Role of the macrophage derived XL313 epitope in angiogenesis and tumor growth

虽然在控制恶性肿瘤的新疗法的开发方面取得了重大进展， 尽管在黑色素瘤中，大多数治疗的转移性疾病患者的总体5年生存率仍然很低， 科目因此，迫切需要更详细地了解免疫和炎症是如何发生的。 机制控制黑色素瘤的进展，以提高长期持久的反应，在更大的 患者的百分比。有证据表明，肿瘤微环境中的免疫浸润， 巨噬细胞在血管生成、肿瘤生长和逃避免疫控制中起关键作用。黑素瘤 通常使用主动重编程基质成分的适应性策略， 表型。肿瘤相关巨噬细胞（TAM）可以改变内皮细胞和T细胞的行为，从而 调节血管生成、肿瘤生长和许多癌症疗法的功效。识别新的亲- TAM产生的血管生成和免疫抑制因子可能提供新的治疗机会 并有助于更深入地了解肿瘤微环境如何控制黑色素瘤 增长为此，我们做了一个令人惊讶的观察，一个进化上保守的RGDKGE包含 M2样巨噬细胞可产生胶原抗原表位，其表达在M2样巨噬细胞内升高3倍以上， 黑色素瘤患者队列的循环。值得注意的是，这种RGDKGE胶原蛋白表位，而不是其他胶原蛋白表位。 RGD胶原肽，增强内皮细胞生长，应力纤维形成，核转位， 是的，相关蛋白雅普，并诱导剂量依赖性的血管生成和促炎反应， vivo.基于这些和其他数据，我们将检验RGDKGE表位调节 血管生成和肿瘤生长的一种新的整合素YAP依赖性机械转导途径，导致 启动促血管生成信号程序

Whiles significant progress has been made in the development of new therapeutics to control malignant melanoma, the overall 5-year survival of patients with metastatic disease remains low in the majority of treated subjects. Thus, there is an urgent need for a more detailed understanding of how immune and inflammatory mechanisms govern melanoma progression in order to enhance long-term durable responses in a larger percentage of patients. Evidence indicates that immune infiltrates within the tumor microenvironment such as macrophages play critical roles in angiogenesis, tumor growth and escape from immune control. Melanomas often use an adaptive strategy of actively reprogramming stromal elements towards an immunosuppressive phenotype. Tumor associated macrophages (TAM) can modify both endothelial and T-cell behavior, thereby regulating angiogenesis, tumor growth and the efficacy of many cancer therapies. Identifying novel pro- angiogenic and immune suppressive factors generated by TAMs may provide new therapeutic opportunities and contribute to a more in depth understanding of how the tumor microenvironment controls melanoma growth. To this end, we made the surprising observation that an evolutionarily conserved RGDKGE containing collagen epitope can be generated by M2-like macrophages, and its expression was elevated over 3-fold within the circulation of a cohort of melanoma patients. Remarkably, this RGDKGE collagen epitope, but not other RGD collagen peptides, enhanced endothelial cell growth, stress fiber formation, nuclear translocation of the Yes-associated protein YAP, and induced a dose-dependent angiogenic and pro-inflammatory response in vivo. Based on these and other data, we will test the hypothesis that the RGDKGE epitope regulates angiogenesis and tumor growth by a novel integrin-YAP-dependent mechano-transduction pathway leading to the initiation of a pro-angiogenic signaling program.