An absence of stromal caveolin-1 is associated with advanced prostate cancer, metastatic disease and epithelial Akt activation

Abstract

Here, we examined the status of stromal Cav-1 expression in patients with benign prostatic hypertrophy (BPH), primary prostate cancers (PCa), and prostate-cancer metastases (Mets). Interestingly, an absence of stromal Cav-1 directly correlated with prostate cancer disease progression. For example, virtually all BPH samples showed abundant stromal Cav-1 immunostaining. In contrast, in a subset of patients with primary prostate cancer, the stromal levels of Cav-1 were significantly decreased, and this correlated with a high Gleason score, indicative of a worse prognosis and poor clinical outcome. Remarkably, all metastatic tumors (either from lymph node or bone) were completely negative for stromal Cav-1 staining. Thus, stromal Cav-1 expression may be considered as a new biomarker of prostate cancer disease progression and metastasis. Mechanistically, stromal Cav-1 levels were inversely correlated with the epithelial expression levels of Cav-1 and epithelial phospho-Akt. Thus, loss of stromal Cav-1 is predictive of elevated levels of epithelial Cav-1 and epithelial Akt-activation. This provides important new clinical evidence for paracrine signaling between prostate cancer epithelial cells and the tumor stromal micro-environment, especially related to disease progression and metastasis.

Figure 1

Expression of stromal Cav-1 in benign, primary prostate cancers and metastatic tumor samples. Two images are shown for each diagnostic category. Note that benign prostate samples abundantly express stromal Cav-1. Primary prostate cancers showed differential expression of stromal Cav-1, with either high (left), moderate (not shown), or absent/low expression (right). Finally, metastatic tumor samples [either from lymph node (at left) or bone (at right)] showed an absence of stromal Cav-1 staining. Note that in all cases, the vasculature remained Cav-1 positive. Arrowheads point at the tumor stroma in all six panels.

Figure 2

Stromal Cav-1 inversely correlates with epithelial Akt activation and epithelial Cav-1 overexpression in advanced prostate cancer and metastasis. Data presented in Table 3 (A) and Table 4 (B) are plotted here graphically. Only patients with positive expression are shown. For simplicity, primary prostate cancers and metastastic tumors are plotted as one group as “Tumors”, versus “Benign” lesions. In (A), Cav-1 refers to stromal Cav-1. In (B), E denotes epithelial, and S denotes stromal staining. Asterisks denote statistical significance.