Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells

Abstract

The importance of tumor microenvironment (TME) as a relevant contributor to cancer progression and its role in the development of de novo resistance to targeted therapies has become increasingly apparent. However, the mechanisms of microenvironment-mediated drug resistance for nonspecific conventional chemotherapeutic agents, such as platinum compounds or antimetabolites, are still unclear.Here we describe a mechanism induced by soluble factors released by carcinoma-associated fibroblasts (CAFs) that induce the translocation of AKT, Survivin and P38 to the nucleus of tumor cells. These changes are guided to ensure DNA repair and the correct entrance and exit from mitosis in the presence of chemotherapy. We used conditioned media (CM) from normal-colonic fibroblasts and paired CAFs to assess dose response curves of oxaliplatin and 5-fluorouracil, separately or combined, compared with standard culture medium. We also evaluated a colony-forming assay and cell death to demonstrate the protective role of CAF-CM. Immunofluorescence confirmed the translocation of AKT, P38 and Survivin to the nucleus induced by CAF-soluble factors. We also have shown that STAT3 or P38 inhibition provides a promising strategy for overcoming microenvironment-mediated resistance. Conversely, pharmacologic AKT inhibition induces an antagonistic effect that relieves a cMET and STAT3-mediated compensatory feedback that might explain the failure of AKT inhibitors in the clinic so far.

5‐Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes

“…Higher levels of phosphorylated CHK2 consistent with lower CDC25B expression have been observed in 5‐FU‐treated cells cultured in CAF‐CM 56 . Moreover, CAF soluble factors stimulate and activate PI3K/AKT/mTOR and JAK/STAT pathways as well as the subsequent nuclear translocations of p38, AKT, and STAT activated forms, which increase Survivin expression 56 . Therefore, STAT3 constitutes a promising target to overcome CAF‐mediated CRC 5‐FU resistance, as STAT3 inhibition sensitizes CRC cells to 5‐FU even in the presence of CAF‐CM.…”

“…This cell cycle arrest seems to be mediated by the activation of G 2 /M checkpoint kinase 2 (CHK2) and the subsequent decrease in expression of cell division cycle 25B (CDC25B, a phosphatase that enables a cell to resume the cell cycle after its arrest induced by DNA damage). Higher levels of phosphorylated CHK2 consistent with lower CDC25B expression have been observed in 5‐FU‐treated cells cultured in CAF‐CM 56 . Moreover, CAF soluble factors stimulate and activate PI3K/AKT/mTOR and JAK/STAT pathways as well as the subsequent nuclear translocations of p38, AKT, and STAT activated forms, which increase Survivin expression 56 .…”

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

“…They produce growth factors that activate p38 and STAT3 in CRC cells, and p38 inhibition can reverse drug resistance [129].…”

Differential expression of microRNAs in colorectal cancer: Different patterns between isolated cancer gland and stromal cells

“…Recent studies have shown dysregulation of miRNAs in stromal cells in various cancers . High miRNA‐21 expression in CAFs was associated with a poor prognosis in lung adenocarcinoma, suggesting that at least some miRNAs are associated with cancer progression . In the present study, 10 of the 13 miRNAs evaluated were downregulated (hsa‐miRNA‐130a‐3p, hsa‐miRNA‐143‐3p, hsa‐miRNA‐206, hsa‐miRNA‐195‐5p, hsa‐miRNA‐27a‐3p, hsa‐miRNA‐19a‐3p, hsa‐miRNA‐34b‐3p, hsa‐miRNA‐186‐5p, hsa‐miRNA‐191‐5p and hsa‐let‐7a‐5p), and 3 miRNAs (hsa‐miRNA‐21‐5p, hsa‐miRNA‐31‐5p and hsa‐miRNA‐27b‐3p) were upregulated, in stromal cells from CRC compared with non‐cancer specimens.…”