Fibroblast growth factors: An epigenetic mechanism of broad spectrum resistance to anticancer drugs
Fibroblast growth factors: An epigenetic mechanism of broad spectrum resistance to anticancer drugs
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DOI：
10.1073/pnas.140210697
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发表时间：
2000-07-18
影响因子：
11.1
通讯作者：
Au, JLS
中科院分区：
文献类型：
--
作者：
Song, SH;Wientjes, MG;Au, JLS
根据观察，肿瘤从转移器官切除逆转了它们的化疗耐药，我们假设化疗耐药是由肿瘤器官的细胞外因子诱导的。通过比较不同肿瘤（原发与转移）和不同培养系统（来自同一肿瘤的肿瘤片段组织培养与单层培养）的化学敏感性和蛋白质，我们发现在固体和转移肿瘤的条件培养基（CM）中酸性（aFGF）和碱性（bFGF）成纤维细胞生长因子水平升高。这些CM诱导了对具有不同结构和作用机制的药物（紫杉醇、阿霉素、5-氟尿嘧啶）的广谱耐药。单抗抑制bFGF并通过免疫沉淀去除bFGF导致CM诱导的化疗耐药完全逆转，而抑制/去除aFGF导致部分逆转。利用去除aFGF和/或bFGF的CM，然后用各自的人重组蛋白进行重组，我们发现bFGF而非aFGF诱导了化学耐药，而aFGF则放大了bFCF的作用。aFGF和bFCF完全解释了CM效应，表明这些蛋白是化学耐药的潜在机制。fgf诱导的耐药不是由于细胞内药物积累减少或细胞增殖改变。我们进一步表明，aFGF/bFGF抑制剂（苏拉明）增强了化疗的体外和体内活性，导致小鼠肺部转移瘤的缩小和根除，而不增强毒性。这些结果表明，细胞外aFGF/bFGF水平升高是癌细胞逃避化疗细胞毒性损伤的一种表观遗传机制，并为设计新的治疗策略提供了基础。
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 inhibition/removal of aFGF resulted in partial reversal. Using CM that had been depleted of aFGF and/or bFGF and subsequently reconstituted with respective human recombinant proteins, we found that bFGF but not aFGF induced chemoresistance whereas aFGF amplified the bFCF effect. aFGF and bFCF 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 aFGF/bFGF (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 aFGF/bFGF as an epigenetic mechanism by which cancer cells elude cytotoxic insult by chemotherapy, and provide a basis for designing new treatment strategies.