Angiogenesis

Development of a functional vasculature is a key event in normal embryonic development as well as in the adult for such things as wound healing, corpus luteum angiogenesis during the female reproductive cycle, and development of the placenta. The process of new blood vessel formation from mesodermal stem cells during embryonic development is called vasculogenesis (Fig. 4-32). Angiogenesis, by contrast, is the term used to describe development of new blood vessels from pre-existing ones. This is the process that takes place during wound healing, the reproductive cycle, and in tumors. In growing tumors, endothelial cells that will form the rudiments of new blood vessels may proliferate 20 to 2000 times faster than normal tissue endothelium in the adult (reviewed in Reference 367).

Initiation of the angiogenesis response is triggered by several factors. Among these are VEGF family members, basic FGF (bFGF or FGF-2), PDGF, angiopoietins, and factors that facilitate blood vessel formation by modulating extracellular matrix (ECM) production or differentiation ofcell types involved in blood vessel formation. These latter factors include TGF-p, avp3 and avp5 integrins, ephrins, and plasminogen activators (Table 4-8).

It is of interest, and some therapeutic importance, that the endothelial cells in different tissues display organ-specific antigens on their surface (reviewed in Reference 366). This has been determined by a ''biopanning'' technique in which peptide libraries are used to screen for binding in vivo to endothelial cell (EC) surface molecules. For example, organ-specific EC surface markers have been observed in the lung, breast, prostate, brain, kidney, pancreas, and a number of other tissues. Of keen interest is that tumor EC cells also have sets of surface markers different from normal ECs. For example, ami-nopeptidase N was found to be a tumor EC-specific marker. In addition, gene expression arrays have shown that 46 transcripts are specifically elevated in the tumor ECs compared to normal adult endothelium (reviewed in Reference 366). Perhaps it's not surprising, however, that many of these transcripts are also found in developing embryonic vasculature and in

commitment and differentiation of mural cell progenitors pericyte differentiation

Figure 4-32. Vessel wall assembly. Angioblasts begin to differentiate into endothelial cells and assemble into tubes, most likely in response to VEGF signals from surrounding tissues. Once endothelial cells form patent tubes, pericytes and smooth muscle cells are recruited to form the vascular wall. In microvessels, PDGF signals are involved in the recruitment of pericytes. In large vessels, the Tie-2 and Ang-1 receptor-ligand pair is involved in the recruitment of smooth muscle cells. (From Cleaver and Melton,366 reprinted with permission from Macmillan Publishers Ltd.)

commitment and differentiation of mural cell progenitors pericyte differentiation

Figure 4-32. Vessel wall assembly. Angioblasts begin to differentiate into endothelial cells and assemble into tubes, most likely in response to VEGF signals from surrounding tissues. Once endothelial cells form patent tubes, pericytes and smooth muscle cells are recruited to form the vascular wall. In microvessels, PDGF signals are involved in the recruitment of pericytes. In large vessels, the Tie-2 and Ang-1 receptor-ligand pair is involved in the recruitment of smooth muscle cells. (From Cleaver and Melton,366 reprinted with permission from Macmillan Publishers Ltd.)

remodeling of vasculature during wound healing in adults. This phenomenon, once again, reiterates the concept of the oncodevelopmental aspects of malignant transformation (see Chapter 2).

The difference in tumor EC surface markers can be taken advantage of therapeutically. For example, Hoffman et al.369 have shown by phage display that peptides with the amino acid sequences CGKRK and CDTRL preferentially bind to tumor neovasculature in skin carcinomas compared to normal skin, and to some extent to premalignant dysplastic skin lesions. Such differences in the molecular diversity of tumor compared to normal ECs can be used to guide anticancer agents selectively to cancer neovas-culature and provide a novel mode of targeted

anticancer therapy.

It has been known for more than 100 years that solid tumors can become vascularized. It was not appreciated until the 1950s, however, that growing tumors elicit new capillary growth from the host,371 a process called tumor angio-genesis. The mechanism of this angiogenesis was shown to involve release of some substance(s) from growing tumors that stimulates outgrowth of capillaries from the host's vasculature. This was demonstrated by implanting tumors into the cheek pouch of hamsters in such a way that the normal stromal tissue of the host animal was separated from the tumor tissue by a filter with very small pores (0.45 m in diameter) that would not allow cells to migrate, but would allow large molecules to diffuse between tumor and host

372 373 T l ■ l tissues. In these experiments, the growing tumors elicited the proliferation of new capillaries in the host tissue, indicating the release of a diffusible substance by the tumor that stimulates capillary growth. This factor was called tumor angiogenesis factor (TAF).374 Folkman and colleagues showed that tumor cells transplanted into the cornea of rabbits initially grew slowly, but after about a week, small capillaries began to grow outward from the iris toward the tumor and when the capillaries reached the tumor, it began to grow rapidly.375 Corneal implants of normal adult tissues or of rapidly dividing embryonic tissue did not induce capillary growth. Injection of tissue extracts into the cornea and application of extracts directly onto the chorioallantoic membrane of a fertile chicken egg have been used to demonstrate the presence of TAF. A wide variety of tumors have been examined for TAF activity, and many tumors have been found to contain it. The ability to induce angiogenesis, however, is not restricted to neoplastic cells. Angiogenesis can also be induced by spleen lymphocytes, thymocytes, peritoneal macrophages, and testicular grafts from newborn mice and by leukocyte invasion of the cornea (reviewed in Reference 376). It is now known that the induction of capillary growth by tumors is, in fact, the result of a combination of factors.

Table 4—8. Angiogenesis Activators and Inhibitors

Activators

Function

Inhibitors

Function

VEGF family members'

PDGF-BB and receptors

receptors FGF, HGF, MCP-1

VE-cadherin; PECAM

(CD31) Ephrins

Plasminogen activators, MMPs

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