CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche.
Highly metastatic and chemotherapy-resistant properties of malignant melanomas stand as challenging barriers to successful treatment; yet, the mechanisms responsible for their aggressive characteristics are not fully defined. We show that a distinct population expressing CD133 (Prominin-1), which is highly enriched after administration of a chemotherapeutic drug, dacarbazine, has enhanced metastatic potential in vivo. CD133(+) tumor cells are located close to tumor-associated lymphatic vessels in metastatic organs such as the regional lymph nodes and lung. Lymphatic endothelial cells promote the migratory activity of a CD133(+) subset to target organs and regulation of lymphatic growth efficiently modulates the metastasis of CD133(+) tumor cells. We found that lymphatic vessels in metastatic tissues stimulate chemokine receptor 4 (CXCR4)(+)/CD133(+) cell metastasis to target organs by secretion of stromal cell-derived factor-1 (SDF-1). The CXCR4(+)/CD133(+) cells exhibited higher metastatic activity compared with CXCR4(-)/CD133(+) cells and, importantly, blockade of CXCR4 coupled with dacarbazine efficiently inhibited both tumor growth and metastasis; dacarbazine alone could not attenuate tumor metastasis. The current study demonstrates a previously unidentified role of the lymphatic microenvironment in facilitating metastasis of chemoresistant melanoma cells via a specific chemotactic axis, SDF-1/CXCR4. Our findings suggest that targeting the SDF-1/CXCR4 axis in addition to dacarbazine treatment could therapeutically block chemoresistant CD133(+) cell metastasis toward a lymphatic metastatic niche.
National Research Laboratory of Vascular Biology and Stem Cells, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Minah
M
Kim
Young Jun
YJ
Koh
Kyung Eun
KE
Kim
Bong Ihn
BI
Koh
Do-Hyun
DH
Nam
Kari
K
Alitalo
Injune
I
Kim
Gou Young
GY
Koh
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001596:Benzylamines; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D003606:Dacarbazine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000473:pathology; D006023:Glycoproteins / Q000096:biosynthesis; D006571:Heterocyclic Compounds / Q000494:pharmacology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
D000071916:AC133 Antigen; D015703:Antigens, CD; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006023:Glycoproteins; D006571:Heterocyclic Compounds; D010455:Peptides; C000606024:Prom1 protein, mouse; D019718:Receptors, CXCR4; D003606:Dacarbazine; C088327:plerixafor