{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T02:37:55Z","timestamp":1774492675404,"version":"3.50.1"},"reference-count":51,"publisher":"American Association for Cancer Research (AACR)","issue":"10","funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["CA125550"],"award-info":[{"award-number":["CA125550"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Deregulated transforming growth factor-\u03b2 (TGF\u03b2) signaling is a common feature of many epithelial cancers. Deletion of TGF\u03b2 receptor type 2 (TGFBR2) in fibroblast specific protein-1 (FSP1)-positive stromal cells induces squamous cell carcinoma in the murine forestomach, implicating fibroblast-derived hepatocyte growth factor (HGF) as the major driver of the epithelium carcinogenesis. Prior to cancer development, hyperproliferative FSP1+ fibroblasts lacking TGFBR2 accumulate in the forestomach, disrupting the regulatory signaling cross-talk with the forestomach epithelium. Here, concurrent loss in TGFBR2 and SMAD4 completely abrogates the development of forestomach cancer. Bone morphogenic protein-7 (BMP7) was highly upregulated in forestomach cancer tissue, activating Smad1\/5\/8 signaling, cell proliferation, and HGF production in TGFBR2-deficient FSP1+ fibroblasts. This stimulation by BMP7 was lost in the combined TGFBR2 and SMAD4 double knockout fibroblasts, which included a profound decrease in HGF expression. Thus, Smad4-mediated signaling is required to initiate epithelial carcinogenesis subsequent to TGFBR2 deletion in FSP1+ fibroblasts.<\/jats:p>\n                  <jats:p>Implications: These findings reveal a complex cross-talk between epithelial cells and the stroma, wherein Smad4 is required to elicit squamous cell carcinomas in the forestomach of mice with TGFBR2-deficient stromal cells. Mol Cancer Res; 16(10); 1568\u201378. \u00a92018 AACR.<\/jats:p>","DOI":"10.1158\/1541-7786.mcr-18-0120","type":"journal-article","created":{"date-parts":[[2018,6,22]],"date-time":"2018-06-22T10:05:15Z","timestamp":1529661915000},"page":"1568-1578","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["BMP7 Signaling in\n                    <i>TGFBR2<\/i>\n                    -Deficient Stromal Cells Provokes Epithelial Carcinogenesis"],"prefix":"10.1158","volume":"16","author":[{"given":"Hans Petter","family":"Eikesdal","sequence":"first","affiliation":[{"name":"1Department of Cancer Biology, Metastasis Research Center, University of Texas, MD Anderson Cancer Center, Houston, Texas."},{"name":"2Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts."}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1879-8789","authenticated-orcid":false,"given":"Lisa M.","family":"Becker","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, Metastasis Research Center, University of Texas, MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Yingqi","family":"Teng","sequence":"additional","affiliation":[{"name":"2Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts."}]},{"given":"Akane","family":"Kizu","sequence":"additional","affiliation":[{"name":"2Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts."}]},{"given":"Julienne L.","family":"Carstens","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, Metastasis Research Center, University of Texas, MD Anderson Cancer Center, Houston, Texas."}]},{"given":"Keizo","family":"Kanasaki","sequence":"additional","affiliation":[{"name":"2Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts."}]},{"given":"Hikaru","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, Metastasis Research Center, University of Texas, MD Anderson Cancer Center, Houston, Texas."},{"name":"2Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts."}]},{"given":"Valerie S.","family":"LeBleu","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, Metastasis Research Center, University of Texas, MD Anderson Cancer Center, Houston, Texas."},{"name":"2Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts."}]},{"given":"Raghu","family":"Kalluri","sequence":"additional","affiliation":[{"name":"1Department of Cancer Biology, Metastasis Research Center, University of Texas, MD Anderson Cancer Center, Houston, Texas."},{"name":"2Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts."},{"name":"3Harvard\u2013MIT Division of Health Sciences and Technology, Boston, Massachusetts."},{"name":"4Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts."}]}],"member":"1086","published-online":{"date-parts":[[2018,10,2]]},"reference":[{"key":"2022060706440104400_bib1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cell.2008.07.001","article-title":"TGFbeta in cancer","volume":"134","author":"Massague","year":"2008","journal-title":"Cell"},{"key":"2022060706440104400_bib2","first-page":"320","article-title":"Mutational inactivation 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