Introduction

Although the mortality rates for specific cancers have declined modestly in recent years, overall, cancer remains the second leading cause of death, behind heart disease, in the entire population and is the leading cause of death for people in the United States between 60 and 79 years old. Estimates were that there would be 291,610 newly diagnosed cancers of the genitourinary (GU) tract in men and 46,840 deaths caused by those cancers in 2009; prostate cancer (PCa) alone would account for 66% of the new cases of GU cancer and 60% of cancer-related deaths in men [39]. PCa is androgen sensitive, and hormone therapy, mainly achieved by androgen deprivation, is one of the main treatment modalities in the clinical management of advanced PCa. However, this treatment is only palliative and has numerous side effects [56]. Recent clinical studies also indicate that docetaxel chemotherapy provides modest survival benefits in castrate-resistant PCa (CRPC) [66]. The development of therapies for metastatic PCa is the most significant challenge today in translational PCa research. Although metastatic PCa is a multifocal disease, bone is the principal organ involved by metastases. It is critically important to gain increased understanding of the mechanisms that underlie the development and progression of PCa to facilitate the development of biomarkers and novel therapeutic strategies to control this devastating malignancy.

Caveolin-1 (Cav-1) is a major structural component of the caveolae, which are specialized plasma membrane invaginations that are involved in multiple cellular processes, such as molecular transport, cell adhesion, and signal transduction [78, 84]. Cav-1 is expressed at relatively high levels in differentiated smooth muscle cells, pneumonocytes, chondrocytes, endothelial cells, adipocytes, and osteoblasts, in which it is associated with the acquisition and maintenance of specialized cell functions [29, 71, 80, 81]. Cav-1 exerts various biological functions through protein–protein interactions. Specific proteins, such as receptor tyrosine kinases, serine/threonine kinases, phospholipases, G protein-coupled receptors, and Src family kinases, are localized in lipid rafts and caveolar membranes, where they interact with Cav-1 through the Cav-1 scaffolding domain (CSD). CSD-mediated activities result in the generation of platforms for compartmentalization of discrete signaling events [64, 76].

The role of Cav-1 in tumorigenesis is complex and depends on the cell type and biological context. Under some conditions, Cav-1 may suppress tumorigenesis [103]. However, Cav-1 is associated with and contributes to malignant progression of multiple malignancies, including PCa [77, 93, 103]. Although the regulation of Cav-1 expression is complex, previous studies showed that Cav-1 expression is stimulated by testosterone and by multiple growth factors that are known to promote the development and progression of PCa [50, 52]. Cav-1 overexpression leads to promiscuous binding of Cav-1 to multiple signaling molecules in the cancer tyrosine-kinase regulatory network, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor α/β (PDGFRα/β), Src, protein phosphatase 1/protein phosphatase 2A (PP1/PP2A) (negative regulator of Akt), and Phospholipase C γ1 (PLCγ1) through CSD–CSD binding-site interactions [51, 87]. These interactions increase PCa cell survival [51]. In addition, Cav-1 overexpression in PCa cells leads to Akt-mediated up-regulation of multiple cancer-promoting growth factors, including VEGF, transforming growth factor β1 (TGF-β1), and fibroblast growth factor 2 (FGF2) [50].

A critically important characteristic of many androgen-insensitive PCa cell lines is secretion of biologically active Cav-1 protein. PCa cell-derived secreted Cav-1 can promote PCa-cell viability through antiapoptotic activities and clonal growth in vitro, similar to those observed following enforced expression of Cav-1 within the cells [5, 51, 89, 104]. A recent study showed that recombinant Cav-1 protein is taken up by PCa cells and endothelial cells in vitro and that recombinant Cav-1 increases angiogenic activities both in vitro and in vivo by activating Akt- and/or nitric oxide synthase (NOS)-mediated signaling [90]. Cav-1-stimulated autocrine and paracrine engagement of the local tumor microenvironment involve but are not likely to be limited to the pro-angiogenic activities previously documented. It is important to note that significantly higher serum Cav-1 levels have been documented in men with PCa cancer than in men with benign prostatic hyperplasia [88] and in patients with elevated risk of cancer recurrence after radical prostatectomy [86].

Similar to the local effects of tumor cell-derived secreted Cav-1, serum Cav-1 can promote metastasis at distant sites [96]. Therefore, the pervasive effects of intracellular and secreted Cav-1 constitute positive-feedback loop that promotes PCa progression through unprecedented effects on the tumor microenvironment and metastatic environment. This chapter is a brief discussion of the complex and context-dependent activities of Cav-1 and delineation of the oncogenic functions of Cav-1 in PCa.

Aberrant Cav-1 Expression: Complexity and Context

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 dimethylbenzanthracene [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.

Overexpression of Cav-1 in Prostate Cancer

In previous studies, we reported greater Cav-1 immunostaining in human PCa cells than in adjacent normal prostatic epithelial cells, which express low to undetectable levels of Cav-1 [108, 109]. We further showed that increased Cav-1 immunostaining had independent prognostic potential in men undergoing radical prostatectomy [109]. These results were supported by two subsequent independent reports that also immunohistochemically evaluated PCa tissue and yielded similar conclusions [30, 44]. An important common observation from the cases examined in these studies is that immunostaining of Cav-1 in localized PCa is focal and that it is expressed in only a relatively small percentage of PCa cells. These results also showed that the presence of Cav-1 correlated positively with Gleason grade, an important suggestion that even though it is focally expressed, Cav-1 is a biomarker for clinically aggressive disease.

The molecular basis for the initiation of Cav-1 expression in PCa and other malignancies is not clear. The Cav-1 and Cav-2 genes are colocalized at 7q31.1, a highly conserved region that encompasses a known fragile site that is deleted, associated with loss of heterozygosity, or amplified in various human cancers, including PCa [13, 24, 63, 103]. Although some investigators have used these data to support a case for both loss and gain of Cav-1 expression, no convincing data specifically correlate genetic alterations at this site with changes in Cav-1 expression for PCa [4, 36]. The Cav-1 gene promoter has multiple CpG sites, and alterations in gene methylation have been demonstrated in PCa [15]. However, patterns of Cav-1 gene methylation have not, thus far, provided a convincing argument for up-regulation of Cav-1 in PCa. It is interesting that the authors of a recent article suggest that loss of function for a tumor-suppressor microRNA (miR-205) may lead to up-regulation of Cav-1 in PCa [26].

Because many genetic alterations that occur in primary PCa have also been documented in premalignant disease such as high-grade prostatic intraepithelial neoplasia, it would be interesting to analyze Cav-1 in those premalignant lesions. Although it is focally expressed in primary PCa, it is important to note that Cav-1 is expressed in most metastatic cells [89]. This focal expression in primary PCa and significantly increased Cav-1 expression in associated metastases fits well with the notion that Cav-1 is more aligned with the criteria of a progression-related protein than with those of a protein that significantly affects localized tumor growth [92]. The idea of association of Cav-1 with clinically significant PCa is novel, and the prospect that Cav-1 expression may distinguish clinically significant PCa from clinically insignificant PCa is exciting [16].

Although the association between Cav-1 overexpression in PCa and aggressive, clinically significant disease has been found consistently in multiple studies, the relationship between Cav-1 overexpression and androgen sensitivity is less clear. Early studies showed that Cav-1 overexpression was inversely associated with androgen sensitivity and positively associated with tumor growth in mouse models of PCa [62]. The Cav-1 gene is transcriptionally up-regulated in androgen-sensitive PCa cells, although the level of induction was modest [52]. In general, Cav-1 has been associated with the stimulatory effects of steroid receptors, including the androgen receptor, suggesting a point of convergence for further mechanistic studies [57, 69]. Overall, the available information on Cav-1 expression fits the hypothesis that PCa progression, even in the presence of normal levels of circulating testosterone, is coincidental with the development of androgen insensitivity. Certainly, the development of CRPC involves selection for unique malignant properties that allow PCa cells to metastasize in the presence of castrate levels of androgens. However, the emergence of CRPC does not preclude coselection of metastatic and androgen-insensitive PCa in men who have not undergone hormone therapy.

Cav-1-Mediated Oncogenic Activities in Prostate Cancer

The results of numerous studies that demonstrated overexpression of Cav-1-specific malignancies have led many investigators to attempt to identify Cav-1-related oncogenic pathways. Although Cav-1 activities impinge on various oncogenic pathways and can inhibit or activate these pathways, depending on the cell type and context [103], the results of multiple studies now indicate that Akt activation plays an important role in Cav-1-mediated oncogenic functions in PCa. The first demonstration of a direct association between Cav-1 expression and Akt indicated that the overexpression of Cav-1 increased binding to and inhibited the serine/threonine protein phosphatases PP1 and PP2A in human PCa cells. These interactions, which were likely mediated through the binding of Cav-1 to a CSD-binding site on PP1 and PP2A and inhibition of their activities, led to significantly increased levels of phospho-Akt and sustained activation of downstream oncogenic Akt targets [51]. Findings from a recent independent study supported this mechanism and further showed that the putative oncogene inhibitor of differentiation-1 (ID-1) induced Akt activation by promoting the binding activity of Cav-1 and PP2A [111]. It is important to consider that activation of Akt has been previously associated with PCa and is clearly one of the most important oncogenic activities that underlie progression of the disease [49].

A recent study further showed that alterations in Akt activities regulate the expression of fatty acid synthase, a putative metabolic oncogene, and its colocalization with Cav-1 in lipid rafts in PCa cells [18]. The same article reported that Src, an oncogenic tyrosine kinase, plays an important role in this process. It is notable that Cav-1 was initially identified as a v-Src substrate, P-Y14-Cav-1 [28]. Overall, these recent articles have suggested that an interactive and interdependent network of oncogenic proteins, including Cav-1, Akt, fatty acid synthase, and Src, plays an important role in PCa.

We recently demonstrated that in addition to promotion and maintenance of Akt activities, induction of Cav-1 expression led to enhanced tyrosine kinase signaling, which involved increased basal and VEGF-stimulated phosphorylation of VEGFR2, PLCγ1, and Akt, in PCa cells [87]. We have also shown that in PCa cells, a positive-feedback loop is established in which VEGF, TGF-β1, and FGF2 up-regulate Cav-1 expression, which in turn leads to increased levels of VEGF, TGF-β1, and FGF2 mRNA and protein, resulting in enhanced invasive activities (migration, motility) of PCa cells [50]. In the same study, we found that Akt-mediated Cav-1-enhanced mRNA stability is a major mechanism for the up-regulation of these cancer-promoting growth factors. In particular, Cav-1-mediated up-regulation and secretion of growth factors may lead to cell–cell signaling that involves the recruitment and functional activation of cancer-associated stromal cells (Fig. 1.1).

Fig. 1.1
figure 1_1

Caveolin-1 (Cav-1)-growth factor (GF) positive-feedback system leads to prostate cancer (PCa) progression. GF-stimulated endogenous and secreted Cav-1 induces expression and secretion of GFs, which maintain Cav-1 expression and stimulate malignant activities both locally and at distant metastatic sites. T: Testosterone; TK: tyrosine kinase

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These oncogenic protein networks appear to be important pathways through which Cav-1 promotes malignant activities in PCa. The results of a recent study showed that cellular levels of P-Y14-Cav-1 are critically associated with Rho/ROCK and Src-dependent regulation of tumor cell motility and invasion [41]. These results demonstrate that there are multiple pathways through which overexpression of Cav-1 may promote progression of PCa and other malignancies.

Secretion of Cav-1 by Prostate Cancer Cells

Cav-1, which is secreted by mouse and human PCa cell lines, promotes cancer cell survival in vitro [89]. These results were validated in independent studies and extended to include perineural cells in the PCa microenvironment [3, 5]. At the time these results were reported, those from a previous study had shown that Cav-1 was secreted by normal pancreatic acinar cells in vitro [54] but, to our knowledge, there were no previous reports of the secretion of Cav-1 by malignant cells.

These results raised the question about the mechanism responsible for Cav-1 secretion from cancer cells and whether this mechanism was specific to PCa cells or the PCa microenvironment. An intriguing article reported that Cav-1 was found in “prostasomes,” which are vesicular organelles enriched with raft components, of PC-3 cells, suggesting that Cav-1 is secreted by PCa cells through a unique mechanism [55]. The results of a more recent study supported the concept that Cav-1 is secreted by PCa cells through a unique exosome–prostasome-mediated pathway [58]. More recently, Cav-1 was shown to be a major component of “oncosomes,” i.e., membrane-derived microvesicles secreted by cancer cells. Oncosome formation was stimulated by epidermal growth factor receptor stimulation and by overexpression of membrane-targeted Akt in PCa cells. It was further demonstrated that “oncosomes” that were shed from PCa cells contained signal-transduction proteins, including Cav-1, that are capable of activating phospho-tyrosine and Akt-signaling pathways [19].

Additional studies are warranted to further characterize the specificity and mechanism(s) involved in Cav-1 secretion by PCa cells and potentially by specific stromal cells within the PCa microenvironment. It will also be important to further investigate the mechanism(s) underlying the release of microvesicles, i.e., “prostasomes” and/or “oncosomes,” from PCa cells and their potential uptake by other cancer cells and PCa-associated stromal cells, vis-à-vis expression, secretion, and uptake of Cav-1.

Prostate Cancer-Derived Secreted Cav-1 Alters the Local Tumor Microenvironment

PCa is unique in its capacity to influence and become dependent on stromal cells that reside in the tumor microenvironment. Growth factors derived from PCa cells, including VEGF, TGF-β1, and multiple FGFs, are known to significantly affect, through autocrine and paracrine activities, the capacity of PCa cells to grow and metastasize [12, 47, 61, 72]. Various mechanisms are reportedly involved in the deregulation of these growth factors in cancer cells, including transcriptional regulation [42] and alteration of mRNA stability [11, 43, 82, 95].

We recently found, unexpectedly, that PCa-derived secreted Cav-1 is also capable of substantially altering the tumor microenvironment by stimulating angiogenesis. Specifically, Cav-1 is taken up by Cav-1-negative tumor cells and/or endothelial cells, leading to stimulation of specific angiogenic activities through the PI3K–Akt–eNOS signaling module [90]. This work followed a previous study that had found greater angiogenesis in Cav-1-positive PCa than in Cav-1-negative PCa and that also showed co-localization of Cav-1 with VEGFR2 in tumor-associated endothelial cells [106].

Recently we have extended these results in studies which demonstrated that treatment of PCa cells or endothelial cells with recombinant Cav-1 leads to induction of VEGF/VEGFR-mediated angiogenic signaling [87]. These angiogenic signaling activities likely play a central role in the positive-feedback loop that is established when VEGF, TGF-β1, and FGF2 up-regulate Cav-1 expression, which in turn leads to increased levels of VEGF, TGF-β1, and FGF2 mRNA and protein, resulting in enhanced invasive activities (migration, motility) of PCa cells [50]. It is notable that a common focal point of Cav-1 stimulated oncogenic signaling is activation of Akt. We have shown that Cav-1 can activate Akt through the binding of Cav-1 to a CSD-binding site on PP1 and PP2A and inhibition of their Akt-inhibitory activities [50]. We recently found that Akt-mediated Cav-1-enhanced mRNA stability is a major mechanism for the up-regulation of VEGF, TGF-β1, and FGF2 [50]. Clearly Akt activation is an important oncogenic target for endogenously expressed and secreted Cav-1 [50, 87, 90].

The combined action of PCa-derived secreted Cav-1 and its stimulation of growth factors and/or angiogenic cytokines could have a profound effect on the PCa microenvironment. Cav-1 uptake by and growth factor binding to tumor-associated stromal cells, including endothelial cells, could potentially result in structural modification of the preexisting signaling pathways through the interaction of Cav-1 with specific signaling molecules (Fig. 1.1).

Because many of the molecules involved in angiogenic signaling pathways possess CSD-binding sites, e.g., VEGFR2 and Src [14, 53, 64], these interactions are likely mediated in part through the CSD-binding site interface. To demonstrate the biologic effect of these activities, we recently showed that adult male PBcav-1 transgenic mice had significantly greater prostatic wet weight and a higher incidence of prostatic epithelial hyperplasia than did their nontransgenic littermates [96]. Prostatic tissues from the PBcav-1 transgenic mice, which also had greater Cav-1 secretory activities than did those from their nontransgenic littermates, also showed greater immunostaining for proliferative cell nuclear antigen and P-Akt, less nuclear p27Kip1 in hyperplastic lesions, and increased resistance to castration-induced prostate regression. An important note is that orthotopic prostatic injection of androgen-sensitive Cav-1-secreting RM-9 mouse PCa cells resulted in tumors that were significantly larger in PBcav-1 mice than they were in the nontransgenic littermates [96]. These results demonstrate that prostate cell-derived secreted Cav-1 can result in hyperplastic epithelial growth abnormalities and lead to a prostatic environment that permits PCa growth.

The expression and secretion of Cav-1 by PCa cells presents an opportunity for the development of Cav-1-based biomarkers for PCa. We previously developed an immunoassay for measuring serum Cav-1 levels and showed that the median serum Cav-1 level in men with clinically localized PCa was significantly higher than that in healthy control men (i.e., those with normal findings on digital rectal examination and serum prostate-specific antigen (PSA) levels of ≤1.5 ng mL−1 over a period of 2 years) and in men with clinical benign prostatic hyperplasia [88]. Further, in a larger population study in men with a serum PSA of >10 ng mL−1, high levels of Cav-1 in serum prior to treatment were associated with a shorter time to biochemical recurrence (defined as a serum PSA level of ≥ 0.2 ng mL−1 on two consecutive measurements) [86]. High pretreatment serum Cav-1 levels were established using a cutoff determined by using the minimum P value method.

These initial clinical and basic laboratory study results, together with those of pathology-based tissue analysis, demonstrate the potential of serum Cav-1 as a prognostic biomarker for identification of men with clinically aggressive PCa. Specifically, the pretreatment serum Cav-1 concentration may be used to identify men with clinically significant PCa who are likely to experience rapid recurrence of the cancer following radical prostatectomy. Although further studies are necessary to validate these results, it is conceivable that serum Cav-1 analysis would contribute to the identification of a subset of men undergoing localized therapy for presumed localized disease who would benefit from neoadjuvant or adjuvant therapy, e.g., local radiotherapy, localized biologic therapy, androgen-deprivation therapy, and/or targeted systemic therapy [2, 22, 67, 83].

Prostate Cancer-Derived Secreted Cav-1 Alters Metastatic Tumor Microenvironment

Generation of the PBcav-1 transgenic mouse gave us the opportunity to test the potential role of prostate epithelial cell-derived secreted Cav-1 in PCa metastasis. We demonstrated that male PBcav-1 mice had significantly greater serum Cav-1 levels than did their nontransgenic littermates [96]. Tail-vein inoculation of RM-9 mouse PCa cells produced significantly more experimental lung metastases in male PBcav-1 than in their nontransgenic littermates and in male Cav-1 +/+ mice than in male Cav-1 −/− mice [96]. Systemic treatment with anti-Cav-1 antibody dramatically reduced the number of experimental metastases, demonstrating prometastatic activities for PCa-derived secreted Cav-1 in this model system. These results further reveal the possibility that secreted Cav-1 is a therapeutic target for PCa. Because targeted systemic antibody therapy has been used successfully to treat specific malignancies [59, 97], the development of Cav-1-targeted antibody therapy should be further pursued as a potential therapy for PCa.

Summary

The initial observations that PCa cells overexpress Cav-1 and that Cav-1 is associated with clinically significant PCa have led to extensive basic laboratory and clinical studies of the role of Cav-1 in PCa and other malignancies. Although the molecular and cellular biology of Cav-1 is complex, the studies thus far have shown that the overexpression and secretion of Cav-1 leads to amplification of the tumor-promoting effects of Cav-1 through activation of endogenous oncogenic pathways and engagement of the tumor microenvironment. The remarkable capacity of Cav-1 to restructure and participate in PCa cell signaling and to stimulate expression of cancer-associated growth factors is a novel paradigm in oncogene research. Recent studies have extended our knowledge of the unique and unprecedented effects of PCa-derived secreted Cav-1 on the local and metastatic tumor microenvironments. According to study results that show Cav-1 as a component of “prostasomes” and/or “oncosomes,” it is important to better understand the relationships between membrane-mediated and “free” Cav-1 release and uptake by other PCa cells and by PCa-associated stromal cells, including endothelial cells. The association between Cav-1 and clinically significant PCa is unique, and the prospect that Cav-1 expression may differentiate clinically significant from clinically insignificant PCa is exciting. By virtue of the capacity of PCa cells to secrete Cav-1, specific Cav-1-based biomarkers and therapeutic strategies have been proposed and tested. The initial results are promising and indicate that further studies may lead to clinically useful prognostic and therapeutic tools for PCa.