The platelet aggregation-inducing factor aggrus/podoplanin promotes pulmonary metastasis.
Tumor cell-induced platelet aggregation has been reported to facilitate hematogenous metastasis. Aggrus/podoplanin is a platelet aggregation-inducing factor that is up-regulated in a number of human cancers and has been implicated in tumor progression. We studied herein the role of Aggrus in tumor growth, metastasis , and survival in vivo. Aggrus expression in Chinese hamster ovary cells promoted pulmonary metastasis in both an experimental and a spontaneous mouse model. No differences in the size of metastatic foci or in primary tumor growth were found in either set of mice. Aggrus expressing cells , which were covered with platelets, arrested in the lung microvasculature 30 minutes after injection. In addition, lung metastasis resulting from Aggrus expression decreased the survival of the mice. By generating several Aggrus point mutants, we revealed that point mutation at the platelet aggregation-stimulating domain of Aggrus(Thr34 and Thr52) obliterated both platelet aggregation and metastasis. Furthermore, administration of aspirin to mice reduced the number of metastatic foci. These results indicate that Aggrus contributes to the establishment of metastasis by promoting platelet aggregation without affecting subsequent growth. Thus, Aggrus could serve as an ideal therapeutic target for drug development to block metastasis.
Kunita
Akiko
A
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo 135-8550, Japan.
Kashima
Takeshi G
TG
Morishita
Yasuyuki
Y
Fukayama
Masashi
M
Kato
Yukinari
Y
Tsuruo
Takashi
T
Fujita
Naoya
N
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D015153:Blotting, Western; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000517:prevention & control / Q000556:secondary*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009374:Neoplasms, Experimental / Q000097:blood / Q000235:genetics / Q000473:pathology*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D016019:Survival Analysis; D014162:Transfection; D014183:Transplantation, Heterologous; D000098853:Podoplanin
D001241:Aspirin; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; C117468:PDPN protein, human; D000098853:Podoplanin