Oncotarget

Research Papers:

Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis

Liyong Zhang, Yan Wang, Mohammad H. Rashid, Min Liu, Kartik Angara, Nahid F. Mivechi, Nita J. Maihle, Ali S. Arbab and Lan Ko _

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Oncotarget. 2017; 8:51591-51607. https://doi.org/10.18632/oncotarget.18196

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Abstract

Liyong Zhang1, Yan Wang1, Mohammad H. Rashid1, Min Liu2, Kartik Angara1, Nahid F. Mivechi1, Nita J. Maihle1,3, Ali S. Arbab1 and Lan Ko1,4

1Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA

2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

3Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA

4Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, USA

Correspondence to:

Lan Ko, email: LKO@augusta.edu

Keywords: angiogenesis, pericytes, oral cancer, glioblastoma

Received: October 21, 2016     Accepted: May 01, 2017     Published: May 25, 2017

ABSTRACT

Angiogenesis promotes tumor development. Understanding the crucial factors regulating tumor angiogenesis may reveal new therapeutic targets. Human GT198 (PSMC3IP or Hop2) is an oncoprotein encoded by a DNA repair gene that is overexpressed in tumor stromal vasculature to stimulate the expression of angiogenic factors. Here we show that pericytes expressing GT198 give rise to tumor cells through angiogenesis. GT198+ pericytes and perivascular cells are commonly present in the stromal compartment of various human solid tumors and rodent xenograft tumor models. In human oral cancer, GT198+ pericytes proliferate into GT198+ tumor cells, which migrate into lymph nodes. Increased GT198 expression is associated with increased lymph node metastasis and decreased progression-free survival in oral cancer patients. In rat brain U-251 glioblastoma xenografts, GT198+ pericytes of human tumor origin encase endothelial cells of rat origin to form mosaic angiogenic blood vessels, and differentiate into pericyte-derived tumor cells. The net effect is continued production of glioblastoma tumor cells from malignant pericytes via angiogenesis. In addition, activation of GT198 induces the expression of VEGF and promotes tube formation in cultured U251 cells. Furthermore, vaccination using GT198 protein as an antigen in mouse xenograft of GL261 glioma delayed tumor growth and prolonged mouse survival. Together, these findings suggest that GT198-expressing malignant pericytes can give rise to tumor cells through angiogenesis, and serve as a potential source of cells for distant metastasis. Hence, the oncoprotein GT198 has the potential to be a new target in anti-angiogenic therapies in human cancer.


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