title: Stromal extracellular matrix reduces chemotherapy-induced apoptosis in colon cancer cell lines.
abstract: 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.
authors.affiliation: Surgical Oncology Department, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Guenadi
authors.initials: G
authors.lastname: Kouniavsky
authors.forename: Marat
authors.initials: M
authors.lastname: Khaikin
authors.forename: Isabel
authors.initials: I
authors.lastname: Zvibel
authors.forename: Dov
authors.initials: D
authors.lastname: Zippel
authors.forename: Shlomo
authors.initials: S
authors.lastname: Brill
authors.forename: Zamir
authors.initials: Z
authors.lastname: Halpern
authors.forename: Moshe
authors.initials: M
authors.lastname: Papa
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005109:Extracellular Matrix / Q000737:chemistry*; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D005347:Fibroblasts / Q000737:chemistry; D005353:Fibronectins / Q000494:pharmacology; D005472:Fluorouracil / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019254:Genes, bcl-2; D022781:Hepatocytes / Q000737:chemistry; D006801:Humans; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D017154:Stromal Cells / Q000737:chemistry*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000473:pathology; D051020:bcl-X Protein
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D051020:bcl-X Protein; D005047:Etoposide; D003094:Collagen; D005472:Fluorouracil; D002166:Camptothecin