Fibroblast growth factors: An epigenetic mechanism of broad spectrum resistance to anticancer drugs

Abstract

Based on the observation that removal of tumors from metastatic organs reversed their chemoresistance, we hypothesized that chemoresistance is induced by extracellular factors in tumor-bearing organs. By comparing chemosensitivity and proteins in different tumors (primary vs. metastases) and different culture systems (tumor fragment histocultures vs. monolayer cultures derived from the same tumor), we found elevated levels of acidic (aFGF) and basic (bFGF) fibroblast growth factors in the conditioned medium (CM) of solid and metastatic tumors. These CM induced broad spectrum resistance to drugs with diverse structures and action mechanisms (paclitaxel, doxorubicin, 5-fluorouracil). Inhibition of bFGF by mAb and its removal by immunoprecipitation resulted in complete reversal of the CM-induced chemoresistance, whereas inhibition͞removal of aFGF resulted in partial reversal. Using CM that had been depleted of aFGF and͞or bFGF and subsequently reconstituted with respective human recombinant proteins, we found that bFGF but not aFGF induced chemoresistance whereas aFGF amplified the bFGF effect. aFGF and bFGF fully accounted for the CM effect, indicating these proteins as the underlying mechanism of the chemoresistance. The FGF-induced resistance was not due to reduced intracellular drug accumulation or altered cell proliferation. We further showed that an inhibitor of aFGF͞bFGF (suramin) enhanced the in vitro and in vivo activity of chemotherapy, resulting in shrinkage and eradication of well established human lung metastases in mice without enhancing toxicity. These results indicate elevated levels of extracellular aFGF͞bFGF as an epigenetic mechanism by which cancer cells elude cytotoxic insult by chemotherapy, and provide a basis for designing new treatment strategies.R esistance of tumor cells to chemotherapy and the limited efficacy of chemotherapy in metastatic disease are two major challenges in patient management. A common resistance mechanism observed in preclinical studies is the overexpression of drug efflux proteins (1-3). However, clinical studies show that inhibition of the drug efflux proteins does not significantly improve the effectiveness of chemotherapy in patients (4, 5), suggesting the existence of other chemoresistance mechanisms.Using the transplantable, metastatic rat prostate MAT-LyLu tumor, we have shown that the antitumor activity of paclitaxel in lymph node metastases was 20-fold lower than in s.c. implanted primary tumors. When the metastatic tumor was reimplanted at the s.c. site, the resistance was lost in the second generation primary tumor but regained in the second generation metastases. We further found that the chemoresistance in metastatic tumors is not due to reduced intracellular drug accumulation or retention (6). These results led to the hypothesis of an epigenetic chemoresistance mechanism that is mediated by extracellular factors present in tumor-bearing organs. The present study tested the hypothesis, identified the factors that induce resistance, and determined the resto...

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

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