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.
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