Diabetes Mellitus Promotes Breast Tumor Progression via Glycation Mediated Matrix Stiffening

项目总结/摘要 糖尿病是一种与高血糖相关的复杂疾病。越来越多的流行病 有证据表明，糖尿病和乳腺癌合并症的患者， 与非糖尿病患者相比预后差和死亡。然而，肿瘤和肿瘤之间的相互作用 进展和糖尿病的机制仍不清楚。高血糖导致肿瘤内的糖化 细胞外基质（ECM），其中糖通过非酶促反应交联胶原，导致 增加基质硬度。值得注意的是，ECM硬度与转移性相关，并促进肿瘤的恶性程度。 通过多个方面，如促进增殖和上皮-间质转化（EMT）来治疗肿瘤。 ECM硬度也调节内皮细胞，因为我们的实验室以前已经表明，ECM硬度促进 肿瘤血管生成并损害血管完整性。畸形和高渗透性的脉管系统是 乳腺肿瘤的转移，并已知导致更多的转移和更具侵略性的肿瘤表型。注意到 糖基化的致癌作用以及糖尿病和肿瘤进展之间的关联，我的研究旨在 了解糖尿病高血糖通过糖化促进乳腺肿瘤进展的机制， 介导基质硬化。我最近建立了一个小鼠模型，在此模型中， 到肿瘤发生。通过这个模型，我发现高血糖会增加肿瘤的生长，肿瘤的硬度， 糖基化终产物（AGEs）浓度和肿瘤细胞的EMT。在用糖化处理糖尿病小鼠后， 抑制剂，我观察到先前在糖尿病肿瘤中测试的指标降低到与 非糖尿病肿瘤。这些发现描述了一种新的机制，糖尿病高血糖促进 乳腺肿瘤进展，并提供证据表明，糖化抑制是一种潜在的辅助治疗糖尿病 癌症患者，因为其在这两种疾病中的基质硬化的关键作用。在本申请的F99阶段，这些 通过确定糖基化介导的ECM硬化激活的机制， 肿瘤血管生成（Aim 1）。注意到糖基化使ECM变硬并产生AGEs，AGEs启动细胞信号传导 through通过binding神经元receptors受体. AGE-beta信号转导与血管生成行为有关。特定 因此，重点将是梳理除了AGE-binding信号和基质硬化对肿瘤的影响， 血管生成巨噬细胞参与的慢性炎症正在成为糖尿病和乳腺癌之间的联系 癌我的初步数据显示，在较硬的肿瘤中有更多的M2巨噬细胞。因此，在K 00中 阶段（目标2），将寻求研究/培训环境，以检查糖基化的机制， 介导的ECM硬化通过增加肿瘤免疫细胞浸润促进肿瘤进展， 影响免疫细胞的行为。我研究的最终目标是提供一个更全面的 了解糖尿病高血糖如何影响肿瘤进展，并作为未来研究的基础。 治疗干预

PROJECT SUMMARY/ABSTRACT Diabetes mellitus is a complex disease associated with hyperglycemia. A growing body of epidemiological evidence supports that patients with comorbidity of diabetes mellitus and breast cancer are at a greater risk of poor prognosis and death compared with non-diabetic patients. However, the interplay between tumor progression and diabetes is still mechanistically unclear. Hyperglycemia results in glycation within the tumor extracellular matrix (ECM), where sugars crosslink collagen through a non-enzymatic reaction resulting in increased matrix stiffness. Notably, ECM stiffness is correlated with metastatic and promotes malignancy of tumors through multiple aspects, such as promoting proliferation and epithelial-mesenchymal transition (EMT). ECM stiffness also regulates endothelial cells, as our lab has shown previously that ECM stiffness promotes tumor angiogenesis and damages vascular integrity. Malformed and hyper-permeable vasculature is a hallmark of breast tumors and is known to lead to more metastasis and a more aggressive tumor phenotype. Noting the carcinogenic effect of glycation and the association between diabetes and tumor progression, my study aims to understand the mechanism by which diabetic hyperglycemia promotes breast tumor progression via glycation- mediated matrix stiffening. I have recently established a murine model where hyperglycemia was induced prior to tumorigenesis. With this model, I find that hyperglycemia increases tumor growth, tumor stiffness, advanced glycation end-product (AGEs) concentration, and EMT of tumor cells. Upon treating diabetic mice with glycation inhibitors, I observed a reduction of the previously tested metrics in diabetic tumors to levels comparable with non-diabetic tumors. These findings describe a novel mechanism by which diabetic hyperglycemia promotes breast tumor progression and provide evidence that glycation inhibition is a potential adjuvant therapy for diabetic cancer patients due to its key role of matrix stiffening in both diseases. In the F99 phase of this application, these findings will be extended by determining the mechanisms by which glycation-mediated ECM stiffening activates tumor angiogenesis (Aim 1). Noting that glycation stiffens ECM and produces AGEs which initiate cell signaling through RAGE receptors. AGE-RAGE signaling has been implicated in angiogenic behavior. A particular emphasis will thus be to tease apart the effect of AGE-RAGE signaling and matrix stiffening on tumor angiogenesis. Macrophage-involved chronic inflammation is emerging as a link between diabetes and breast cancer. My preliminary data show that there are more M2 macrophages within stiffer tumors. Thus, in the K00 phase (Aim 2), a research/training environment will be sought to examine the mechanism by how glycation- mediated ECM stiffening promotes tumor progression via increasing tumor immune cell infiltration and influencing immune cell behaviors. The ultimate goal of my studies will be to provide a more holistic understanding of how diabetic hyperglycemia influences tumor progression and to serve as a basis for future therapeutic intervention.