observed. Similar events have been suggested in several H-ras transgenic tumor models wherein profound tumor regressions have been noted following treatment with FTIs 99,100 . The apoptotic events appear to be derived from an inhibition of H-Ras activation of the PI3-kinase Akt-3 pathway 101 . Furthermore, activation of the PI3-kinase Akt survival pathway can block FTI-induced anoikis 102 . The findings suggest the possibility that a small pool of H-Ras protein that is highly sensitive to FTIs can be...

Cytokine Modified Tumor Vaccine

Several cytokines such as IFN-a, IFN-g, IL-12, and IL-2 have been used to enhance an antitumor CD8+ response (32-35), of which one of the most effective cytokines used as an immune adjuvant is GM-CSF (36). GM-CSF is a powerful immune adjuvant, and attracts and activates DCs at a site of vaccination (37). Transducing polyvalent tumor cells with GM-CSF has the advantage of recruiting DCs to the vaccine where it encounters a multitude of potential tumor antigens to provide a wide-ranging and durable response. Preclinical studies in a B16 mouse-melanoma model have demonstrated that GM-CSF transduced tumor cells, in comparison to other cytokines such as IL-4 and IL-6, and induced the most potent systemic antitumor effect (36). Many subsequent studies in other murine tumor models have validated the potent systemic immunity induced by GM-CSF-transduced tumor-cell immunotherapies (38-40).

Lessons Learned From Traditional Cancer Vaccine Trials And Infectious Disease Vaccine Models

Over the past two decades, cancer vaccines as a possible treatment modality have seen much promise. While a variety of approaches in preclinical studies have induced a cure for mouse cancers, several of these approaches have been tried in human with limited success. The only approved therapeutic cancer vaccine, a xenogeneic DNA vaccine, was for the treatment of canine melanoma (74). However, the field has substantially matured, with information from a host of clinical trials now available to help in the understanding of major aspects of preclinical and clinical vaccine development. In contrast, infectious disease vaccines target an invading pathogen, and the success in developing this type of vaccine is inherently straightforward. Taken collectively, there are some elements from these studies that may be useful in developing therapeutic cancer vaccines regardless of whether the cancer arises from self-tissue or is induced by a pathogen.

Hyaluronan Oligosaccharides A Examples of Biological Activity

These studies on angiogenesis continued and soon it was shown that fragments of 3-10 disaccharides of HA (approximately 1.2-4 kDa) stimulated endothelial cell proliferation (47) and that this occurred by induction of protein tyrosine kinase activity (48). The same size fragments (1.2-3.6 kDa) activate messenger RNAs for collagen synthesis in an X-irradiation model of lung fibrosis (20). Fragments of tetra- and hexasaccharide size (approximately 0.8-1.2 kDa), but not intermediate size nor high molecular weight HA, induced immuno-phenotypic maturation of human monocyte-derived dendritic cells (49). HA oligomers consisting mainly of 5-6 disaccharide units, around 2 kDa, inhibited B16F10 melanoma growth (50). HA fragments less than 500 kDa stimulated inflammatory genes which direct the production of cytokines (51-53) whereas polymers of 3 X 103 - 6 X 103 kDa did not. Fragments of HA are produced by the action of hyaluronidases and by free radical reactions and these...

Antitumor Sulfonamides

The development of CAIs possessing potent tumor cell growth inhibitory properties was reported by this group (Supuran and Scozzafava 2000b, 2000c Scozzafava and Supuran 2000a Supuran et al. 2001). Such compounds were discovered in a large screening program in collaboration with the National Institutes of Health (NIH) of sulfonamide CAIs. Several hundred aromatic heterocyclic sulfonamides were assessed in vitro as potential inhibitors of growth of a multitude of tumor cell lines, such as leukemia, nonsmall cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancers. The active compounds (most of them nanomolar inhibitors of CA II and CA IV), of types 4.212 to 4.223, belong to both the aromatic and the heterocyclic sulfonamide classes and showed GI50 values (molarity of inhibitor producing a 50 inhibition of tumor cell growth after a 48-h exposure to the drug) in the micromolar range (Supuran and Scozzafava 2000b, 2000c). Better antitumor compounds were then...

Section 4 Significance Of Mirna Cgh Assay

If the location of miRNAs is relevant to tumorigenesis, then structural or functional alterations of miRNAs should be identified in various types of cancers. A growing number of reports are providing such evidence and suggest that abnormal expression of miRNAs is central to cancer pathogeny. The majority of miRNAs causally linked to human tumorigenesis are located in genomic regions altered in cancer, and the genomic abnormality is concordant with expression deregulation (genomic deletion for downregulation and amplification for upregulation, respectively). The combination of nonrandom chromosomal abnormalities and other types of genetic or epigenetic events could contribute to downregulation or overexpression of miRNAs. An extensive study of high-resolution array-based comparative genomic hybridization by Zhang et al. (2006) on 227 human ovarian cancer, breast cancer, and melanoma specimens clearly proved that regions hosting miRNAs exhibit high-frequency genomic alterations in human...

Angiogenesis and Cancer

VEGF overexpression is associated with tumorigenesis and a poor prognosis in a multitude of cancers, including gastric carcinoma (Maeda et al. 1996), colorectal carcinoma (Lee et al. 2000 Takahashi et al. 1995), lung cancer (Fontanini et al. 1997), melanoma (Gorski et al. 2003), prostate cancer (George et al. 2001), breast (Berns et al. 2003), and ovarian carcinoma (Paley et al. 1997). VEGF is upregulated in cancer cells in vivo by hypoxia and starvation (Zhang et al. 2002), and also by oncogene activation, which drives constitutive VEGF overexpression (Zhang et al. 2003b). VEGF directly promotes tumor angiogenesis through multiple mechanisms such as endothelial cell proliferation and survival, endothelial cell migration, vessel destabilization via Tie-2 (Zhang et al. 2003c), and enhancing chemotaxis of bone marrow-derived vascular precursor cells (e.g., endothelial cells, pericytes, vascular leukocytes) (Conejo-Garcia et al. 2004 Ellis and Hicklin 2008). In addition, VEGF promotes...

Heat Shock Protein Inhibitors

These natural products showed potent antitumor activities in preclinical models 184 , but, due to several development issues, the clinical evaluation of these compounds has not been pursued. In the case of geldanamycin, extensive medicinal chemistry efforts have been made to generate analogues with improved pharmaceutical properties. One of these derivatives, 17-allyamino-17-demethoxygeldanamycin (17-AAG, compound 45, Fig. 8) 185 , has undergone Phase I clinical trials and Phase II monotherapy trials began last year (malignant melanoma). Although 17-AAG has shown some encouraging clinical responses, it presents important drawbacks (e.g., liver toxicity and cumbersome formulation) that may limit its clinical application. KOS953 and CNF1010, which contain proprietary forms

Exudative Retinal Detachment

A malignant melanoma of the choroid might present as a retinal detachment. Often the melanoma is evident as a black lump with an adjacent area of detached retina. If the retina is extensively detached over the tumour, the diagnosis can become difficult. It is important to avoid performing retinal surgery on such a case because of the risk of disseminating the tumour. Suspicion should be raised by a balloon detachment without any visible tears, and the diagnosis can be confirmed by transilluminating the eye to reveal the tumour.

Biology and Pathology

Most cases of Ewing sarcoma have a clonal translocation within the tumor cells. Eighty-five percent of the time this translocation occurs between the long arms of chromosomes 11 and 22 and can be found with standard cytogenetics in 80 of tumors and with reverse-transcriptase polymerase chain reaction (RT-PCR) in up to 95 53 . This translocation results in a fusion protein containing the amino terminus of the EWS protein joined to the carboxyl terminus of the FLI-1 protein 54 . The FLI-1 protein is a member of the ETS family of transcription factors, which directly bind DNA and either activate or repress transcription. Less is known about the EWS protein, yet some evidence suggests that it has a strong transcriptional activation domain. Researchers have suggested that following DNA binding by FLI-1 within the fusion protein, there is replacement of the weak transcrip-tional activation domain of FLI-1 with the strong activation domain of EWS 55 . The second most common translocation in...

Tyrosine Kinase Inhibitors

Thus, STI571 should also have activity in diseases associated with constitutive activation of these kinases. In the case of c-kit, activating mutations are associated with a gastrointestinal stromal tumor (GIST) (77,78), which is highly refractory to chemotherapy. Results from an ongoing phase I study using STI571 to treat patients with GIST have shown response rates close to 60 (79,80). A particularly interesting finding from this study was that activating mutations of c-kit correlated with response, whereas patients expressing wild-type c-kit had a significantly lower response rate (79). This suggests that other tumors where c-kit is expressed but not activated by mutation may also be less likely to respond to STI571. Tumors that express c-kit include germ cell tumors, small-cell lung cancer (SCLC), AML, neuroblastoma, melanoma, ovarian cancer, and myeloma. The exception to this might be the fraction of patients with AML who express...

Industrial Chemicals and Occupational Cancers

Several epidemiologic studies have shown increased frequency of leukemia in workers exposed to benzene.81-83 Two studies of workers exposed to bis(chlorome-thyl) ether have indicated an increased risk of lung cancer, primarily small-cell carcinoma.81 There is also an increased risk of lung cancer among workers in chromium industries. Occupational exposure to 2-naphthylamine has long been known to be associated with urinary bladder cancer.81 Since the time of Percival Pott and his study of chimney sweeps (see Chapter 2), coal soot has been known as a cause of skin cancer. Since that time, occupational exposure to soot, coal tar, pitch, coal fumes, and some crude shale and cutting oils has been shown to be associated with cancers of the skin, lung, bladder, and gastrointestinal tract. The carcinogenicity of these latter agents is probably related to their content of polycyclic aromatic hydrocarbons (PAH).

TbR and the Tumor Endothelial Barrier to T Cell Homing

ETBR is overexpressed in melanoma and is associated with aggressive tumor phenotype (Bachmann-Brandt et al. 2000). Highlighting the role of ETBR in melanoma, the receptor antagonist BQ-788 inhibited the growth of human melanoma cell lines and reduced human melanoma tumor growth in a nude mouse model (Lahav 2005 Lahav et al. 1999). ETBR is also overexpressed in ovarian cancer, Kaposi's sarcoma, glioblastoma, and breast cancer (Bagnato et al. 2004 Egidy et al. 2000 Kefford et al. 2007 Rosano 2003). Interestingly, ETBR upregu-lation predicts poor outcome in both breast and ovarian cancers (Grimshaw et al. 2004 Wulfing et al. 2003), and ETBR overexpression has even been proposed as tumor progression marker (Demunter et al. 2001).

Effects of SLRPs on Cell Behavior

Investigated in relation to decorin, has attracted considerable interest, largely because of its implications for tumor growth, invasion, and metastasis, and prospects for control of these pathological processes. Decorin expression is often very low in carcinoma cells but is upregulated in the connective tissue stroma surrounding tumors (68). Induction of decorin expression in carcinoma cells reduces their proliferative and metastatic potential (69) and lumican expression in melanoma cells has similar effects (70).

Hyaluronan in Adhesion Migration and Invasion of Cancer

Cancer metastasis requires genetic and cellular changes to the tumour cells which facilitate their invasion into surrounding tissues, entry into the lymphatic system and or bloodstream followed by establishment and colonisation of the tumour at the secondary site. Several studies have correlated HA on the surface of tumour cells with metastatic behaviour of cells and have shown that this is dependent on CD44-HA interaction. However, there are many mechanisms for cells to acquire invasive and metastatic properties and generation of this cell behaviour may be cell type and cell environment specific highlighting an underlying complex process. For example, other studies have also demonstrated that CD44 variant isoforms confer a metastatic phenotype in pancreatic carcinoma which is independent of HA binding (60). In melanoma, HA and HA recognition have been closely studied and data have shown positive association of HA-CD44 mediation of melanoma cell line migration and invasion (61,62)....

Air and Water Pollutants

Air, water, and soil pollution is estimated to account for only 1 -4 of all cancers. A small percentage of lung cancer (less than 5 ) may be due to chronic inhalation of outdoor air pollutants such as industrial or engine exhaust chemicals. Indoor air pollutants such as secondhand smoke and radon are thought to be contributors, but this risk is most likely exaggerated (see below). In China and some other Asian countries, chronic inhalation of cooking oil smoke may be a causative agent of lung cancer.90 The contamination of the atmosphere by chlorofluorocar-bons (whose production is now banned in developed countries) in refrigerant and propellants has been implicated in destruction of the ozone layer and a resultant increase in skin cancer due to a lower filtering of UV irradiation from the sun. Occupational exposure to inhaled asbestos, such as occurred in Liberty Ship building in World War II, has been clearly linked to me-sothelioma. Regarding water pollution, high exposure to...

Manipulation of Hyaluronan Function as Potential Therapeutic Strategies

Even though HA oligos have demonstrated angiogenic effects in tumours, paradoxically, Zeng et al. (109) have shown that HA oligo administration in vivo, inhibited melanoma tumour growth and these observations are now being extended to ovarian cancer. The tumour inhibitory effects of HA oligos in this instance are thought to arise from competition for endogenous polymeric HA and replacing high affinity multivalent interactions with weaker low affinity low valency interactions (110). The growth inhibitory effects of HA oligos was further supported by Ghatak et al. (111). In this study HA oligos were shown to inhibit anchorage independent growth in TA3 St murine mammary carcinoma and HCT116 colon adenocarcinoma models. Furthermore, this inhibition was shown to correlate with inhibition of PI3-kinase and phosphorylation of Akt, both of which exert strong anti-apoptotic signals. In addition, HA oligos also stimulated expression of PTEN, which caused downstream decrease in phosphorylation...

Epidemiology 1721 incidence Trends

The incidence of melanoma has increased steadily in the United States (Figs. 17.1 and 17.2) and in many other countries with a predominantly white population. For the period 1975-2000, the incidence rate among 15- to 29-year-olds increased at a statistically significant average annual rate of 1.3 for females (Fig. 17.1), or more than triple in the last quarter century 1 . The increase in young men was slower, but for men and women over the same interval, 20- to 25-year-olds had a peak increase of > 1.2 per year (Fig. 17.2), also a tripling. The current rates for whites are 18.3 per 100,000 for males, and 13 per 100,000 for females 2 . In New Zealand and Australia, the two countries with the highest incidence of melanoma in the world, the age-standardized rates for melanoma are 562 and 289 per year per million, respectively 1 . The age-standardized incidence of melanoma in Scotland for men and women rose from 35 and 70 per year per million, respectively, in 1979, to 106 and 131 per...

Incidence by Anatomic Location

In the United States, age-adjusted rates for invasive melanoma have increased for the trunk as well as lower and upper limbs in men and for the trunk and lower limbs in females 4 . The incidence of melanoma tends to be higher in anatomic areas that have been intermittently exposed to sun (trunk and limbs) in patients younger than 50 years of age, whereas chronically sun-exposed areas such as the head and neck predominate in older patients 4 . Figure 17.7 demonstrates that in the 15- to 29-year age group, females have a higher incidence than males of melanoma of both the lower and upper limbs and trunk. Only the incidence of head and neck melanoma is higher in males in this age group. Incidence of malignant melanoma by gender, United States SEER 1975-2000 1 Female male ratio of malignant melanoma as function of age at diagnosis, United States SEER 1975-2000 1 Incidence of melanoma by gender and site, United States SEER 1975-2000 1 Average annual percent change (AAPC) in malignant...

Incidence Trends by Anatomic Location

The rising incidence of melanoma over time has been well established (Figs. 17.1 and 17.2) however, as shown in Fig. 17.8, this increase has been slowing in age groups younger than 45 years. Although the overall incidence trend in younger patients appears unchanged during the past decade (Fig. 17.8), the incidence of melanoma for 15- to 29-year-old females had been increasing in all age groups at all of the anatomic locations evaluated except the upper extremity (Fig. 17.9). In males younger than age 30 years, there has been no statistically significant change in the incidence of melanoma during the past quarter century at any of the anatomic sites evaluated (Fig. 17.10). Some of the increase in melanoma at specific anatomic sites may be explained by better reporting.

Stage andthickness trends in incidence

The majority of invasive melanomas (86.4 ) in the United States are localized and only 4 have distant metastases at the time of initial diagnosis. Over the last 15 years there has been a shift toward an increased number of in situ melanomas, with the percentage increasing from 3.6 in 1973 to 35.3 in 1998. In the United States, between 1973 and 1997, the rate of melanoma for each stage, as well as the estimated annual percentage change in each tumor stage was higher for males than for females 7 . During the same time period, rates for patients under age 40 years decreased for each tumor stage in males, while in females only rates for metastatic disease decreased. However, the rates increased statistically for regional disease among females. For patients aged 40-59 years, the rates for localized disease increased only among males and for those 60 years of age or older, statistically significant upward trends were evident for localized and regional disease among males and for localized...