Hematology Division , Brigham & Women's Hospital, Lund University, Lund, Sweden.
Cancer Discov. 2013 Aug;3(8):922-35. doi: 10.1158/2159-8290.CD-13-0041. Epub 2013 May 20.
The causes for malignant progression of disseminated tumors and the reasons 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 show 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. Systemic signals provided by overt TNBCs cause the formation of a tumor-supportive microenvironment enriched for EGF and insulin-like growth factor-I (IGF-I) at distant indolent tumor sites. Bioavailability of EGF and IGF-I enhances the expression of transcription factors associated with pluripotency, proliferation, and epithelial-mesenchymal transition. Combinatorial therapy with EGF receptor and IGF-I receptor 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.
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，我们报告了由微环境因素决定的肿瘤可塑性的新机制，并表明复发率并非严格归因于细胞内在特性。具体而言，与腔乳腺癌相比，三阴性乳腺癌（TNBC）小鼠中同一群初始肿瘤的生长速度加快。显性 TNBC 提供的系统信号导致富含表皮生长因子（EGF）和胰岛素样生长因子-I（IGF-I）的肿瘤支持性微环境在远处惰性肿瘤部位形成。EGF 和 IGF-I 的生物利用度增强了与多能性、增殖和上皮-间充质转化相关的转录因子的表达。EGF 受体和 IGF-I 受体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系统因素决定，并为 TNBC 患者提供新的治疗潜力。
