The Platelet Aggregation-Inducing Factor Aggrus/Podoplanin Promotes Pulmonary Metastasis

• Published in: The American journal of pathology Vol. 170; no. 4; pp. 1337 - 1347
• Main Authors: Kunita, Akiko, Kashima, Takeshi G, Morishita, Yasuyuki, Fukayama, Masashi, Kato, Yukinari, Tsuruo, Takashi, Fujita, Naoya
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.04.2007; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Aspirin - pharmacology; Biological and medical sciences; Blotting, Western; Cell Survival - drug effects; Cell Survival - genetics; Cell Survival - physiology; CHO Cells; Cricetinae; Cricetulus; Female; Flow Cytometry; Humans; Investigative techniques, diagnostic techniques (general aspects); Lung Neoplasms - genetics; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Proteins - physiology; Mice; Mice, Inbred BALB C; Mice, Nude; Mutagenesis, Site-Directed; Mutation, Missense; Neoplasms, Experimental - blood; Neoplasms, Experimental - genetics; Neoplasms, Experimental - pathology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Platelet Aggregation - drug effects; Platelet Aggregation - physiology; Platelet Aggregation Inhibitors - pharmacology; Pneumology; Regular; Survival Analysis; Transfection; Transplantation, Heterologous; Tumors of the respiratory system and mediastinum; Lung disease; Anatomic pathology; Platelet aggregation factor; Malignant tumor; Lung metastasis; Respiratory disease
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2007.060790

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.