In vivo promotion of human epithelial tumor growth mediated by Pa3-expressing fibroblasts

Abstract

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In cancer, alterations in the stroma that follow the malignant change of epithelial cells help drive cancer cell invasion and metastasis. Using DNA array technology, we identified a type Ia integral membrane protein (Pa3) whose mRNA is selectively upregulated in cancer-associated stroma. Antibodies generated against Pa3 demonstrate that Pa3 is selectively expressed by tumor stromal fibroblasts in various epithelial carcinomas, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. Experiments indicate that Pa3 can be clipped and shed from the cell surface of Pa3-transfected cells and that a Pa3-Fc fusion protein can bind specifically to certain cancer cell lines, including MDA-MB-468. However, the biological function of Pa3 in the tumor microenvironment is unknown. To address this issue, murine fibroblasts (3T12) transfected with human Pa3 were xenografted into SCID mice together with MDA-MB-468 breast cancer cells. The presence of 3T12- Pa3 cells dramatically increased the development of subcutaneous tumors and showed an enhancement of tumor growth compared to mock or parental 3T12 cells. These data demonstrate the ability of Pa3 to potentiate tumor growth in an animal model and suggest a possible therapeutic role for functional inhibition of Pa3 activity.