The Metastatic Microenvironment: Melanoma-Microglia Cross-Talk Promotes the Malignant Phenotype of Melanoma Cells.

Publication Title

International journal of cancer. Journal international du cancer

Authors

Sivan Izraely
Shlomit Ben-Menachem
Orit Sagi-Assif
Alona Telerman
Inna Zubrilov
Ofir Ashkenazi
Tsipi Meshel
Shelly Maman
Javier I J Orozco, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
Matthew P Salomon, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.Follow
Diego M Marzese, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.Follow
Metsada Pasmanik-Chor
Eli Pikarsky
Marcelo Ehrlich
Dave S B Hoon, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.Follow
Isaac P Witz

Document Type

Article

Publication Date

7-11-2018

Keywords

brain metastasis; melanoma; microglia

Abstract

Melanoma has the highest propensity to metastasize to the brain compared to other cancers, as brain metastases are found frequently high in patients who have prolonged survival with visceral metastasis. Once disseminated in the brain, melanoma cells communicate with brain resident cells that include astrocytes and microglia. Microglia cells are the resident macrophages of the brain, and are the main immunological cells in the CNS involved in neuroinflammation. Data on the interactions between brain metastatic melanoma cells and microglia and on the role of microglia-mediated neuroinflammation in facilitating melanoma brain metastasis is lacking. To elucidate the role of microglia in melanoma brain metastasis progression, we examined the bidirectional interactions between microglia and melanoma cells in the tumor microenvironment. We identified the molecular and functional modifications occurring in brain-metastasizing melanoma cells and microglia cells following the treatment of each cell type with supernatants of the counter cell type. Both cells induced alteration in gene expression programs, cell signaling and cytokine secretion in the counter cell type. Moreover, melanoma cells exerted significant morphological changes on microglia cells, enhanced proliferation, induced matrix metalloproteinase-2 (MMP-2) activation and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype: increased melanoma proliferation, MMP-2 activity, cell migration, brain endothelial penetration, and tumor cells ability to grow as spheroids in 3D cultures. Our work provides a novel insight into the bi-directional interactions between melanoma and micoglia cells, suggesting the contribution of microglia to melanoma brain metastasis formation. This article is protected by copyright. All rights reserved.

Clinical Institute

Cancer

Specialty/Research Institute

Oncology