title: Tumor-α9β1 integrin-mediated signaling induces breast cancer growth and lymphatic metastasis via the recruitment of cancer-associated fibroblasts.
abstract: Tumor-derived matricellular proteins such as osteopontin (OPN) and tenascin-C (TN-C) have been implicated in tumor growth and metastasis. However, the molecular basis of how these proteins contribute to tumor progression remains to be elucidated. Importantly, these matricellular proteins are known to interact with α9β1 integrin. Therefore, we hypothesized that tumor-derived α9β1 integrin may contribute to tumor progression. To clarify the roles of α9β1 integrin in tumor growth and lymphatic metastasis, we used an inhibitory anti-human α9β1 integrin antibody (anti-hα9β1 antibody) and a α9β1 integrin-positive human breast cancer cell line, MDA-MB-231 luc-D3H2LN (D3H2LN), in vitro functional assays, and an in vivo orthotopic xenotransplantation model. In this study, we demonstrated that tumor, but not host α9β1 integrin, contributes to tumor growth, lymphatic metastasis, recruitment of cancer-associated fibroblasts (CAFs), and host-derived OPN production. We also found that CAFs contributed to tumor growth, lymphatic metastasis, and host-derived OPN levels. Consistent with those findings, tumor volume was well-correlated with numbers of CAFs and levels of host-derived OPN. Furthermore, it was shown that the inoculation of D3H2LN cells into mammary fat pads with mouse embryonic fibroblasts (MEFs), obtained from wild type, but not OPN knock-out mice, resulted in enhancement of tumor growth, thus indicating that CAF-derived OPN enhanced tumor growth. These results suggested that tumor α9β1-mediated signaling plays a pivotal role in generating unique primary tumor tissue microenvironments, which favor lymphatic metastasis and tumor growth.
  
  
  CONCLUSIONS
  Tumor α9β1 integrin promotes lymphatic metastasis through enhancing invasion. Tumor α9β1 integrin promotes tumor growth through CAFs. Tumor α9β1 integrin enhances the recruitment of CAFs into the primary tumor. Tumor cells induce the production of OPN by CAFs in the primary tumor. CAF-derived OPN promotes tumor growth.
authors.affiliation: Department of Matrix Medicine, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-0815, Japan, dai-o@igm.hokudai.ac.jp.
authors.forename: Daichi
authors.initials: D
authors.lastname: Ota
authors.forename: Masashi
authors.initials: M
authors.lastname: Kanayama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Matsui
authors.forename: Koyu
authors.initials: K
authors.lastname: Ito
authors.forename: Naoyoshi
authors.initials: N
authors.lastname: Maeda
authors.forename: Goro
authors.initials: G
authors.lastname: Kutomi
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
authors.forename: Akinori
authors.initials: A
authors.lastname: Takaoka
authors.forename: Ann F
authors.initials: AF
authors.lastname: Chambers
authors.forename: Junko
authors.initials: J
authors.lastname: Morimoto
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016023:Integrins / Q000032:analysis / Q000378:metabolism*; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D053495:Osteopontin / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016023:Integrins; C113256:integrin alpha 9 beta 1; D053495:Osteopontin
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