Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes.
Chemokines and their receptors play key roles in leukocyte trafficking and are also implicated in cancer metastasis to specific organs. Here we show that mouse B16F10 melanoma cells constitutively express chemokine receptor CXCR3, and that its ligands CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC induce cellular responses in vitro, such as actin polymerization, migration, invasion, and cell survival. To determine whether CXCR3 could play a role in metastasis to lymph nodes (LNs), we constructed B16F10 cells with reduced CXCR3 expression by antisense RNA and investigated their metastatic activities after s.c. inoculations to syngeneic hosts, C57BL/6 mice. The metastatic frequency of these cells to LNs was markedly reduced to approximately 15% (P < 0.05) compared with the parental or empty vector-transduced cells. On the other hand, pretreatment of mice with complete Freund's adjuvant increased the levels of CXCL9 and CXCL10 in the draining LNs, which caused 2.5-3.0-fold increase (P < 0.05) in the metastatic frequency of B16F10 cells to the nodes with much larger foci. Importantly, such a stimulation of metastasis was largely suppressed when CXCR3 expression in B16F10 cells was reduced by antisense RNA or when mice were treated with specific antibodies against CXCL9 and CXCL10. We also demonstrate that CXCR3 is expressed on several human melanoma cell lines as well as primary human melanoma tissues (5 of 9 samples tested). These results suggest that CXCR3 inhibitors may be promising therapeutic agents for treatment of LN metastasis, including that of melanoma.
Kawada
Kenji
K
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto.
Sonoshita
Masahiro
M
Sakashita
Hiromi
H
Takabayashi
Arimichi
A
Yamaoka
Yoshio
Y
Manabe
Toshiaki
T
Inaba
Kayo
K
Minato
Nagahiro
N
Oshima
Masanobu
M
Taketo
Makoto Mark
MM
D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D003599:Cytoskeleton / Q000378:metabolism; D022001:Focal Adhesions / Q000502:physiology; D005620:Freund's Adjuvant / Q000494:pharmacology; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D000199:Actins; C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D005620:Freund's Adjuvant