Human and mouse colon cancer utilizes CD95 signaling for local growth and metastatic spread to liver.
OBJECTIVE
Analysis of clinical colon cancer specimens show alterations in the CD95 (Fas Ag/Fas L) pathway as tumors progress from local to metastatic disease, suggesting that this pathway may play a role in invasive behavior of colon cancer. However, direct causality between these alterations and clinical disease progression has not been shown.


METHODS
Surgically resected metastatic colon cancer samples were evaluated for Fas Ag/L and apoptosis. Alterations in the Fas-signaling pathway found in human samples were recreated through a series of staged transfection experiments in the MC38 mouse colon cancer cell line and the effects on growth tested in vitro and in vivo.


RESULTS
Expression of FLICE-like inhibitory protein confers apoptosis resistance, increasing the incidence of primary tumors through a survival advantage by avoiding apoptosis and inducing Fas-mediated proliferation. Coexpression of Fas L enables colon cancer cells to metastasize to the liver from local tumors as well as from intravenous injection of cells. MC38-FasL/FLICE-like inhibitory protein colon cancer cells induce apoptosis in hepatocytes via activation of type II Fas Ag signaling, thus creating a niche conducive to tumor growth and fueling their own growth via Fas proliferative signaling.


CONCLUSIONS
Alterations in the Fas Ag pathway which inhibit apoptosis and increase Fas-mediated proliferation directly increase local colon cancer growth, and enhance metastasis to the liver. Delineating points in the pathway responsible for growth and metastasis will offer targets that may be exploited for therapy.
Li
Hanchen
H
Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01635, USA.
Fan
Xueli
X
Stoicov
Calin
C
Liu
Jian Hua
JH
Zubair
Sharif
S
Tsai
Elena
E
Ste Marie
Ronald
R
Wang
Timothy C
TC
Lyle
Stephen
S
Kurt-Jones
Evelyn
E
Houghton
Jeanmarie
J
D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; D019014:fas Receptor