Vascular Biology in Cancer

1.癌症发展中的免疫抑制和血管生成。逃避免疫监视和促进肿瘤血管生成对于肿瘤的发展是必不可少的。肿瘤微环境在肿瘤的生长和发展中起着积极的作用。髓源性抑制细胞（MDSC）在癌症患者和携带大肿瘤的动物中显著增加。已知MDSC具有免疫抑制性。非常有趣的是，我们观察到这些细胞浸润到肿瘤中，并通过MMP 9介导的调节肿瘤组织中VEGF的生物利用度来促进肿瘤血管生成和血管成熟。MDSC还被发现直接掺入肿瘤内皮，并通过血管发生促进肿瘤血管形成。此外，我们发现MDSC优先聚集在肿瘤的侵袭前沿，促进肿瘤细胞的侵袭和转移。基于这些发现，我们提出肿瘤利用宿主造血，产生大量未成熟的骨髓细胞。MDSC的替代分化是肿瘤使用的一种策略，不仅通过免疫抑制，而且通过促进肿瘤血管发育来促进其生长。目前的工作是了解是什么控制了MDSC的产生和分化，以及我们如何调控这些细胞以提高抗肿瘤免疫应答并同时抑制肿瘤血管生成，以达到一石二鸟的效果。 2.δ-连环蛋白的杂合缺陷损害病理性血管生成。血管形成对于组织生长、修复和再生是必不可少的，这基本上涵盖了大多数人类疾病。如何区分正常发育过程中的生理性血管生成与疾病条件下的病理性血管生成是一个非常重要的问题。它对治疗干预具有重要意义。我们认为生理性和病理性血管生成之间的主要区别是炎症。这一假设得到以下方面的支持：1）炎性细胞因子是促血管生成的;和2）炎性细胞浸润到损伤的组织中并提供多种血管生成因子。相反，血管生成通过运输更多的炎性细胞来增强炎症。此外，血管内皮通过提供炎性细胞因子以吸引循环炎性细胞以及细胞粘附分子以捕获这些循环细胞而在炎症中是必不可少的。了解炎症和病理性血管生成之间的相互作用使我们能够优先靶向疾病条件下的血管生成，并保留正常血管。在寻找病理性血管生成的新型分子介质时，我们发现δ-连环蛋白以基因剂量依赖性方式在病理性血管生成中发挥关键而特异的作用。我们发现在血管内皮中表达δ-连环蛋白，一种调节神经元细胞-细胞粘附和细胞运动性的神经元连环蛋白，并且表明仅缺失δ-连环蛋白的一个等位基因就足以损害体外内皮细胞运动性和血管组装以及体内病理性血管生成，从而抑制肿瘤生长和伤口愈合。与此相反，删除一个或两个等位基因的δ-连环蛋白没有影响子宫内的子宫内膜诱导的生理性血管生成。分子分析证实了δ-连环蛋白对RhoGT酶活性的基因剂量效应。此外，我们发现，炎症细胞因子，而不是血管生成因子，调节δ-连环蛋白的表达，和δ-连环蛋白的水平呈正相关的人类肺癌。总之，我们的数据表明，炎症，通常与疾病的条件，诱导δ-连环蛋白的表达，特别是调节病理，而不是生理，血管生成。因为只有病理性血管生成对降低的δ-连环蛋白水平敏感，这可能为抗血管生成治疗提供良好的靶点。

1. Immune suppression and angiogenesis in cancer development. Escape from immune surveillance and promotion of tumor angiogenesis are essential for tumor development. It is becoming clear that the tumor microenvironment play an active role in tumor growth and progression. Myeloid derived suppressor cells (MDSC) are significantly increased in cancer patients and animals bearing large tumors. MDSCs are known to be immune suppressive. Very interestingly, we have observed that these cells infiltrated into tumors and promoted tumor angiogenesis and vascular maturation through MMP9 mediated regulation of VEGF bioavailability in tumor tissues. MDSCs were also found to directly incorporate into tumor endothelium and contributed to tumor vascular formation through vasculogenesis. In addition, we found that MDSCs are preferentially accumulated in the invasive front of tumors and promotes tumor cell invasion and metastasis. Based on these findings, we propose that tumors exploit host hematopoiesis, generating a large number of immature myeloid cells. Alternative differentiation of MDSCs is a strategy used by tumors to benefit their growth not only through immune suppression, but also by promoting tumor vascular development. Current effort is engaged to understand what controls the production and differentiation of MDSCs, and how we can modulate these cells to improve anti-tumor immune response and concurrently inhibit tumor angiogenesis, to achieve the effects of killing two birds with one stone. 2. Heterozygous deficiency of delta-catenin impairs pathological angiogenesis. Vascular formation is essential for tissue growth, repair and regeneration, which cover basically the majority of human diseases. What distinguishes physiological angiogenesis during normal development from pathological angiogenesis in disease conditions is a very important question. It has significant implications for therapeutic interventions. We believe the major differences between physiological and pathological angiogenesis is inflammation. This hypothesis is supported by 1) inflammatory cytokines are pro-angioegnic; and 2) inflammatory cells infiltrate into injured tissues and provide a variety of angiogenic factors. Conversely, angiogenesis enhances inflammation by transporting more inflammatory cells. In addition, vascular endothelium is essential in inflammation by providing inflammatory cytokines to attract circulating inflammatory cells as well as cell adhesion molecules to catch these circulating cells. Understanding the interaction between inflammation and pathological angiogenesis allows us to preferentially target angiogenesis in disease conditions and spare normal blood vessels. In searching for novel molecular mediators in pathological angiogenesis, we found delta-catenin plays a critical and specific role in pathological angiogenesis in a gene dosage dependent manner. We found expression of delta-catenin, a neuronal catenin regulating neuron cell-cell adhesion and cell motility, in vascular endothelium, and show that deletion of only one allele of delta-catenin is sufficient to impair endothelial cell motility and vascular assembly in vitro and pathological angiogenesis in vivo, thereby inhibiting tumor growth and wound healing. In contrast, deletion of one or both allele of delta-catenin had no effects on hormone-induced physiological angiogenesis in the uterus. Molecular analysis confirmed a gene dosage effect of delta-catenin on RhoGTPase activity. Moreover, we show that inflammatory cytokines, but not angiogenic factors, regulate delta-catenin expression, and the levels of delta-catenin positively correlate to human lung cancers. Taken together, our data suggest that inflammation, commonly associated with disease conditions, induces delta-catenin expression that specifically regulates pathological, and not physiological, angiogenesis. Because only pathological angiogenesis is sensitive to decreased levels of delta-catenin, this may provide a good target for anti-angiogenic therapy.