FAS/FAS Ligand Ratio: A Marker of Oxaliplatin-Based Intrinsic and Acquired Resistance in Advanced Colorectal Cancer

Abstract

Purpose: Oxaliplatin-5-fluorouracil combinations have increased responses in first-line therapy up to 40% in advanced colorectal cancer. Unfortunately, those patients who will respond are unknown and initially sensitive patients become rapidly resistant to current therapies. FAS (CD95) and FAS ligand (FASL; CD95L) have been implicated in chemosensitivity through leading to apoptosis in response to DNA-damaging drugs.Whereas the proapoptotic role of FAS and FASL is well characterized, the function of their soluble forms as predictors of chemosensitivity remains unknown. Patients and Methods: Blood samples were obtained from 68 patients with advanced colorectal cancer who received oxaliplatin-5-fluorouracil combinations in first-line therapy. Computed tomographic scans were done every 3 months and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. ELISA soluble FAS and soluble FASL analysis were done before treatment and every 3 months until disease progression. Ratios between soluble FAS and soluble FASL were established and its values and variations through time were related to treatment responses. Results: We found a significant increase in soluble FAS levels and a significant decrease in FASL at 3 months compared with baseline (13.2 versus 10.02 ng/mL; P = 0.0001; 0.07 versus 0.14 ng/mL; P = 0.007, respectively). A significant increase in the soluble FASL levels up to 9 months (fourth to fifth extractions; 0.26 ng/mL) of therapy compared with first to third extractions (0.11ng/mL; P = 0.003) was also found. A random effect regression statistical model determined that >1.2-fold increase in soluble FAS/soluble FASL ratio was a marker of chemosensitivity (P = 0.001). Conclusions: These data strongly indicate that an increment of soluble FAS/soluble FASL ratio after treatment could be an excellent marker of chemosensitivity in colorectal cancer. On the other hand, a decreased ratio after treatment can be a predictor of chemoresistance despite an initial response.Colorectal cancer is the most common cancer in western Europe, with f70 new cases a year per 100,000 inhabitants. In spite of advances in screening, 15% to 20% of patients show initially advanced disease, and 30% to 50% are destined to metastasize. Recently, oxaliplatin/5-fluorouracil (5-FU)/leucovorin or irinotecan-5-FU/leucovorin have increased responses in first-line therapy up to 40%, with median survival between 16 and 20 months, but 2-year overall survival still remains <20% (1, 2). Unfortunately, those patients who will benefit from first-line chemotherapy are unknown. Furthermore, the initially sensitive patients become rapidly resistant to current therapies.The FAS (CD95) receptor is a cell surface protein that mediates apoptotic cell death on triggering by FAS ligand (FASL). This interaction causes FAS receptor homo-oligomerization and this leads to activation of the caspase cascade (apoptotic extrinsic pathway). A FASL-independent activation of the FAS receptor has also been described (3).Whereas proapopt...

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

“…Moreover, in another study, specific cleavage of Fas by MMP-7 resulted in decreased sensitivity of HT-29 colon carcinoma cells to Fas-mediated apoptosis. 43 In the same study, the authors found a markedly increased susceptibility of these cells to Fas-mediated apoptosis when their MMP-7 expression was suppressed by transient transfection of the antisense oligonucleotide for this proteinase. There is then a strong suggestion that increased levels of MMP-7 are associated with the development of refractoriness to chemotherapy agents.…”

“…Our group and others, have demonstrated that MMP-7 blocks lymphocyte cytotoxicity, by cleaving of the NH 2 -terminal ''preligand assembly domain'' of FAS membrane (FASm) 41 and the extracellular surface of FASL membrane (FASLm) 17 leading to a decreased sFAS/sFASL ratio, 42 and therefore escaping from the immune system and favoring resistance to chemotherapy. Recently, Wang et al 43 have demonstrated that MMP-7 increases resistance to Fas-mediated apoptosis and, the authors conclude that high MMP-7 tissue expression is a poor prognostic factor of patients with CRC. Vargo-Gogola et al 44 have determined that FASL cleavage from the cell surface by MMP-7 provides apoptosis resistance and subsequently leads to tumor formation in murine mammary glands.…”

“…There is then a strong suggestion that increased levels of MMP-7 are associated with the development of refractoriness to chemotherapy agents. Although, this issue requires further clinical validation, in vitro and in vivo studies 43,44 are highly suggestive of this association which has great clinical implications.…”

Targeted therapy of cancer: new roles for pathologists in colorectal cancer

“…28,40,41 Increment in the ratio of soluble FAS to FAS ligand/CD95 by enzyme-linked immunosorbent assay in blood after treatment with oxaliplatin and 5-FU combination chemotherapy has been reported as a marker of chemosensitivity in advanced colorectal cancer patients, and decreased ratio as a predictor of chemoresistance. 42 It seems likely that the finding is a generic effect for platinum agents, rather than specific to oxaliplatin. Favorable germline genotypes from polymorphisms in XPD-751, ERCC1-188, GSTP1-105, and TS-3 0 -untranslated region have also been associated with improved survival in this setting.…”

The effect of bevacizumab on serum soluble FAS/FASL and TRAIL and its receptors (DR4 and DR5) in metastatic colorectal cancer

“…The role of FAS/FASL and TRAIL systems in CRC patients treated with chemotherapeutic agents was discussed in some reported studies (Nadal et al 2005;van Geelen et al 2006;Granci et al 2008). To the best of our knowledge, the changes in the levels of these markers in MCRC patients treated with bevacizumab-based regimens have not been described yet.…”