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In this mechanism, cancer cells interact with fibronectin fibrils assembled on CAFs mainly through integrin\u2010\u03b15\u03b21. Here we tested whether this mechanism is applicable to the collective invasion of cancer cells, using two E\u2010cadherin\u2010expressing adenocarcinoma cell lines, DLD\u20101 (colon) and MCF\u20107 (breast). When hybrid spheroids of DLD\u20101 cells with CAFs were embedded into collagen gel, DLD\u20101 cells collectively but very slowly migrated through the collagen matrix in contact with CAFs. Epidermal growth factor and tumor necrosis factor\u2010\u03b1 promoted the collective invasion, possibly by reducing the E\u2010cadherin junction, as did the transforming growth factor\u2010\u03b2 inhibitor SB431542 by stimulating the outgrowth of CAFs. Transforming growth factor\u2010\u03b2 itself inhibited the cancer cell invasion. Efficient collective invasion of DLD\u20101 cells required large CAF fibers or their assembly as stable adhesion substrates. Experiments with function\u2010blocking Abs and siRNAs confirmed that DLD\u20101 cells adhered to fibronectin fibrils on CAFs mainly through integrin\u2010\u03b15\u03b21. Anti\u2010E\u2010cadherin Ab promoted the single cell invasion of DLD\u20101 cells by dissociating the E\u2010cadherin junction. Although the binding affinity of MCF\u20107 cells to CAFs was lower than DLD\u20101, they also collectively invaded the collagen matrix in a similar fashion to DLD\u20101 cells. Our results suggest that the direct interaction with CAFs, as well as environmental cytokines, contributes to the collective invasion of cancers.<\/jats:p>","DOI":"10.1111\/cas.14664","type":"journal-article","created":{"date-parts":[[2020,9,26]],"date-time":"2020-09-26T22:10:48Z","timestamp":1601158248000},"page":"4381-4392","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Collective cancer cell invasion in contact with fibroblasts through integrin\u2010\u03b15\u03b21\/fibronectin interaction in collagen matrix"],"prefix":"10.1111","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2831-2183","authenticated-orcid":false,"given":"Kaoru","family":"Miyazaki","sequence":"first","affiliation":[{"name":"Molecular Pathology Division Kanagawa Cancer Center Research Institute Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsaku","family":"Togo","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine Juntendo University of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Bio Science Division Material Integration Laboratories Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alimjan","family":"Idiris","sequence":"additional","affiliation":[{"name":"Bio Science Division Material Integration Laboratories Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromichi","family":"Kumagai","sequence":"additional","affiliation":[{"name":"Technology General Division AGC Inc. Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Miyagi","sequence":"additional","affiliation":[{"name":"Molecular Pathology Division Kanagawa Cancer Center Research Institute Yokohama 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