Melanoma is highly metastatic and frequently metastasizes to the brain. Formation of melanoma brain metastasis is facilitated by the brain microenvironment. The main goal of our study is to elucidate the interactions between metastasizing melanoma cells (MMC) and cells in the brain microenvironment.
An insight into the early interactions between disseminated melanoma cells and the brain microenvironment is an essential pre-requisite for the development of effective targeted therapy that may prevent the formation of melanoma brain metastasis. We have developed an experimental mouse model in which we can characterize microenvironmental changes duringdifferent stages of brain metastasis, including pre-metastatic niche, micro- and macro- metastases. We found that dissemination of melanoma cells to brain occurs very early after orthotopic (skin) tumor implantation. Melanoma cells express the chemokine receptor CCR4. We found that CCR4 is up-regulated by both melanoma cells and brain stromal cells and that the up-regulation of CCR4 in brain stromal cells precedes the formation of brain metastases, suggesting that it may have a role in forming a hospitable pre-metastatic niche. Astrocytes are brain stromal cells that perform many functions in maintaining brain homeostasis. Astrocytes deregulation is thought to contribute to the pathogenesis of several diseases, including brain cancer and metastasis. In order to investigate the role of astrocytes in facilitating brain metastasis we are characterizing, in in vitro studies interactions between MMC and human astrocytes (HA) from primary cultures. It was found that HA induce migration of MMC. Moreover, Co-culturing MMC with HA modified expression of pro-inflammatory and pro-metastatic genes in HA.
Based on this study, we hypothesize that the dissemination of melanoma cells to the brain occurs very early following the orthotopic inoculation. Disseminated melanoma cells arrest along blood vessels,interact with brain endothelial cells and transduce signals to astrocytes. This tumor-microenvironment interaction may prepare a pre- metastatic niche for tumor colonization, growth and metastasis.
