Molecular and Environmental Toxicology Program, University of Wisconsin-Madison, Madison, WI, USA; Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA.
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA.
Cancer Lett. 2018 Oct 1;433:1-9. doi: 10.1016/j.canlet.2018.06.025. Epub 2018 Jun 20.
Metastatic estrogen receptor alpha positive (ERα+) cancers account for most breast cancer mortality. Cancer stem cells (CSCs) and dense/stiff extracellular matrices are implicated in aggression and therapy resistance. We examined this interplay and response to mTOR inhibition using ERα+ adenocarcinomas from NRL-PRL females in combination with Col1a1 (mCol1a1) mice, which accumulate collagen-I around growing tumors. Orthotopic transplantation of tumor cells to mCol1a1 but not wildtype hosts resulted in striking desmoplasia. Mammary tumors in mCol1a1 recipients displayed higher CSC activity and enhanced AKT-mTOR and YAP activation, and these animals developed more and larger lung metastases. Treatment with the mTOR inhibitor, rapamycin, with or without the anti-estrogen, ICI182780, rapidly diminished mammary tumors, which rapidly reversed when treatment ceased. In contrast, lung metastases, which exhibited lower proliferation and pS6RP, indicating lower mTOR activity, were unresponsive, and mCol1a1 hosts continued to sustain greater metastatic burdens. These findings shed light on the influence of desmoplastic tumor microenvironments on the CSC niche and metastatic behavior in ERα+ breast cancer. The differential mTOR dependence of local mammary tumors and pulmonary lesions has implications for success of mTOR inhibitors in advanced ERα+ disease.
转移性雌激素受体 alpha 阳性（ERα+）癌症占大多数乳腺癌死亡的原因。癌症干细胞（CSCs）和密集/僵硬的细胞外基质与侵袭性和治疗耐药性有关。我们使用 NRL-PRL 雌性的 ERα+腺癌与 Col1a1（mCol1a1）小鼠结合，研究了这种相互作用以及对 mTOR 抑制的反应，mCol1a1 小鼠在生长的肿瘤周围积累胶原蛋白-I。将肿瘤细胞原位移植到 mCol1a1 而非野生型宿主中会导致明显的间质增生。mCol1a1 受者的乳腺肿瘤显示出更高的 CSC 活性，并增强了 AKT-mTOR 和 YAP 的激活，这些动物发展出更多和更大的肺转移。用 mTOR 抑制剂雷帕霉素治疗，无论是否联合抗雌激素 ICI182780，均可迅速缩小乳腺肿瘤，但当治疗停止时，肿瘤又迅速增大。相比之下，肺转移瘤增殖和 pS6RP 较低，表明 mTOR 活性较低，对治疗无反应，mCol1a1 宿主继续承受更大的转移负担。这些发现揭示了致密肿瘤微环境对 ERα+乳腺癌中 CSC 生态位和转移行为的影响。局部乳腺肿瘤和肺病变对 mTOR 抑制剂的依赖性不同，这对晚期 ERα+疾病中 mTOR 抑制剂的成功应用具有重要意义。
