Stromal aminopeptidase N expression: correlation with angiogenesis in non-small-cell lung cancer.

PURPOSE: Aminopeptidase-N (APN) is a membranebound protein that acts as a zinc-binding protease and participates in extracellular proteolysis. APN plays important roles in tumor progression through promoting invasion and metastasis, prolonging survival of tumor cells, and tumor angiogenesis. METHODS: We evaluated APN expression in non-small-cell lung cancer patients by immunohistochemistry. RESULTS: Of the 95 patients reviewed in the present study, 9 (9.5%), all with adenocarcinoma (Ad), showed positive APN expression on the tumors' cells. In all, 31 (32.6%) and 19 (20.0%) patients showed positive APN expression on the tumors' stromal cells (fibroblasts) and microvessels, respectively. APN expression on the tumors' stromal cells was more frequently observed in squamous cell carcinoma patients than in adenocarcinoma patients (P = 0.005). The mean microvessel density (MVD) for APNpositive tumor stromal cells was 59.9, which was significantly higher than that for APN-negative tumor stromal cells (mean MVD 27.4; P = 0.001). The 5-year survival rates for APN-positive and APN-negative tumor stromal cells were 66.0% and 69.8%, respectively, showing no difference in patient survival according to APN status on the tumors' stromal cells. CONCLUSION: That APN expression on stromal cells was observed predominantly in squamous cell carcinoma may account for the efficacy of ubenimex in the postoperative adjuvant setting for squamous cell carcinoma.

MDA-7/IL-24-based cancer gene therapy: translation from the laboratory to the clinic.

Despite recent advances in treatment strategies, the overall 5-year survival rate for patients with common epithelial cancers is poor largely because of the difficulty in treating metastatic cancers. Therefore, therapeutic agents are urgently needed that can effectively inhibit both primary epithelial tumors and their metastases. One such agent that has shown promise in preclinical studies is the tumor suppressor/cytokine, melanoma differentiation associated gene-7 also known as interleukin-24 (mda-7/IL-24). Preclinical studies from our and other laboratories have shown that overexpression of MDA-7/IL-24 causes a strong tumor- suppressive effect in many human cancer cells but spares normal cells. This gene therapy also enhances the tumor-suppressive activity of radiotherapy and chemotherapy. Secreted MDA-7 protein that is glycosylated also has been shown to have potent antiangiogenic activity both in vitro and in vivo. Studies examining the immune properties of mda-7 have shown that MDA-7/IL-24 unlike the related IL-10, functions as a Th1 cytokine. Recently, an MDA-7 protein-mediated "bystander effect" on tumor cells has been documented. Building on these findings we successfully completed a Phase I clinical trial of adenovirus-based mda-7 cancer therapy that confirmed the safety of this gene therapy. Phase II trials evaluating the efficacy of mda-7-based gene therapy are warranted. The outcome of such ongoing mda-7-based gene therapy trials will allow us to better understand this therapy's clinical utility.