Fig. 2

The many routes to brain metastasis for melanoma. a Schematic representation of the dissemination of melanoma cells to the brain. Important factors are the Pleckstrin Homology Domain Containing, Family A Member 5 (PLEKHA5), which mediates cells’ transmigration through the BBB and the chemokine receptor CCR4 and its ligand CCL17. CCR4⁺ melanoma cells are probably “homed” to the brain by astrocyte-secreted CCL17; loss of the Phosphatase and Tensin Homolog (PTEN) is frequently observed and leads to hyperactivation of the PI3K/AKT pathway, which can be mimicked by the forced expression of activated AKT1. CD271 may serve as both a “homing” receptor that guides melanoma cells to the brain and a survival factor. Following migration to and intravasation into blood vessels, melanoma cells disseminate either hematogeneously or via lymphatic vessels (not shown). Cells which survive passage through the circulation need to transmigrate through the BBB through a process such as disrupting endothelial tight junctions or secreting of proteolytic enzymes. The BBB is composed of tightly connected endothelial cells which are in close proximity to perivascular endfeet of astrocytes. b In the brain, activated astrocytes secrete IL23 or CCL17 or exosome-loaded PTEN targeting miRNAs. The binding of IL23 to the receptor heterodimer IL23R/IL12Rβ1 induces STAT3 phosphorylation and expression of MMP2. Secreted CCL17 attracts CCR4⁺ melanoma cells and CCL17 binding to CCR4 induces the expression of MMP13 through NFkB. The loss of PTEN in brain metastatic melanoma cells induces the secretion of CCL2 which in turn leads to the recruitment of Iba1⁺ myeloid cells. The latter promote the proliferation of brain metastatic melanoma cells. Expression of the negative regulator of STAT-signaling SOCS1 (suppressor of cytokine signaling 1) was down-regulated in melanoma BM. c Cerebral migration of melanoma cells is facilitated through the binding of pro-NGF to the NGF-receptor (CD271, NGFR, p75^NTR) and the secretion of HPSE1. d Upper panels: CD271⁺ cells were found in brain micro- and macro-metastases. Lower panels: Brain slice cultures of A375^GFP or A375^CD271/NGFR cells revealed an extensive migration of melanoma cells with endogenous or stable forced expression of CD271