1. IL-32 in inflammatory diseases. Humans differ from other animals in many aspects of anatomy, physiology and behavior;however, the genotypic basis of most human-specific traits remains largely unknown. Understanding these genetic differences of humans from other species has major implications to our health. Interleukin-32 (IL-32) is a newly discovered cytokine, which is highly expressed in vascular endothelium, and pro-inflammatory cytokines upregulate its expression. We found that IL-32 sensitizes endothelial response to inflammatory cytokine stimulation in cell adhesion molecule expression and leukocyte adhesion on endothelium. During disease initiation, leukocytes must first adhere to inflamed vasculature, then migrate through the vessel wall before accumulating in target tissues. Thus, the interaction of leukocytes with inflamed endothelium is a paramount process in disease development. Consistently, endothelial expression of IL-32 in transgenic mice elevated inflammation and worsened sepsis. Since inflammation closely links to tumorigenesis, we observed a significant elevation of IL-32 in human tumor samples, and expression of IL-32 in vivo changed the tumor microenvironment and enhanced tumor progression, supporting a positive role of IL-32 in inflammation associated tumor development. In addition, in collaboration with Dr Howard Young at the CCR, we found that expression of IL-32 in mice leads to a lupus phenotype. Current effort is engaged to determine the molecular and cellular mechanisms, as well as determine the correlation of IL-32 expression in lupus patient samples in collaboration with Dr Tom Anue at Vanderbilt University.2. Interaction of Vav and delta-catenin in vascular formation and vascular homeostasis. 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 reported that delta-catenin, a neuronal catenin, is also expressed in vascular endothelial cells, and deletion of only one allele of delta-catenin in mice is sufficient to impair endothelial cell motility and vascular assembly in vitro and pathological angiogenesis in vivo, thereby inhibiting tumor growth. In contrast, deletion of one or both allele of delta-catenin had no effects on hormone-induced physiological angiogenesis in the uterus. Because only pathological angiogenesis is sensitive to decreased levels of delta-catenin, this may provide a good target for anti-angiogenic therapy. Further analysis suggests that delta-catenin regulates RhoGTPase activity via interacting with Vav1, a guanine nucleotide exchange factor (GEF). Vav1 is specifically expressed in hematopoietic cells and regulates cell differentiation. Since hematopoietic cells and endothelial cells share a common progenitor, Vav1 is also detected in vascular endothelium. However, its function in the vasculature is currently unknown. Our initial analysis indicates that Vav1 possesses opposite roles in angiogenesis and vasculogenesis. Consistent with its GEF function, neutralization of Vav1 in endothelial cells impaired cell motility and angiogenesis. Unexpectedly, genetic deletion of Vav1 in mice resulted in a significant increase of tumor vascular formation and tumor growth. We found significant more endothelial progenitor cells (EPCs) in Vav1 null mice than in wild type mice. Interestingly, replacement of Vav1 null bone marrow with bone marrow from wild type mice completely abolished the promotion of tumor vascular formation and tumor growth. These data imply that Vav1 negatively regulates vasculogenesis and this is sufficient to overcome angiogenic defects. Moreover, deletion of Vav1 caused a decrease of basement membrane and an increase of vascular leakiness. Together, these findings illustrate important and complex functions of Vav1 and delta catenin interaction in vascular formation and integrity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011390-02
Application #
8553146
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2012
Total Cost
$1,834,539
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
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
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
Zhou, Weiying; Fong, Miranda Y; Min, Yongfen et al. (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25:501-15

Showing the most recent 10 out of 23 publications