Abstract #1125: Fibroblast activation protein (FAP) as a mediator of TGF-\#946; activation
Authors: W. Brennen, Samuel Denmeade
Journal: Cancer Research (2009)

Tumors are dependent upon the reactive stroma for nutritional support, survival and growth signals necessary for maintenance of the primary mass. The stroma has been shown to not only contribute to, but potentially drive, the progression of cancerous cells into a metastatic phenotype. The stroma recruits reactive fibroblasts & macrophages, increases secretion of growth factors and proteases, induces angiogenesis, as well as, produces an altered extracellular matrix (ECM) when associated with a transformed epithelium. Fibroblasts, in particular, have been shown to consistently undergo several changes in both morphology and expression profiles when present in the tumor microenvironment. One defining characteristic of these carcinoma-associated fibroblasts, or myofibroblasts, is the expression of fibroblast activation protein-alpha (FAP). FAP is a membrane-bound serine protease that has both dipeptidase and gelatinase activity. FAP has been shown to be selectively expressed on myofibroblasts in the stroma surrounding >90% of epithelial cancers examined, with minimal to no expression in either cancerous epithelial or adjacent normal tissues. FAP has been implicated in tumor promotion through studies demonstrating increases in tumor incidence, growth, and microvessel density using in vivo models. In contrast, other studies have shown that expression of FAP decreased tumorigenicity suggesting that the physiologic response to FAP may be context dependent. Recently it was found that FAP\#8217;s extracellular region was homologous to Antiplasmin Cleaving Enzyme (APCE), which is present in plasma and slows fibrinolysis. Moreover, FAP expression has been found in multiple sites undergoing wound healing and tissue remodeling, in addition to, sites of chronic damage including arthritic joints and fibrotic tissue. These studies demonstrate a more generalized expression pattern of FAP localized to the stromal compartment of many tissues displaying injury or disease could lead one to conclude that FAP has a more significant physiologic role in the wound response than has previously been documented. This line of thought together with the seemingly dichotomous roles FAP plays in tumor progression is reminiscent of TGF-\#946; function. We present evidence that FAP releases TGF-\#946; sequestered in the ECM by cleaving the large latent complex in the protease-accessible hinge region. This liberation was evaluated in part through the cleavage of peptides designed from LTBP1-4. The role of TGF-\#946; initially as a tumor suppressor and later as a promoter has been well documented. Given that TGF-\#946; is also known to regulate the conversion of fibroblasts to the FAP-positive myofibroblast phenotype raises the possibility of a positive feedback loop. Myofibroblasts are known to play critical roles not only in inflammation and repair, but have been implicated in tumor progression of several malignancies, including cancers of the breast and prostate.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1125.