Figure 3

Hypothetical model of malignant melanoma-initiating cell (MMIC) homing and extravasation into secondary tissues. (a) Step 1: circulating MMICs co-expressing the MMIC markers ABCB5 and CD271 tether and roll in blood flow on microvascular endothelial cells of the metastatic target tissue. MMIC tethering and rolling might involve binding between constitutively active MMIC α4β1 integrin and endothelial VCAM-1 as well as potentially MMIC E-selectin glycoprotein and glycolipid ligands interacting with endothelial E-selectin. Step 2: rolling MMICs might then transition to firm adherence upon α5β1 integrin (elevated on MMICs) engagement with its major endothelial ligand, fibronectin (FN). Step 3: MMICs might traverse endothelial cell–cell junctions via α5β1 and α6β4 (also elevated on MMICs) binding to putative surface and basement membrane integrin ligands, FN and laminin (LN), respectively. MMIC transendothelial migration might further involve IL-8 and SDF1 binding CXCR1 and CXCR4, respectively, mechanosignaling circuits identified previously in migratory melanoma cells and CSCs in other cancers. Note that several other integrins, chemokine receptors and chemokines identified previously on bulk melanoma cells or CSCs in other cancers yet heretofore not analyzed on MMICs may also contribute to MMIC rolling, firm adhesion and transmigration via activation of integrins or induction of directional movement. Also unclear is the role of β2 integrins in MMIC dissemination. Aside from the aforementioned homing molecules, additional factors may promote MMIC-driven metastasis formation. For instance, vasculogenic markers, including VEGR-1, VE-cadherin, and TIE-1, known to be preferentially expressed by MMICs, could help foster a metastatic niche and facilitate tumor expansion in the metastatic target tissue. (b) A second possibility in melanoma extravasation involves the contribution of leukocytes, wherein neutrophils are believed to bind melanoma expressed ICAM-1 via αLβ2 and αMβ2 integrins, thereby bridging melanoma cells to the endothelial layer. The neutrophil, anchored to the endothelium via ICAM-1-β2 integrin and E-selectin-E-selectin ligand interactions, as depicted, might then help to drag the melanoma cell through the endothelial layer (not shown). Whether MMICs utilize a similar process is unclear.