Do Metastatic Melanoma Cells Utilize CD40-CD40L Axis in the Post-Stroke Regenerative Niche for the Establishment of Brain Metastasis?

Stroke and metastasis are devastating diseases with significant mortality and morbidity. Post-stroke regeneration and brain metastasis could consist of overlapping cellular and molecular processes, including: angiogenesis, inflammation and secretion of inflammatory mediators. Therefore, further investigation of the molecular pathways shared by the regenerative niche after stroke and brain metastasis is required.

CD40-CD40L signaling has been shown to play a major role in inducing the pro-inflammatory phenotype after stroke. In the CNS, CD40 is expressed on a variety of cells, including brain endothelial cells (BECs), astrocytes and microglia. In addition, plasma levels of CD40L in patients after stroke is significantly increased. Thus, CD40 and CD40L constitute important molecular targets for therapeutic intervention of diseases.

We found that brain metastatic melanoma cells express CD40. Also, we found that "stroked" BECs and astrocytes secret higher levels of CD40L than "non-stroked" cells. In Addition, brain metastatic melanoma cells migrate significantly better through BECs stimulated by recombinant CD40L (rhCD40) than through unstimulated BECs. Stimulation of BECs, and brain metastatic melanoma cells with rhCD40L elevated the levels of phosphorylated JNK, compared to the basic phosphorylation level.

In view of these data, the fact that CD40 is expressed by BECs, secreted CD40L from these cells could induce, by an autocrine mechanism, the expression of adhesion molecules on BECs. This in turn could mediate adhesion of brain metastatic melanoma cells to BECs. The activation of JNK signaling in brain metastatic melanoma cells could increase trans-endothelial migration and subsequently the formation of brain metastasis.

The therapeutic options for both melanoma metastasis and stroke are extremely limited. Uncovering common mechanisms may lead to a novel druggable system that could manipulate cancer progression and neural repair.