Abstract A66: Galectin-1 expression correlated with mesenchymal differentiation and resistance to chemotherapy in carcinoma cells

Abstract

Abstract Background: Galectin-1, a multifunctional lectin regulating various aspects of tumorigenesis such cell migration and invasiveness, has been involved in cancer cells chemoresistance and in metastasis induction. Epithelial-to-mesenchymal transition (EMT) also allows carcinoma cells to acquire invasive properties and resistance to chemotherapy. The aim of the study is to evaluate galectin-1 and EMT markers as predictive biomarkers of chemoresistance in human cancer. Material and Methods: The antiproliferative effects (IC50) of 5-fluorouracil and docetaxel were evaluated by MTT assay and mRNA expressions of galectin-1, vimentin, N-cadherin, SNAIL, SLUG, ZEB1, TWIST, E-cadherin, claudin-4, keratin-8 and -18 by qRT-PCR in a panel of 11 human cancer cell lines. Galectin-1, vimentin, E-cadherin protein expressions were analyzed by immunohistochemistry in tumor biopsies (prior to chemotherapy) from patients with locally advanced pharyngolaryngeal carcinomas subsequently treated with an induction chemotherapy combining cisplatin, 5fluorouracil, and docetaxel as part of an organ preservation program. Protein expressions was quantified in responders (>50% reduction in tumor size on CT-scan or MRI) and compared to non-responders (<50% reduction in tumor size on CT-scan or MRI) to chemotherapy. Results: In our panel of human cancer cells, mRNA expression of galectin-1 was correlated with resistance to docetaxel (R2=0.617, p-value=0.04). Higher mRNA expression of galectin-1 was also correlated with higher expression of mesenchymal marker vimentin (R2=0.308, p-value=0.02) and lower expression of epithelial markers such as E-cadherin (R2=0.461, p-value=0.02), keratin-8 (R2=0.493, p-value=0.02) and keratin-18 (R2=0.382, p-value=0.04). Cancer cells displaying higher mRNA levels of mesenchymal markers such as vimentin, N-cadherin, SNAIL, ZEB1, and TWIST and lower levels of epithelial markers as E-cadherin, claudin-4 and keratin-8 and -18 were more resistant to 5-fluorouracil and docetaxel. Galectin-1, vimentin and E-cadherin protein-expressions were evaluated in biopsies patients with squamous cell carcinoma prior to chemotherapy. Galectin-1 positive staining was more frequently observed in non-responder compared to responder patients. Interestingly, galectin-1 was preferentially expressed in the nucleus of cancer cells in responders whereas in non-responders, galectin-1 was mainly found in the stroma. Resistance to chemotherapy was also more frequently observed in tumors with mesenchymal differentiation. A decreased E-cadherin and an increased vimentin expression were observed in non-responder compared to responder patients (p<0.05). Conclusion: High galectin-1 expression correlated with EMT differentiation of cancer cells and was associated with resistance to several cytotoxic agents. Targeting galectin-1 should be evaluated to counteract resistance to chemotherapies.