New Model System to Aid Studies on Melanoma's Metastasis to the Brain

Cancer investigators have established a mouse model system for the study of the molecular mechanisms that control the metastasis of melanoma from the skin to the brain.

Brain metastasis occurs frequently in melanoma patients with advanced disease, and when this happens, the prognosis is dismal. To better understand why melanoma spreads to the brain investigators at Tel Aviv University (Israel) generated a reproducible melanoma brain metastasis model, consisting of brain-metastasizing variants and local, subdermal variants that originated from the same melanomas, thus sharing a common genetic background.

The brain-metastasizing variants were obtained by intracardiac inoculation. Brain metastasis variants when inoculated into mice subdermally yielded spontaneous brain dormant micrometastasis. Cultured cells from the spontaneous brain micrometastasis grew very well in vitro and generated subdermal tumors that did not metastasize to the brain after an inoculation into the skin.

The investigators reported in the September 1, 2012, issue of the International Journal of Cancer that expression analysis assays indicated that the brain metastasis and micrometastasis cells expressed higher levels of angiopoietin-like 4, prostaglandin-synthesizing enzyme cyclooxygenase-2, matrix metalloproteinase-1 and preferentially expressed antigen in melanoma, and lower levels of claudin-1 and cysteine-rich protein 61 than the corresponding cutaneous variants.

"This is a good way for us to concentrate on the genes that are specific to metastatic cells. Because we have these two types of cellular variants, where only one goes to the brain and metastasizes, it is an important tool for future research," said senior author Dr. Isaac Witz, professor of immunology at Tel Aviv University. "These interactions between the chemokines in the brain and the melanoma cell receptors could be potential targets for new therapies. With medications that suppress these molecules, you could hope to interfere with this specific migration. If there already is metastasis, it is too late — so what we want to do is to prevent development by understanding the mechanism that keeps the non-metastatic cells dormant."

The investigators hope that the establishment of reproducible models of human melanoma that metastasize experimentally and spontaneously to the brain will facilitate the identification of novel biomarkers and targets for therapy and contribute to the deciphering of mechanisms underlying melanoma metastasis.

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Tel Aviv University