Oncotarget

Priority Research Papers:

Knockout of MDA-9/Syntenin (SDCBP) expression in the microenvironment dampens tumor-supporting inflammation and inhibits melanoma metastasis

Swadesh K. Das _, Chunqing Guo, Anjan K. Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xue-Ning Shen, Luni Emdad, Mark A. Subler, Jolene J. Windle, Devanand Sarkar, Xiang-Yang Wang and Paul B. Fisher

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Oncotarget. 2016; 7:46848-46861. https://doi.org/10.18632/oncotarget.10040

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Abstract

Swadesh K. Das1,2,3, Chunqing Guo1, Anjan K. Pradhan1, Praveen Bhoopathi1, Sarmistha Talukdar1, Xue-Ning Shen1, Luni Emdad1,2,3, Mark A. Subler1, Jolene J. Windle1,2,3, Devanand Sarkar1,2,3, Xiang-Yang Wang1,2,3 and Paul B. Fisher1,2,3

1 Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA

2 VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA

3 VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA

Correspondence to:

Swadesh K. Das, email:

Paul B. Fisher, email:

Keywords: melanoma differentiation associated gene-9/syntenin (mda-9/syntenin), syndecan binding protein (SDCBP), tumor microenvironment, myeloid-derived tumor suppressor cells (MDSC), interleukin -17A (IL-17A)

Received: March 09, 2016 Accepted: May 25, 2016 Published: June 21, 2016

Abstract

Cancer development and progression to metastasis is a complex process, which largely depends on bidirectional communication between tumor cells and their microenvironment. Melanoma differentiation associated gene-9 (mda-9, also known as Syntenin-1, SDCBP), a gene first cloned by our group, is robustly expressed in multiple cancers including melanoma and contributes to invasion and metastasis in a tumor cell-intrinsic manner. However, the role of MDA-9/Syntenin in the tumor cell-extrinsic microenvironment remains unclear even though MDA-9/Syntenin is ubiquitously expressed in most organs that are active metastatic sites for melanoma, e.g., lung, lymph node, brain, and liver. In this study, we explored the effect of environmental mda-9/syntenin expression on melanoma growth and metastasis using multiple immunocompetent animal models, syngeneic B16 xenograft and intravenous B16 mouse model and a genetically engineered mouse (GEM) model of melanoma. Host-deficient expression of mda-9/syntenin in mice negatively impacted on subcutaneously implanted B16 tumor growth and lung metastasis. Absence of MDA-9/Syntenin in the lung microenvironment suppressed tumor growth by modulating in situ Interleukin 17A (IL17A) expression and impaired the recruitment of myeloid derived suppressor cells (MDSCs) and Th17 cells as compared to genetically wild type animals. Additionally, loss of mda-9/syntenin expression in a spontaneous melanoma model (melanocyte-specific pten loss and BrafV600E mutation) significantly delayed tumor initiation and suppressed metastasis to the lymph nodes and lungs. The present study highlights a novel role of mda-9/syntenin in tumor-promoting inflammation and immune suppression. These observations along with other documented roles of MDA-9/Syntenin in cancer and metastasis support the potential relevance of MDA-9/Syntenin in the carcinogenic process and as a target for developing improved therapies by using either genetic or pharmacologic approaches to treat and prevent melanoma and other cancers.


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