Vascular Biology in Cancer

1.肿瘤发生过程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是肿瘤发生发展的关键。越来越清楚的是，肿瘤微环境在肿瘤的生长和发展中起着积极的作用。在癌症患者和携带大肿瘤的动物中，髓系来源的抑制细胞(MDSC)显著增加。已知MDSCs具有免疫抑制作用。非常有趣的是，我们观察到这些细胞通过MMP9介导的调节肿瘤组织中血管内皮生长因子的生物利用度，渗透到肿瘤中，促进肿瘤血管生成和血管成熟。MDSCs还被发现直接结合到肿瘤内皮细胞中，并通过血管生成促进肿瘤血管的形成。此外，我们还发现MDSCs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，我们认为肿瘤利用宿主的造血系统，产生大量未成熟的髓系细胞。MDSCs的选择性分化是肿瘤所使用的一种策略，不仅通过免疫抑制，而且通过促进肿瘤血管的发展来促进其生长。目前致力于了解是什么控制着MDSCs的产生和分化，以及我们如何调控这些细胞来提高抗肿瘤免疫反应，同时抑制肿瘤血管生成，达到一举两得的效果。2.β-连环蛋白杂合性缺失损害病理性血管生成。血管形成对组织的生长、修复和再生是必不可少的，这些组织基本上涵盖了人类的大多数疾病。如何区分正常发育中的生理性血管生成和疾病条件下的病理性血管生成是一个非常重要的问题。这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。这一假说得到以下支持：1)炎性细胞因子是促血管生成因子；2)炎性细胞渗入损伤组织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症细胞来增强炎症。此外，血管内皮细胞通过提供炎性细胞因子来吸引循环中的炎症细胞以及细胞黏附分子来捕捉这些循环中的细胞，从而在炎症中发挥重要作用。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针对疾病条件下的血管生成，而不是正常血管。在寻找病理性血管生成的新分子介质的过程中，我们发现β-连环蛋白以基因剂量依赖的方式在病理性血管生成中发挥着关键而特异的作用。我们在血管内皮细胞中发现了一种调节神经细胞-细胞黏附和细胞运动的神经元连环蛋白--Delta-catenin的表达，并表明只要缺失一个等位基因就足以在体外损害内皮细胞的运动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。相反，Delta-catenin的一个或两个等位基因的缺失对激素诱导的子宫生理性血管生成没有影响。分子分析证实了β-连环蛋白对RhoGTP酶活性的基因剂量效应。此外，我们发现是炎性细胞因子而不是血管生成因子调节了Delta-catenin的表达，并且Delta-catenin的水平与人类肺癌呈正相关。综上所述，我们的数据表明，炎症通常与疾病状况有关，诱导DeltaCatenin的表达，这种表达专门调节病理性的，而不是生理性的血管生成。因为只有病理性血管生成对降低的β-连环蛋白水平敏感，这可能为抗血管生成治疗提供一个很好的靶点。

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.