Recombinant TSR1 of ADAMTS5 Suppresses Melanoma Growth in Mice via an Anti-angiogenic Mechanism.

Bhuvanasundar Renganathan,Vinoth Durairaj,Ruowen Ge,Paa Esubonteng,Swee Ang,Dogan Kirman

doi:10.3390/cancers10060192

Bhuvanasundar Renganathan, Vinoth Durairaj + Show 4 more

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https://doi.org/10.3390/cancers10060192

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Journal: Cancers	Publication Date: Jun 11, 2018
Citations: 8	License type: CC BY 4.0

Affiliation: National University of Singapore

Abstract

Inhibiting tumor angiogenesis is a well-established approach for anticancer therapeutic development. A Disintegrin-like and Metalloproteinase with ThromboSpondin Motifs 5 (ADAMTS5) is a secreted matrix metalloproteinase in the ADAMTS family that also functions as an anti-angiogenic/anti-tumorigenic molecule. Its anti-angiogenic/anti-tumorigenic function is independent from its proteinase activity, but requires its first thrombospondin type 1 repeat (TSR1). However, it is not known if recombinant TSR1 (rTSR1) can function as an anticancer therapeutic. In this report, we expressed and purified a 75-residue recombinant TSR1 polypeptide from E. coli and investigated its ability to function as an anticancer therapeutic in mice. We demonstrate that rTSR1 is present in the blood circulation as well as in the tumor tissue at 15 min post intraperitoneal injection. Intraperitoneal delivery of rTSR1 potently suppressed subcutaneous B16F10 melanoma growth as a single agent, accompanied by diminished tumor angiogenesis, increased apoptosis, and reduced cell proliferation in the tumor tissue. Consistently, rTSR1 dose-dependently induced the apoptosis of cultured human umbilical vein endothelial cells (HUVECs) in a caspase-dependent manner. This work indicates that rTSR1 of ADAMTS5 can function as a potent anticancer therapy in mice. It thus has the potential to be further developed into an anticancer drug.

Highlights

The tumor microenvironment predominantly displays excessive angiogenesis, due to the high level of pro-angiogenic factors present [1]
We showed that this anticancer function is independent of the catalytic activity of ADAMTS5, but is mediated by its central ThromboSpondin independent of the catalytic activity of ADAMTS5, but is mediated by its central ThromboSpondin type 1 repeat domain (TSR1)
We reported that E. coli produced recombinant TSR1, but not the C-terminus TSR2, which inhibits human umbilical recombinant TSR1, but not the C-terminus TSR2, which inhibits human umbilical vein endothelial cell (HUVEC) tube formation and proliferation in vitro

Summary

Introduction

The tumor microenvironment predominantly displays excessive angiogenesis, due to the high level of pro-angiogenic factors present [1]. Endogenous angiogenesis inhibitor proteins have gained much attention owing to their high specificity and low side effects [3,4]. A Disintegrin-like and Metalloproteinase with ThromboSpondin Motifs 5 (ADAMTS5) is an extracellular proteoglycanase of the ADAMTS family. It is widely studied for its role in osteoarthritis, as the main aggrecanase that cleaves aggrecans in the articular cartilage [5,6]. Contrasting roles for ADAMTS5 have been reported with regards to cancer. A recent report indicated that high ADAMTS5 expression in colorectal cancer patients correlated with higher levels of lymphatic invasion and lymph node

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