Stromal extracellular matrix reduces chemotherapy-induced apoptosis in colon cancer cell lines

Several studies have shown that extracellular matrix reduces chemotherapeutic drugs-induced apoptosis in small cell lung cancer cells, myelomas and gliomas. We have investigated the protective effect of defined extracellular matrix components and of extracellular matrix from different cell types (fibroblasts, hepatocytes and intestinal epithelial cells) on the toxicity of three types of chemotherapeutic drugs on colon cancer cells. Human colon cancer cell lines LS174T and LiM6 were plated on plastic, on hepatocyte-derived ECM or on stromal ECM and in the presence of the antimetabolite 5-fluorouracil (5-FU). the topoisomerase I inhibitor camptothecin and the topoisomerase II inhibitor etoposide. We determined IC50 for the drugs for each of these culture conditions. We also determined the expression of the anti-apoptotic proteins bcl-2 and bcl-x (L) under these culture conditions. We found that stromal ECM protected LiM6 cells from the toxicity of etoposide and LS174T, but not LiM6 cells, from the toxicity of camptothecin. Collagen 1, fibronectin and fibroblast-derived ECM rendered LiM6 cells, but not LS174T, more sensitive to the harmful effect of 5-FU. Both colon cell lines had increased expression of anti-apoptotic proteins bcl-2 and bcl-x(L) when cultured on the various ECMs and with the drugs, but there was no correlation between a protective ECM effect and expression of the anti-apoptotic proteins. Stromal-derived ECM may protect colon cancer cells from etoposide and camptothecin-induced apotosis, through a mechanism that is not bcl-2 or bcl-x(L) dependant.