Tumor fibroblasts actively participate in cancer progression by synthesizing and regulating the activation of a wide range of proteases, growth factors, and adhesion molecules, thereby playing a crucial role in the tumor microenvironment. The objective of this project is to better understand how tumor stromal fibroblasts contribute to tumor growth, invasion, and metastasis by expressing fibroblast activation protein (FAP). FAP is unique in its selective expression by tumor stromal fibroblasts in epithelial carcinomas, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. Although FAP is expressed on tumor stromal fibroblasts in over 90% of epithelial carcinomas, its biologic function in the tumor microenvironment is unknown. FAP has in vitro dipeptidyl peptidase and collagenase activities, but its natural substrates and mechanistic pathways by which it potentiates tumor growth are unknown. The specificity of FAP expression in the tumor stroma provides a unique opportunity to investigate stromal contributions to tumor growth and invasion.
To investigate its function, we have studied the biologic effects of FAP expression in a number of animal models. We have shown that the overexpression of murine FAP potentiates tumor growth in a murine model of human epithelial cancers, and that inactivation of the enzymatic activity of FAP by mutation of the catalytic site obviates this FAP-driven tumor growth. In addition we have shown that antibodies and small molecules that inhibit the serine protease activity of FAP attenuate tumor growth in a colorectal cancer model that induces FAP expression by tumor-associated fibroblasts. These findings suggest that the enzymatic activity of FAP is pivotal for FAP-induced tumor growth, and can be exploited as a therapeutic target. We have recently initiated a phase II clinical trial of a small molecule inhibitor of FAP enzymatic activity in patients with metastatic colorectal cancer. Current activities are aimed at understanding the biologic significance of FAP which include identifying natural substrates and transcriptional factors of FAP to gain a better understanding of its mechanisms of tumor growth promotion. Better understanding of these tumor-host interactions will permit the development of novel therapeutic interventions aimed at disrupting the tumor-stromal interface.