Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model.
Fibroblast activation protein (FAP) is a type II integral membrane glycoprotein belonging to the serine protease family. Human FAP is selectively expressed by tumor stromal fibroblasts in epithelial carcinomas, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. FAP has been shown to have both in vitro dipeptidyl peptidase and collagenase activity, but its biological function in the tumor microenvironment is unknown. The modeled structure of murine FAP consists of a short cytoplasmic tail, a single hydrophobic transmembrane region, and a large extracellular domain. A seven-bladed beta-propeller domain is situated on top of the catalytic triad and may serve as a "gate" to selectively filter protein access to the catalytic site. HEK293 cells transfected to constitutively express murine FAP, when xenografted into scid mice, were 2-4 times more likely to develop s.c. tumors and showed a 10-40-fold enhancement of tumor growth compared with mock-transfected HEK293 cells. Rabbits immunized with recombinant murine FAP developed polyclonal anti-FAP antibodies that significantly inhibited murine FAP dipeptidyl peptidase activity in vitro. HT-29 xenografts treated with these inhibitory anti-FAP antisera exhibited attenuated growth compared with tumors treated with preimmunization rabbit antisera. These data demonstrate the ability of FAP to potentiate tumor growth in an animal model. Moreover, tumor growth is attenuated by antibodies that inhibit the proteolytic activity of FAP. These findings suggest a possible therapeutic role for functional inhibition of FAP activity.
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. j_cheng@fccc.edu
Jonathan D
JD
Cheng
Roland L
RL
Dunbrack
Matthildi
M
Valianou
André
A
Rogatko
R Katherine
RK
Alpaugh
Louis M
LM
Weiner
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002455:Cell Division / Q000502:physiology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D010450:Endopeptidases; D018093:Gelatinases; D006133:Growth Substances / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D019073:HT29 Cells / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000099167:Fibroblast Activation Protein Alpha
D000906:Antibodies; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D010450:Endopeptidases; D018093:Gelatinases; D006133:Growth Substances; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha