title: C-type lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice.
abstract: Essentials The role of C-type lectin-like receptor-2 (CLEC-2) in cancer progression is unclear. CLEC-2-depleted mouse model is generated by using a rat anti-mouse CLEC-2 monoclonal antibody. CLEC-2 depletion inhibits hematogenous tumor metastasis of podoplanin-expressing B16F10 cells. CLEC-2 depletion prolongs cancer survival by suppressing thrombosis and inflammation.
  
  
  
  Background C-type lectin-like receptor 2 (CLEC-2) is a platelet activation receptor of sialoglycoprotein podoplanin, which is expressed on the surface of certain types of tumor cells. CLEC-2-podoplanin interactions facilitate hematogenous tumor metastasis. However, direct evidence of the role of CLEC-2 in hematogenous metastasis and cancer progression is lacking. Objective and methods We generated immunological CLEC-2-depleted mice by using anti-mouse CLEC-2 monoclonal antibody 2A2B10 and investigated whether CLEC-2 promoted hematogenous tumor metastasis and tumor growth and exacerbated the prognosis of mice bearing podoplanin-expressing B16F10 melanoma cells. Results Our results showed that hematogenous metastasis was significantly inhibited in CLEC-2-depleted mice. B16F10 cells co-cultured with wild-type platelets, but not with CLEC-2-deficient platelets, showed increased proliferation. However, B16F10 cell proliferation was not inhibited in CLEC-2-depleted mice. Histological analysis showed that thrombus formation in tumor vessels was significantly inhibited and functional vessel density was significantly increased in CLEC-2-depleted mice. These data suggest that CLEC-2 deficiency may inhibit thrombus formation in tumor vessels and increase the density of functional vessels, thus improving oxygen and nutrient supply to tumors, indirectly promoting tumor proliferation. Furthermore, the overall survival of CLEC-2-depleted mice was significantly prolonged, which may be due to the suppression of thrombus formation in the lungs and subsequent inhibition of systemic inflammation and cachexia. Conclusions These data provide a rationale for the targeted inhibition of CLEC-2 as a new strategy for preventing hematogenous tumor metastasis and for inhibiting cancer-related thromboembolism.
authors.affiliation: Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shirai
authors.affiliation: Infection Control Office, Yamanashi University Hospital, Yamanashi, Japan.
authors.forename: O
authors.initials: O
authors.lastname: Inoue
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tamura
authors.affiliation: Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Tsukiji
authors.affiliation: Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Food Science and Nutrition, School of Human Cultures, University of Shiga Prefecture, Shiga, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Endo
authors.affiliation: Division of Laboratory Medicine, Yamanashi University Hospital, Yamanashi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Satoh
authors.affiliation: Division of Laboratory Medicine, Yamanashi University Hospital, Yamanashi, Japan.|School of Medical Technology, Faculty of Health Science, Gumma Paz College, Takasaki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Osada
authors.affiliation: Department of Clinical Nursing, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sato-Uchida
authors.affiliation: First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ozaki
authors.affiliation: Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Suzuki-Inoue
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D018450:Disease Progression; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006454:Hemoglobins / Q000737:chemistry; D037181:Lectins, C-Type / Q000378:metabolism*; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology*; D015539:Platelet Activation; D010974:Platelet Aggregation; D011379:Prognosis; D051381:Rats; D013927:Thrombosis / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; C529518:CLEC-2 protein, mouse; D006454:Hemoglobins; D037181:Lectins, C-Type; D049452:Green Fluorescent Proteins
keywords: cancer; inflammation; lectins, C-type; platelet; thrombosis