Diabetes Mellitus Promotes Breast Tumor Progression via Glycation Mediated Matrix Stiffening

项目摘要/摘要 糖尿病是一种与高血糖相关的复杂疾病。不断增长的流行病学机构 有证据表明，患有糖尿病和乳腺癌的患者患糖尿病的风险更高。 与非糖尿病患者相比，预后差，死亡率高。然而，肿瘤之间的相互作用 进展和糖尿病在机制上仍然不清楚。高血糖导致肿瘤内的糖基化。 细胞外基质(ECM)，其中糖通过非酶反应使胶原交联，从而导致 增加了矩阵的硬度。值得注意的是，细胞外基质僵硬与肿瘤的转移和恶性程度有关。 肿瘤通过促进增殖、上皮-间充质转化(EMT)等多方面发挥作用。 细胞外基质僵硬也调节内皮细胞，因为我们的实验室以前已经表明，细胞外基质僵硬促进 肿瘤血管生成和破坏血管完整性。畸形和高渗透性的血管系统是一个标志 而且已知会导致更多的转移和更具侵袭性的肿瘤表型。请注意 糖基化的致癌作用以及糖尿病与肿瘤进展之间的关系，我的研究旨在 了解糖尿病高血糖通过糖基化促进乳腺肿瘤进展的机制- 介导性基质硬化。我最近建立了一个小鼠模型，在这个模型中， 肿瘤的发生。在这个模型中，我发现高血糖增加了肿瘤的生长，肿瘤僵硬，晚期 糖基化终产物(AGEs)浓度和肿瘤细胞的EMT。用糖基化治疗糖尿病小鼠 抑制剂，我观察到先前在糖尿病肿瘤中测试的指标减少到与 非糖尿病肿瘤。这些发现描述了一种新的糖尿病高血糖促进机制。 乳腺癌的进展和糖基化抑制是糖尿病潜在的辅助治疗的证据 癌症患者由于其在两种疾病中都有基质硬化的关键作用。在此应用程序的F99阶段，这些 通过确定糖基化介导的细胞外基质僵硬激活的机制，将扩大研究结果。 肿瘤血管生成(目标1)。注意到糖基化使细胞外基质变硬，并产生启动细胞信号的AGEs 通过愤怒受体。年龄-RAGE信号与血管生成行为有关。一种特殊的 因此，重点将是梳理年龄-RAGE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房之间的联系 癌症。我的初步数据显示，在僵硬的肿瘤中有更多的M2巨噬细胞。因此，在K00 阶段(目标2)，将寻求一个研究/培训环境，通过糖基化- 介导的ECM硬化通过增加肿瘤免疫细胞的侵袭和 影响免疫细胞行为。我的研究的最终目标将是提供更全面的 了解糖尿病高血糖如何影响肿瘤进展并为未来奠定基础 治疗性干预。

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.