NDLI: Tumor-α9β1 integrin-mediated signaling induces breast cancer growth and lymphatic metastasis via the recruitment of cancer-associated fibroblasts

Content Provider	Springer Nature Link
Author	Ota, Daichi Kanayama, Masashi Matsui, Yutaka Ito, Koyu Maeda, Naoyoshi Kutomi, Goro Hirata, Koichi Torigoe, Toshihiko Sato, riyuki Takaoka, Akiri Chambers, Ann F. Morimoto, Junko Uede, Toshimitsu
Copyright Year	2014
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. 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.
Starting Page	1271
Ending Page	1281
Page Count	11
File Format	PDF
ISSN	09462716
Journal	Journal of Molecular Medicine
Volume Number	92
Issue Number	12
e-ISSN	14321440
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2014-08-08
Publisher Place	Berlin/Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Osteopontin α9β1 integrin Tumor microenvironment Cancer-associated fibroblasts Breast cancer Molecular Medicine Human Genetics Internal Medicine
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Molecular Medicine Genetics (clinical)

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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