RETRACTED ARTICLE: Inhibition of Tumor Angiogenesis by Tumstatin: Insights into Signaling Mechanisms and Implications in Cancer Regression

Abstract

Growing tumors develop additional new blood vessels to meet the demand for adequate nutrients and oxygen, a process called angiogenesis. Cancer is a highly complex disease promoted by excess angiogenesis; interfering with this process poses for an attractive approach for controlling tumor growth. This hypothesis led to the identification of endogenous angiogenesis inhibitors generated from type IV collagen, a major component of vascular basement membrane (VBM). Type IV collagen and the angiogenesis inhibitors derived from it are involved in complex roles, than just the molecular construction of basement membranes. Protease degradation of collagens in VBM occurs in various physiological and pathological conditions and produces several peptides. Some of these peptides are occupied in the regulation of functions conflicting from those of their original integral molecules. Tumstatin (α3(IV)NC1), a proteolytic C-terminal non-collagenous (NC1) domain from type IV collagen α3 chain has been highlighted recently because of its potential role in anti-angiogenesis, however its biological actions are not limited to these processes. α3(IV)NC1 inhibits proliferation by promoting endothelial cell apoptosis and suppresses diverse tumor angiogenesis, thus making it a potential candidate for future cancer therapy. The present review surveys the physiological functions of type IV collagen and discovery of α3(IV)NC1 as an antiangiogenic protein with a comprehensive overview of the knowledge gained by us towards understanding its signaling mechanisms.

Dose/dense metronomic chemotherapy with fractioned cisplatin and oral daily etoposide enhances the anti-angiogenic effects of bevacizumab in advanced non-small-cell-lung cancer patients

“…We finally measured the serum levels of collagen IV, a basic component of endothelial cells' basal membrane. 24 After three cycles of treatment, we found a significant reduction of this protein, with a maximal decrease observed again in patients who underwent dose/dense chemotherapy without bevacizumab (Fig. 2D).…”

Inhibition of angiogenesis by a synthetic fusion protein VTF derived from vasostatin and tumstatin

“…The N-terminus of tumstatin peptide was fused to the C-terminus of vasostatin fragment through a flexible linker GSGGSG to ensure that the function of either fragment could not influence each other. Previous research has shown that the antiangiogenic property of tumstatin resides within a 25-amino acid peptide region and is independent of disulfide bond linkage [9,21]. For VTF fusion construction, the amino acids 69-99 of tumstatin were selected, which include six flanking amino acids in addition to the previously identified 74-98 peptide domain.…”

COL4A3 expression correlates with pathogenesis, pathologic behaviors, and prognosis of gastric carcinomas

“…Another immunohistochemical study indicated that tumstatin was expressed largely in well-differentiated lung carcinomas, where it could reduce tumor vascularity and thereby limit tumor progression [27]. Both matrix metalloproteinases 2 and 9 are necessary for the biologic production of tumstatin from COL4A3 [28]. Although COL4A3 expression is decreased from gastric IM to carcinoma, it correlated positively with the aggressive characteristics of carcinomas, including tumor size, lymphatic invasion, venous invasion, and TNM stage.…”