Aberrant Cav1 Expression Complexity and Context

Chemo Secrets From a Breast Cancer Survivor

Breast Cancer Survivors

Get Instant Access

Genetically engineered mouse models have proved invaluable for gaining an understanding of gene function and gaining insight into the role of specific proteins in human disease. Three independent groups of investigators have reported generation of Cav-1-knockout mice [8, 21, 70]. In all cases, Cav-1~'~ mice were reported to be viable with no obvious abnormalities. However, further analysis revealed multiple abnormalities in cardiovascular, pulmonary, and urogenital tissues [13, 37, 65]. It is interesting that many of the functional abnormalities that were documented in studies of Cav-1~'~ mice involved growth-related disorders in stromal cells that normally have high levels of Cav-1. A recent analysis of Cav-1~'~ mice revealed stromal cell hyperplasias that could be interpreted as incomplete differentiation related to lack of Cav-1 [107]. In many organs in which loss of Cav-1 led to disorganized and/or hyperplastic stroma, growth and/or differentiation abnormalities were also observed in adjacent epithelial cells that normally express low to nondetectable levels of Cav-1. It was proposed that loss of Cav-1 function in stromal cells of various organs directly leads to a disorganized stromal compartment that, in turn, indirectly promotes abnormal growth and differentiation of adjacent epithelium.

Although the absence of Cav-1 has not been reported to increase the incidence of spontaneous malignancies, more hyperplastic lesions and tumors were observed in the skin of Cav-1~'~ mice than in that of wild-type mice after application of dimethylbenzan-thracene [9]. Further studies showed that loss of Cav-1 gene expression can accelerate the development of hyperplastic and dysplastic mammary lesions and enhance tumorgenesis and metastasis in cancer-prone genetically engineered mice [100, 102], These results were consistent with those of previous studies, which showed that targeted down-regulation of Cav-1 increases tumorigenicity in NIH-3T3 mouse fibroblasts [25] and that enforced expression of Cav-1 suppresses the growth of fibroblasts and specific human breast cancer cell lines with myoepithelial cell features in vitro [48]. These and other study results led to the notion that Cav-1 is a tumor-suppressor gene [103],

In accordance with that notion, some reports have documented down-regulation of Cav-1 in various malignant human tissues, including osteosarcomas [7], fibrosarcomas [98], colon cancer [6], follicular thyroid cancer [1], ovarian cancer [17, 98], mucoepidermoid carcinoma of the salivary gland [79], lung adenocarcinoma [46, 99], and relatively small, estrogen receptor-positive breast cancer [73]. Numerous studies have not revealed any inactivating Cav-1 mutations in tumors with Cav-1 down-regulation, but the recent identification of a dominant-negative mutation, a proline-to-leucine substitution at position 132 in human breast cancer tissues, may lead to further information about tumor-suppressor functions of Cav-1 [31]. Although there is not a perfect correlation, it is remarkable that many of these malignancies are of stromal cell origin. A recent novel and somewhat surprising observation is the reduction of Cav-1 levels in human cancer-associated fibroblasts from breast cancers and PCa [20, 60].

In contrast to studies of Cav-1~'~ that revealed its potential tumor-suppressor activities, recently published study results showed that Cav-1~'~ TRAMP (transgenic mouse prostate) mice demonstrate significantly fewer primary tumors and lesions than Cav-1*'* TRAMP mice do [101]. Additional studies showed that transgenic mice with targeted overexpression of Cav-1 in prostatic epithelial cells using the short probasin (PB) promoter (i.e., PBcav-1 mice) demonstrated prostatic hyperplasia [96], In addition, secreted Cav-1 from prostatic epithelial cells in PBcav-1 mice created a local microenvironment that permitted tumor growth and increased serum Cav-1 that was associated with increased experimental PCa lung metastasis activities. These results are consistent with those of numerous studies that have documented Cav-1 overexpression in PCa tissues [75, 105, 108, 109] and other malignancies, including esophageal squamous carcinoma [34, 45], oral carcinoma [35], papillary carcinoma of the thyroid [38], pancreatic cancer [85, 91], renal carcinoma [10, 33, 40], bladder cancer [68, 74], metastatic lung cancer [32], squamous carcinoma of the lung [110], Ewing sarcoma [94], and basal-like breast carcinomas [23, 27],

Although Cav-1 expression is complex, a substantial body of work now clearly indicates that it can demonstrate either growth-suppressive or oncogenic properties, depending on the type of malignant cell. This dichotomy will ultimately be defined at the molecular level through precise signaling analysis in well-controlled experiments and validation in clinical and pathologic studies. One of the clearest examples of a malignancy in which Cav-1 promotes tumor progression is PCa. Studies of PCa have provided insight into the underlying mechanisms of Cav-1-mediated oncogenic activities.

Was this article helpful?

0 0
10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment