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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
Stone, Oliver A; Carter, James G; Lin, P Charles et al. (2017) Differential regulation of blood flow-induced neovascularization and mural cell recruitment by vascular endothelial growth factor and angiopoietin signalling. J Physiol 595:1575-1591
Qu, Peng; Wang, Li-Zhen; Lin, P Charles (2016) Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment. Cancer Lett 380:253-6
Qu, Peng; Wang, Lizhen; Min, Yongfen et al. (2016) Vav1 Regulates Mesenchymal Stem Cell Differentiation Decision Between Adipocyte and Chondrocyte via Sirt1. Stem Cells 34:1934-46
Babaev, Vladimir R; Ding, Lei; Zhang, Youmin et al. (2016) Macrophage IKK? Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis. Arterioscler Thromb Vasc Biol 36:598-607
Kim, Sinae; Song, Jin Hoi; Kim, Seokho et al. (2016) Loss of oncogenic miR-155 in tumor cells promotes tumor growth by enhancing C/EBP-?-mediated MDSC infiltration. Oncotarget 7:11094-112
Wang, Yifan; Liu, Jingyi; Ying, Xuhua et al. (2016) Twist-mediated Epithelial-mesenchymal Transition Promotes Breast Tumor Cell Invasion via Inhibition of Hippo Pathway. Sci Rep 6:24606
Jian, Jiang; Pang, Yanli; Yan, H Hannah et al. (2016) Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis. Oncotarget :
Ghose, Sampa; Min, Yongfen; Lin, P Charles (2015) ?-Catenin activates Rho GTPase, promotes lymphangiogenesis and growth of tumor metastases. PLoS One 10:e0116338
Zuo, Zhenghong; Che, Xun; Wang, Yulei et al. (2014) High mobility group Box-1 inhibits cancer cell motility and metastasis by suppressing activation of transcription factor CREB and nWASP expression. Oncotarget 5:7458-70
Tong, Xiaozhe; Lv, Gang; Huang, Jianhua et al. (2014) Gr-1+CD11b+ myeloid cells efficiently home to site of injury after intravenous administration and enhance diabetic wound healing by neoangiogenesis. J Cell Mol Med 18:1194-202

Showing the most recent 10 out of 23 publications