Stromal EGF and igf-I together modulate plasticity of disseminated triple-negative breast tumors.
Stromal EGF and igf-I together modulate plasticity of disseminated triple-negative breast tumors.
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DOI：
10.1158/2159-8290.cd-13-0041
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发表时间：
2013-08
期刊：
影响因子：
28.2
通讯作者：
McAllister SS
中科院分区：
文献类型：
--
作者：
Castaño Z;Marsh T;Tadipatri R;Kuznetsov HS;Al-Shahrour F;Paktinat M;Greene-Colozzi A;Nilsson B;Richardson AL;McAllister SS
播散性肿瘤恶性进展的原因以及不同乳腺癌亚型女性复发率不同的原因尚不清楚。在这里，我们报告了肿瘤可塑性的新机制，这些机制是由微环境因素决定的，并证明复发率并不严格取决于细胞的内在特性。具体而言，相对于具有管腔乳腺癌（LBC）的小鼠，具有三阴性乳腺癌（TNBC）的小鼠中相同的初始肿瘤群体的生长加速。明显的TNBC提供的全身信号导致在远处惰性肿瘤部位形成富含EGF和IGF-1的肿瘤支持微环境。EGF和IGF-1的生物利用度增强与多能性、增殖和上皮-间质转化相关的转录因子的表达。EGFR和IGF 1 R抑制剂的联合治疗可预防恶性进展。这些结果表明，可塑性和复发率可以由宿主全身因素决定，并为TNBC患者提供新的治疗潜力。
The causes for malignant progression of disseminated tumors and why recurrence rates differ in women with different breast cancer subtypes are unknown. Here, we report novel mechanisms of tumor plasticity that are mandated by microenvironmental factors and demonstrate that recurrence rates are not strictly due to cell intrinsic properties. Specifically, outgrowth of the same population of incipient tumors is accelerated in mice with triple-negative breast cancer (TNBC) relative to those with luminal breast cancer (LBC). Systemic signals provided by overt TNBCs cause formation of a tumor-supportive microenvironment enriched for EGF and IGF-1 at distant indolent tumor sites. Bioavailability of EGF and IGF-1 enhances expression of transcription factors associated with pluripotency, proliferation, and epithelial-mesenchymal transition. Combinatorial therapy with EGFR and IGF1R inhibitors prevents malignant progression. These results suggest that plasticity and recurrence rates can be dictated by host systemic factors and offer novel therapeutic potential for patients with TNBC.