Abstract 1982P
Background
Colorectal cancer (CRC) ranks third in most common diagnosed cancer, and second in cancer-related deaths globally. Novel therapies have shown higher specificity and efficacy in different tumors, but in CCR conventional chemotherapy is still needed and resistance events are often an issue. Cancer-associated fibroblasts (CAFs) are involved in extracellular matrix (ECM) synthesis and remodelling. We propose CAF-Snai1 expression as a potential biomarker to identify a group of patients that could present resistance to treatment by differential composition of the ECM in tumor. The aim of the study is to test chemoresistance of cancer cell lines seeded either on matrices generated by CAFs, with different levels of Snai1 expression; normal fibroblasts (NFs); or fibroblasts knock-out for Snai1 gene.
Methods
Fresh colon tissue samples were obtained from patients operated at Hospital Ramón y Cajal. Primary NFs and CAFs were obtained from tissue as previously described by our group (Herrera et al., 2016). Colon tissue was obtained immediately after surgery, and processed within 24 hours. ECM were generated with wild-type Mouse Embryonic Fibroblasts (MEF), Snai1 knock-out MEFs and primary NFs and CAFs (Herrera et al., 2018). Survival of drug-treated tumor cells seeded on ECM was tested by fluorescence, after 48 h culture.
Results
Our data shown that ECM confer chemoresistance effect when treating tumor cells with oxaliplatin or cetuximab. Moreover, matrices generated by Snai1 KO MEFs confer less resistance than wild-type MEFs derived matrices. It has also been observed that matrices derived from CAFs induce higher survival to colon cancer cells than NFs derived matrices. Accordingly, survival conferred by CAF-derived matrices is related to Snai1 expression levels.
Conclusions
Variations in matrices generation results in different chemoresistance of seeded tumor cell lines. Matrices derived by CAFs and NFs confer different levels of resistance when oxaliplatin or cetuximab are added to cell culture. Preliminarily, we have observed that this chemoresistance is associated to fibroblast-Snai1 expression levels. For a better understanding of this mechanism, drug-related gene expression of tumor cells will be analysed.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Instituto de Salud Carlos III, CIBERONC, AECC.
Disclosure
All authors have declared no conflicts of interest.