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.
Highlights
Angiogenesis has long been recognized as a hallmark of cancer [1, 2], and is essential for the development of many, if not all, human solid tumors [3,4,5]
The current results suggest that angiogenic GT198+ pericytes are frequently present in tumor stroma of multiple types of human solid tumors
Using the oncoprotein GT198 as a marker, we report here that malignant pericytes expressing GT198 give rise to tumor cells through the process of angiogenesis
Summary
Angiogenesis has long been recognized as a hallmark of cancer [1, 2], and is essential for the development of many, if not all, human solid tumors [3,4,5]. Angiogenesis with the formation of new blood vessels is a normal biological process during embryonic development and in adult tissue repair [7,8,9]. This process is hijacked in tumor development. We provide evidence to support existing angiogenesis hypotheses [27], and suggest that the presence of oncoprotein-stimulated malignant pericytes is a shared defect in tumor angiogenesis
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