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

Based on the observation that removal of tumors from metastatic organs reve rsed their chemoresistance, we hypothesized that chemoresistance is induced by extracellular factors in tumor-bearing organs. By comparing chemosensit ivity and proteins in different tumors (primary vs. metastases) and differe nt culture systems (tumor fragment histocultures vs. monolayer cultures der ived from the same tumor), we found elevated levels of acidic (aFGF) and ba sic (bFGF) fibroblast growth factors in the conditioned medium (CM) of soli d and metastatic tumors. These CM induced broad spectrum resistance to drug s with diverse structures and action mechanisms (paclitaxel, doxorubicin, 5 -fluorouracil), Inhibition of bFGF by mAb and its removal by immunoprecipit ation resulted in complete reversal of the CM-induced chemoresistance, wher eas inhibition/removal of aFGF resulted in partial reversal. Using CM that had been depleted of aFGF and/or bFGF and subsequently reconstituted with r espective human recombinant proteins, we found that bFGF but not aFGF induc ed chemoresistance whereas aFGF amplified the bFCF effect. aFGF and bFCF fu lly accounted for the CM effect, indicating these proteins as the underlyin g mechanism of the chemoresistance. The FGF-induced resistance was not due to reduced intracellular drug accumulation or altered cell proliferation. W e further showed that an inhibitor of aFGF/bFGF (suramin) enhanced the in v itro and in vivo activity of chemotherapy, resulting in shrinkage and eradi cation of well established human lung metastases in mice without enhancing toxicity. These results indicate elevated levels of extracellular aFGF/bFGF as an epigenetic mechanism by which cancer cells elude cytotoxic insult by chemotherapy, and provide a basis for designing new treatment strategies.