Background >Prostate Specific Membrane Antigen (PSMA), a type II transmembrane metallo-peptidase highly overexpressed in prostate cancer cells has been studied as a targeting molecule in prostate cancer. Recently, it has been found to be also expressed in the neo-vasculature of multiple non-prostatic solid tumors. Because of its unique expression pattern limited to tumor-associated endothelial cells, PSMA may be an interesting molecule for vascular targeting. Here we investigated the protein expression and cellular distribution of PSMA in a large number of cases of colorectal cancer (CRC) and liver metastasis. >Methods >130 formalin-fixed paraffin-embedded tissue sections of patients with colorectal cancer and 18 samples of metastatic liver lesions of were immunostained with antibodies directed against PSMA and the pan-endothelial marker CD31. Immunoreactivity was scored semiquantitatively based on staining intensity and distribution. Using whole coding region spanning primers, mRNA expression of PSMA was further determined in colorectal cancer and normal mucosa biopsy material. To test the tumor-specificity of PSMA expression, inflammatory bowel disease (IBD), psoriasis and granulation tissue, all know to be associated with neo-angiogenesis as well as normal colon mucosa were evaluated for PSMA expression. Confocal-immuno-fluorescence microscopy was used to determine the expression pattern of CD31 and PSMA in tumor associated vessels. >Results >High endothelial PSMA expression was observed in tumor-associated neo-vasculature of 94 of 130 CRC samples (72 %). 15 of 18 liver metastasis (83%) were positive for PSMA. Interestingly, tumor adjacent vasculature, normal colorectal mucosa as well as inflammatory bowel disease and psoriasis showed no PSMA expression. Confocal-immuno-fluorescence microscopy revealed co-expression of CD31 and PSMA in the majority of tumor-associated endothelial cells. A subpopulation of PSMA positive vessel-lining-cells however, did not show CD31 staining. In addition, 15 (12%) colorectal cancer samples showed strong epithelial PSMA expression. >There was a trend for high grade tumors to higher PSMA expression (Spearman r = 0.18, P = 0.046) and men generally had higher PSMA level than women (Spearman r = 0.23, P = 0.009). No statistically significant association between PSMA expression and overall survival was observed (P = 0.375). >Conclusion >This study gives new insights in PSMA expression pattern in colorectal cancer. Because of its highly tumorspecific expression and its accessibility to antibody based therapies, PSMA represents an excellent target for anti-angiogenic therapy in colorectal cancers. The potential of an anti-PSMA directed therapy warrants testing in clinical trials.
Sixth AACR International Conference on Frontiers in Cancer Prevention Research-- Dec 5-8, 2007; Philadelphia, PA