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

by Bhuvanasundar Renganathan, Vinoth Durairaj, Dogan Can Kirman, Paa Kow A. Esubonteng, Swee Kim Ang and Ruowen Ge

Cancers 2018, 10(6), 192; https://doi.org/10.3390/cancers10060192 - 11 Jun 2018

Cited by 9 | Viewed by 4279

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Tumor Angiogenesis: An Update)

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13 pages, 564 KiB

Open AccessReview

Mechanisms of Lysophosphatidic Acid-Mediated Lymphangiogenesis in Prostate Cancer

by Pei-Yi Wu, Yueh-Chien Lin, Yuan-Li Huang, Wei-Min Chen, Chien-Chin Chen and Hsinyu Lee

Cancers 2018, 10(11), 413; https://doi.org/10.3390/cancers10110413 - 31 Oct 2018

Cited by 17 | Viewed by 4609

Abstract

Prostate cancer (PCa) is the most common noncutaneous cancer in men worldwide. One of its major treatments is androgen deprivation therapy, but PCa frequently relapses as aggressive castration resistant local tumors and distal metastases. Hence, the development of novel agents or treatment modalities [...] Read more.

Prostate cancer (PCa) is the most common noncutaneous cancer in men worldwide. One of its major treatments is androgen deprivation therapy, but PCa frequently relapses as aggressive castration resistant local tumors and distal metastases. Hence, the development of novel agents or treatment modalities for advanced PCa is crucial. Many tumors, including PCa, first metastasize to regional lymph nodes via lymphatic vessels. Recent findings demonstrate that the bioactive lipid lysophosphatidic acid (LPA) promotes PCa progression by regulating vascular endothelial growth factor-C (VEGF-C), a critical mediator of tumor lymphangiogenesis and lymphatic metastasis. Many of the underlying molecular mechanisms of the LPA–VEGF-C axis have been described, revealing potential biomarkers and therapeutic targets that may aid in the diagnosis and treatment of advanced PCa. Herein, we review the literature that illustrates a functional role for LPA signaling in PCa progression. These discoveries may be especially applicable to anti-lymphangiogenic strategies for the prevention and therapy of metastatic PCa. Full article

(This article belongs to the Special Issue Tumor Angiogenesis: An Update)

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25 pages, 1924 KiB

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The Methylation Status of the Epigenome: Its Emerging Role in the Regulation of Tumor Angiogenesis and Tumor Growth, and Potential for Drug Targeting

by Luciano Pirola, Oskar Ciesielski and Aneta Balcerczyk

Cancers 2018, 10(8), 268; https://doi.org/10.3390/cancers10080268 - 10 Aug 2018

Cited by 32 | Viewed by 6948

Abstract

Approximately 50 years ago, Judah Folkman raised the concept of inhibiting tumor angiogenesis for treating solid tumors. The development of anti-angiogenic drugs would decrease or even arrest tumor growth by restricting the delivery of oxygen and nutrient supplies, while at the same time [...] Read more.

Approximately 50 years ago, Judah Folkman raised the concept of inhibiting tumor angiogenesis for treating solid tumors. The development of anti-angiogenic drugs would decrease or even arrest tumor growth by restricting the delivery of oxygen and nutrient supplies, while at the same time display minimal toxic side effects to healthy tissues. Bevacizumab (Avastin)—a humanized monoclonal anti VEGF-A antibody—is now used as anti-angiogenic drug in several forms of cancers, yet with variable results. Recent years brought significant progresses in our understanding of the role of chromatin remodeling and epigenetic mechanisms in the regulation of angiogenesis and tumorigenesis. Many inhibitors of DNA methylation as well as of histone methylation, have been successfully tested in preclinical studies and some are currently undergoing evaluation in phase I, II or III clinical trials, either as cytostatic molecules—reducing the proliferation of cancerous cells—or as tumor angiogenesis inhibitors. In this review, we will focus on the methylation status of the vascular epigenome, based on the genomic DNA methylation patterns with DNA methylation being mainly transcriptionally repressive, and lysine/arginine histone post-translational modifications which either promote or repress the chromatin transcriptional state. Finally, we discuss the potential use of “epidrugs” in efficient control of tumor growth and tumor angiogenesis. Full article

(This article belongs to the Special Issue Tumor Angiogenesis: An Update)

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