Huber Roland M, Lucas Jared M, Gomez-Sarosi Luis A, Coleman Ilsa, Zhao Song, Coleman Roger, Nelson Peter S
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Oncotarget. 2015 Feb 10;6(4):2134-47. doi: 10.18632/oncotarget.3040.
Though metastatic cancers often initially respond to genotoxic therapeutics, acquired resistance is common. In addition to cytotoxic effects on tumor cells, DNA damaging agents such as ionizing radiation and chemotherapy induce injury in benign cells of the tumor microenvironment resulting in the production of paracrine-acting factors capable of promoting tumor resistance phenotypes. In studies designed to characterize the responses of prostate and bone stromal cells to genotoxic stress, we found that transcripts encoding glial cell line-derived neurotrophic factor (GDNF) increased several fold following exposures to cytotoxic agents including radiation, the topoisomerase inhibitor mitoxantrone and the microtubule poison docetaxel. Fibroblast GDNF exerted paracrine effects toward prostate cancer cells resulting in enhanced tumor cell proliferation and invasion, and these effects were concordant with the expression of known GDNF receptors GFRA1 and RET. Exposure to GDNF also induced tumor cell resistance to mitoxantrone and docetaxel chemotherapy. Together, these findings support an important role for tumor microenvironment damage responses in modulating treatment resistance and identify the GDNF signaling pathway as a potential target for improving responses to conventional genotoxic therapeutics.
尽管转移性癌症通常最初会对基因毒性疗法产生反应，但获得性耐药很常见。除了对肿瘤细胞的细胞毒性作用外，诸如电离辐射和化疗等DNA损伤剂会在肿瘤微环境的良性细胞中诱导损伤，从而导致能够促进肿瘤耐药表型的旁分泌作用因子的产生。在旨在表征前列腺和骨基质细胞对基因毒性应激反应的研究中，我们发现，在暴露于包括辐射、拓扑异构酶抑制剂米托蒽醌和微管毒物多西他赛在内的细胞毒性剂后，编码胶质细胞源性神经营养因子（GDNF）的转录本增加了几倍。成纤维细胞GDNF对前列腺癌细胞发挥旁分泌作用，导致肿瘤细胞增殖和侵袭增强，并且这些作用与已知的GDNF受体GFRA1和RET的表达一致。暴露于GDNF还会诱导肿瘤细胞对米托蒽醌和多西他赛化疗产生耐药性。总之，这些发现支持肿瘤微环境损伤反应在调节治疗耐药性中的重要作用，并确定GDNF信号通路是改善对传统基因毒性疗法反应的潜在靶点。
