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.
Highlights
Metastasis is a multifaceted process that initiates with the migration of tumor cells from a primary site and culminates in the formation of new secondary tumors in distant organs [1]
The primary direction of research on MDA-9/ Syntenin (SDCBP) in cancer over the past two decades focused on defining its role in the context of tumor cells from different organ sites (7-11, 30,31,33,45,52,53) expression is significantly lower in normal vs. transformed cells, the MDA-9/Syntenin protein is ubiquitously expressed in the mouse and in adult human organs, e.g., skin, liver, gall bladder, colon
Tamura et al first demonstrated that knockout of MDA-9 in mice was not embryonic lethal and mice that developed did not show obvious abnormalities when grown in pathogen-free conditions [28]
Summary
Metastasis is a multifaceted process that initiates with the migration of tumor cells from a primary site and culminates in the formation of new secondary tumors in distant organs [1]. Through mechanisms that require further clarification, specific biochemical and molecular changes, either induced by invading cancer cells or occurring as spontaneous events, can disrupt this organization and facilitate tumor cell colonization and growth [3]. Numerous studies support the importance of cross talk between the resident cells (in target organs) and invading cells in mediating metastasis [3]. The homing organ can serve as a ‘perfect ecosystem’ that can provide nutritional support and protection from the immune system to facilitate tumor growth
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