FasL is more frequently expressed in liver metastases of colorectal cancer than in matched primary carcinomas

Abstract

Summary Colorectal carcinoma cells have recently been shown to express Fas ligand (FasL). This ligand could allow the tumour cells to evade activated tumour-infiltrating lymphocytes (TILs) by inducing their apoptosis and would thus promote tumour survival and possibly metastasis formation. To test this hypothesis in vivo we analysed the expression of FasL mRNA and protein in paired tissue samples of normal colonic mucosa (N), primary colorectal carcinomas (T) and their metastases (M) from a total of 21 patients by four different methods. Additionally, the presence and activation status of infiltrating lymphocytes, which might contribute to the total amount of FasL in the tissue, was determined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) in the same samples. The frequency of FasL detection was 30-40% in T and was 60-100% in M, depending on the sensitivity of the method. Simultaneously, the amount of CD25 mRNA, used as a measure of the number of activated TILs, was in 90% of patients lower in M than in T. The increased frequency of FasL detection in liver metastases was therefore not due to the presence of activated TILs. We conclude that metastasizing subpopulations of colorectal tumour cells express FasL more frequently than the primary carcinomas and may be able to eliminate activated TILs in vivo via Fas/FasLinduced apoptosis or other hitherto unknown mechanisms.

Tumour-induced apoptosis in human mesothelial cells: a mechanism of peritoneal invasion by Fas Ligand/Fas interaction

“…This has been previously documented in the SW480 cell line in addition to other carcinoma cell lines (Shiraki et al, 1997;Mann et al, 1998;O'Connell et al, 1998). Importantly, we have also shown that human mesothelial cells constitutively express cell-surface Fas, a previously undocumented finding, and that the mesothelial Fas receptor is functionally active.…”

“…FasL, although primarily expressed in cells of lymphoid lineage (Suda et al, 1993) and in immune privileged sites (Bellgrau et al, 1995), has also been shown to be expressed by a number of carcinomas, including colorectal (Shiraki et al, 1997), hepatocellular (Strand et al, 1996) and lung (Niehans et al, 1997). Furthermore, FasL is more frequently expressed in colorectal liver metastases than in matched primary carcinomas (Mann et al, 1998). The expression of FasL would therefore appear to confer a selective advantage to metastasising tumour cells.…”

Prostaglandin E2 stimulates Fas ligand expression via the EP1 receptor in colon cancer cells

“…Studies performed in vitro, as well as evidence from numerous in situ examinations, indicate that tumour-expressed FasL is associated with apoptosis of TIL and may thus protect tumour cells from destruction by the immune system Whiteside, 2007). Tumourexpressed FasL has also been shown to be associated with metastasis of tumour cells to the lymph nodes and liver (Mann et al, 1999;Younes et al, 2000), whereas ligation of Fas by FasL can stimulate cell proliferation (Lambert et al, 2003;Li et al, 2008), and increase tumour cell motility and invasiveness (Barnhart et al, 2004;Peter et al, 2007). Furthermore, recent studies suggest that tumour-expressed FasL may contribute to tumour growth in cancers associated with inflammation, in part through the induction of chemotactic factors (Matsumoto et al, 2007).…”

“…Also recent studies characterising EP receptor expression in a variety of tumour types showed that expression of EP1 is increased in tumour cells relative to normal tissue (Shoji et al, 2004;Miyata et al, 2006;Rask et al, 2006) and is associated with tumour progression and metastasis in prostate cancer (Miyata et al, 2006). Similarly, FasL expression has been shown to be upregulated in tumour cells relative to normal tissue and is associated with tumour progression and metastasis (Mann et al, 1999;Osaki et al, 2001;Belluco et al, 2002). As inhibition of FasL expression in colon cancer cells significantly retards tumour formation in mice (Ryan et al, 2005), these findings suggest that targeting the EP1 receptor may help to prevent or treat colon cancer, in part through preventing FasL upregulation in tumour cells.…”

Prognostic impact of FAS/CD95/APO-1 in urothelial cancers: decreased expression of Fas is associated with disease progression

“…Principally, FasL-bearing tumour cells can induce Fasmediated apoptosis of antitumour lymphocytes bearing Fas, which is known as the Fas -FasL tumour counterattack theory (O'Connel et al, 1996). The validity of the Fas -FasL counterattack theory has been studied in several malignancies, and FasL expression could be a negative prognostic factor, such as in colorectal cancer (Mann et al, 1999;Okada et al, 2000). Second, decoy receptor 3 (DcR3) (TR6, M68), a decoy receptor for FasL, can play an important role in various cancers (Pitti et al, 1998;Roth et al, 2001).…”