Myeloid Vascular Endothelial Growth Factor Expression & its Role in Tumorigenesis

描述（由申请人提供）：我们发现骨髓细胞中血管内皮生长因子- a表达的缺失对乳腺癌小鼠模型具有深远而意想不到的影响。我们最近的研究结果说明了炎症细胞如何在肿瘤中诱导血管变化，以及这些变化如何改变肿瘤灌注和氧合，以及肿瘤细胞的存活和恶性进展。这里提出的工作将使我们能够探索和利用这些新的和新颖的发现，以便：确定肿瘤血管生成过程中骨髓细胞与内皮细胞相互作用的机制；更好地了解骨髓细胞VEGF表达与转移的关系；并确定如何利用这些发现来提高化疗的疗效。我们建议进一步了解这些现象的目的是：1 .确定肿瘤中先天免疫细胞差异VEGF信号传导的分子机制。2：确定骨髓细胞中VEGF的表达如何影响转移。3：确定来自骨髓细胞的VEGF如何影响化疗的递送和疗效。总之，我们相信这一应用将解决围绕炎症、血管生成和肿瘤生长过程的关键问题，特别强调这些过程如何影响乳腺肿瘤的发生和转移。

DESCRIPTION (provided by applicant): We have found that loss of Vascular Endothelial Growth Factor-A expression in myeloid cells has profound and unexpected effects in a mouse model of breast cancer. Our recent findings illustrate how inflammatory cells act to induce vascular changes in tumors, and how these changes alter tumor perfusion and oxygenation, as well as tumor cell survival and malignant progression. The work proposed here will allow us to explore and exploit these new and novel findings, in order to: determine the mechanisms of myeloid cell interactions with endothelial cells during tumor angiogenesis; better understand the relationship between myeloid cell VEGF expression and metastasis; and determine how these findings could be used to increase the efficacy of chemotherapy. The aims we propose to further our understanding of these phenomena are: 1: Determine the molecular mechanisms for differential VEGF signaling through innate immune cells in tumors. 2: Determine how VEGF expression from myeloid cells impacts metastasis. 3: Determine how VEGF from myeloid cells impacts chemotherapy delivery and efficacy. In sum, we believe this application will address key questions surrounding the processes of inflammation, angiogenesis, and tumor growth, with a particular emphasis on how these influence mammary tumorigenesis and metastasis. PUBLIC HEALTH RELEVANCE: These findings speak directly to breast cancer therapies currently used in the clinic, and will explore ways in which these therapies can be improved through modulation of inflammatory response.