Altered mechanisms of apoptosis in colon cancer: Fas resistance and counterattack in the tumor-immune conflict.
Fas (CD95/APO-1) is a cell surface "death receptor" that mediates apoptosis upon engagement by its ligand, FasL. Fas-mediated apoptosis of lymphocytes normally serves immunoregulatory roles, including tolerance acquisition, immune response termination, and maintenance of immune privilege in certain organs. Colon tumors can exploit this lymphocyte death program by expressing FasL. This may enable colon tumors to mount a "Fas counterattack" against antitumor lymphocytes, impairing antitumor immune responses. FasL-expressing colon tumor-derived cell lines can trigger Fas-mediated apoptosis of cocultured T cells in vitro. FasL expressed in esophageal cancer has been significantly associated with apoptosis and depletion of tumor-infiltrating lymphocytes (TIL) in vivo. FasL may also facilitate metastatic colonization of Fas-sensitive organs such as the liver, by inducing apoptosis of target organ cells. Normal colonic epithelial cells express Fas and are relatively sensitive to Fas-mediated apoptosis. By contrast, colon tumor-derived cell lines are usually resistant to induction of Fas-mediated apoptosis, and colon cancer cells frequently coexpress Fas and FasL. The mechanisms allowing resistance to Fas-mediated apoptosis are complex, and defects have been identified at several levels of Fas signal transduction. The "Bcl-2 rheostat" may be pitched against apoptosis in colon cancer, inasmuch as overexpression of Bcl-2, downregulation of Bak, and mutation of Bax are common defects in colon tumors. Caspase-1 is also downregulated in colon cancer. The high frequency of p53 mutations in late-stage cancers may also inhibit Fas signaling. Fundamental defects in apoptosis signaling may contribute to both immuno- and chemoresistance in colon cancer and allow expression of FasL to counterattack antitumor lymphocytes.
Department of Medicine, National University of Ireland, Cork, Ireland. j.oconnell@ucc.ie
J
J
O'Connell
M W
MW
Bennett
K
K
Nally
A
A
Houston
G C
GC
O'Sullivan
F
F
Shanahan
D017209:Apoptosis / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology*; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D019014:fas Receptor / Q000276:immunology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor