Suppression of KSHV-induced angiopoietin-2 inhibits angiogenesis, infiltration of inflammatory cells, and tumor growth.
Kaposi's sarcoma (KS) is a highly angiogenic and inflammatory neoplasia. The angiogenic and inflammatory cytokine angiopoietin-2 (Ang-2) is strongly expressed in KS due to Kaposi's sarcoma-associated herpesvirus (KSHV) infection. In the present study, we determined how Ang-2 contributes to development of KS by using telomerase-immortalized human umbilical vein endothelial cells (TIVE) as a model, which become malignantly transformed and express increased levels of Ang-2 following KSHV infection. Ang-2 released from TIVE-KSHV cells induces tyrosine phosphorylation of Tie-2 receptor from both human and mouse endothelial cells and promotes angiogenesis in nude mice. Functional inhibition or expressional "knock-down" of Ang-2 in these cells blocks angiogenesis and inhibits tumor growth. Ang-2 suppression also reduces the numbers of infiltrating monocytes/macrophages in tumors. In transwell-based cell migration assays, Ang-2 indeed enhances migration of human monocytes in a dose-dependent manner. These results underscore a pivotal role of KSHV-induced Ang-2 in KS tumor development by promoting both angiogenesis and inflammation. Our data also suggest that selective drug targeting of Ang-2 may be used for treatment of KS.
a Department of Biological Sciences , School of Dental Medicine, Case Western Reserve University , Cleveland , OH , USA.|b Hubei Collaborative Innovation Center for Green Transformation of Bio-resources, College of Life Sciences, Hubei University , Wuhan , Hubei , China.
Xiaolan
X
Yu
a Department of Biological Sciences , School of Dental Medicine, Case Western Reserve University , Cleveland , OH , USA.
Jingfeng
J
Sha
a Department of Biological Sciences , School of Dental Medicine, Case Western Reserve University , Cleveland , OH , USA.
Shao
S
Xiang
a Department of Biological Sciences , School of Dental Medicine, Case Western Reserve University , Cleveland , OH , USA.
Sanhai
S
Qin
c Department of Genetics , School of Medicine, Case Western Reserve University , Cleveland , OH , USA.
Patricia
P
Conrad
a Department of Biological Sciences , School of Dental Medicine, Case Western Reserve University , Cleveland , OH , USA.
Santosh K
SK
Ghosh
a Department of Biological Sciences , School of Dental Medicine, Case Western Reserve University , Cleveland , OH , USA.
Aaron
A
Weinberg
a Department of Biological Sciences , School of Dental Medicine, Case Western Reserve University , Cleveland , OH , USA.
Fengchun
F
Ye
D042702:Angiopoietin-2 / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D019288:Herpesvirus 8, Human / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology* / Q000821:virology; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000821:virology*; D010766:Phosphorylation / Q000187:drug effects; D042787:Receptor, TIE-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D019098:Telomerase / Q000378:metabolism; D020298:U937 Cells
D042702:Angiopoietin-2; D011993:Recombinant Fusion Proteins; D042787:Receptor, TIE-2; D019098:Telomerase; C551398:trebananib
KSHV; and Kaposi's sarcoma; angiogenesis; angiopoietin-2; inflammation