Cancer metastasis is the leading cause of mortality among breast cancer patients. Type 2 diabetes mellitus (T2DM) has been suggested as a risk factor of breast cancer; however, whether or not T2DM is associated with breast tumor metastasis remains unclear. In this study, we examined the involvement of T2DM with breast cancer metastasis by a combined approach of a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that diabetes significantly increases the risk of lymph node metastasis by 1.10-fold (P < 0.01). Consistently, our data from experimental research showed that T2DM induced paracrine effects of mesenchymal stem cells (MSCs), a key contributor to cancer progression, to stimulate metastasis of breast cancer cells (BCCs) by two independent mechanisms. First, T2DM induced the excess secretion of interleukin 6 (IL6) from MSCs, which activated the JAK/STAT3 pathway in BCCs, thus promoting the metastasis of BCCs. Second, beside the EGR-1-/IL6-dependent mechanism, T2DM altered the functions of MSC-derived extracellular vesicles (EVs), which are highly associated with the metastasis of BCCs. Our present study showed that T2DM is a risk factor for breast cancer metastasis, and MSC-derived EVs might be useful for developing a novel anti-breast cancer therapy strategy.

中文翻译：

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2 型糖尿病通过源自人类间充质干细胞的细胞外囊泡诱导旁分泌对乳腺癌转移的影响。

癌症转移是乳腺癌患者死亡的主要原因。2 型糖尿病 (T2DM) 已被认为是乳腺癌的危险因素；然而，T2DM 是否与乳腺肿瘤转移有关尚不清楚。在这项研究中，我们通过荟萃分析和实验研究的组合方法检查了 T2DM 与乳腺癌转移的关系。一项系统评价和荟萃分析的结果表明，糖尿病使淋巴结转移的风险显着增加 1.10 倍（P < 0.01)。一致地，我们来自实验研究的数据表明，T2DM 诱导间充质干细胞 (MSCs) 的旁分泌作用，间充质干细胞 (MSCs) 是癌症进展的关键因素，通过两种独立的机制刺激乳腺癌细胞 (BCCs) 的转移。首先，T2DM诱导MSCs过度分泌白细胞介素6（IL6），激活BCCs中的JAK/STAT3通路，从而促进BCCs的转移。其次，除了 EGR-1-/IL6 依赖性机制外，T2DM 还改变了 MSC 衍生的细胞外囊泡 (EV) 的功能，这与 BCC 的转移高度相关。我们目前的研究表明，T2DM 是乳腺癌转移的危险因素，MSC 衍生的 EVs 可能有助于开发新的抗乳腺癌治疗策略。