The metastatic microenvironment: Brain-derived soluble factors alter the malignant phenotype of cutaneous and brain-metastasizing melanoma cells.

Int J Cancer. 2012 Dec 1;131(11):2509-18.

Anat Klein, Orit Sagi-Assif, Sivan Izraely, Tsipi Meshel, Metsada Pasmanik-Chor, Clara Nahmias, Pierre-Olivier Couraud, Neta Erez, Dave S.B. Hoon and Isaac P. Witz

Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

 

Abstract:

BACKGROUND: The frequency of Brain metastasis in melanoma patients is increasing, presenting a significant cause of death in these patients. The working hypothesis of this study is that the interactions between the brain microenvironment and melanoma cells determine metastasis formation at this organ site. The aim of the study was to evaluate the contribution of such interactions to the formation of brain metastasis in nude mice xenografted with human melanoma cells. An insight into these interactions is an essential prerequisite for the development of effective targeted therapy for melanoma brain metastasis.

METHODS: We assessed the effects of soluble factors present in supernatants of short-term cultures of normal mouse brain (referred here after as brain-derived soluble factors – BDSF) on cutaneous and brain metastasizing human melanoma cell variants. As these variants originated from single melanoma tumors they have a common genetic background. Any genetic or phenotypic differences between these variants are therefore linked to differences in their malignancy phenotype.

RESULTS: We found that BDSF affect differentially cutaneous and brain-metastasizing melanoma cells variants in vitro. Such factors enhanced the viability of cutaneous melanoma cells but caused an S phase arrest followed by apoptosis of brain-metastasizing cells. BDSF enhanced the migration of melanoma cells metastasizing to the brain, but did not affect the migration of the cutaneous variants. Such factors up-regulated the expression of the chemokine receptor CCR4 in both cutaneous and brain-metastasizing melanoma cells. BDSF also enhanced the transmigration, across human brain endothelial cells, of cutaneous but not of brain-metastasizing melanoma variants.

IMPACT: These results indicate that the brain microenvironment exerts differential effects on cutaneous brain-metastasizing melanoma cells. Brain-derived soluble factors may take part in shaping the malignancy phenotype of melanoma cells both before such tumor cells reach this metastatic microenvironment as well as during their residence at that microenvironment. Therefore, targeting tumor-promoting microenvironmental interactions could modify tumor progression to the benefit of cancer patients, and hence, should be further explored.

 

Isaac P. Witz-1

 

Figure 1: Brain derived soluble factors (BDSF) differentially affect cutaneous and brain metastasizing melanoma cells. BDSF enhanced the viability of cutaneous melanoma cells but caused an S phase arrest followed by apoptosis of brain-metastasizing cells. BDSF enhanced the migration of melanoma cells metastasizing to the brain, but did not affect the migration of the cutaneous variants. Such factors up-regulate the chemokine receptor CCR3 and CCR4 in both cutaneous and brain-metastasizing melanoma cells.

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