DNA damage induces GDNF secretion in the tumor microenvironment with paracrine effects promoting prostate cancer treatment resistance.
DNA damage induces GDNF secretion in the tumor microenvironment with paracrine effects promoting prostate cancer treatment resistance.
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DOI：
10.18632/oncotarget.3040
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发表时间：
2015-02-10
期刊：
影响因子：
--
通讯作者：
Nelson PS
中科院分区：
文献类型：
--
作者：
Huber RM;Lucas JM;Gomez-Sarosi LA;Coleman I;Zhao S;Coleman R;Nelson PS
虽然转移性癌症通常最初对遗传毒性治疗有反应，但获得性耐药是常见的。除了对肿瘤细胞的细胞毒性作用之外，DNA损伤剂如电离辐射和化疗诱导肿瘤微环境的良性细胞中的损伤，导致能够促进肿瘤抗性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遗传毒性应激的反应的研究中，我们发现编码胶质细胞系源性神经营养因子（GDNF）的转录物在暴露于细胞毒性剂（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）后增加了数倍。成纤维细胞GDNF对前列腺癌细胞产生旁分泌作用，导致肿瘤细胞增殖和侵袭增强，这些作用与已知GDNF受体GFRA 1和RET的表达一致。暴露于GDNF也诱导肿瘤细胞对米托蒽醌和多西他赛化疗的耐药性。总之，这些发现支持肿瘤微环境损伤反应在调节治疗抗性中的重要作用，并将GDNF信号通路确定为改善对常规遗传毒性治疗的反应的潜在靶点。
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.
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影响因子：
56.9
作者：
LIN, LFH;DOHERTY, DH;COLLINS, F
通讯作者：
COLLINS, F
影响因子：
3.6
作者：
Naughton, CK;Jain, S;Milbrandt, J
通讯作者：
Milbrandt, J
影响因子：
8
作者：
Hernandez-Vargas, H.;Palacios, J.;Moreno-Bueno, G.
通讯作者：
Moreno-Bueno, G.
DOI：
10.1016/j.urolonc.2005.11.034
发表时间：
2006-05-01
影响因子：
2.7
作者：
Garzotto, M;Myrthue, A;Beer, TM
通讯作者：
Beer, TM
影响因子：
4.3
作者：
Hernandez-Vargas, Hector;Palacios, Jose;Moreno-Bueno, Gema
通讯作者：
Moreno-Bueno, Gema