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.
Highlights
Colorectal cancer (CRC) is the fourth most prevalent cancer and the leading cause of cancer mortality worldwide [1], but its early diagnosis makes the disease one of the most curable cancers [2], at least in developed countries
The present study showed how soluble factors secreted by carcinomaassociated fibroblasts (CAFs) trigger a cell signaling cascade that protects cells from the action of conventional chemotherapy used in colorectal cancer treatment, a process involving the nuclear translocation of AKT and P38 and the activation of the JAK/STAT pathway
It is intuitive that cytokines, chemokines and growth factors secreted in large quantities by CAFs will activate signaling cascades mainly through the PI3KCA/AKT and JAK/STAT pathways, and that such signaling is a requisite and a key event for cell proliferation, migration and invasion [25, 26]
Summary
Colorectal cancer (CRC) is the fourth most prevalent cancer and the leading cause of cancer mortality worldwide [1], but its early diagnosis makes the disease one of the most curable cancers [2], at least in developed countries. One of the main obstacles that patients have to deal with over the course of the disease is resistance to treatments. Research into therapies against specific targets or signaling pathways is one of the pillars of current cancer research, most tumors are still treated with conventional cytotoxic therapies. Drug resistance remains the main obstacle to the success of cytotoxic therapies [3]. As with many aspects of the tumorigenic process, most research on drug resistance has focused on the acquired resistance of malignant cells, which is basically limited to the reduction of an initial tumor burden, and www.impactjournals.com/oncotarget so fails to eradicate a sufficient number of cancer cells to prevent clinical recurrence. Despite the extensive use of chemotherapy, the specific mechanisms causing tumor regression or recurrence after treatment are poorly known
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