{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T11:47:42Z","timestamp":1770810462708,"version":"3.50.0"},"reference-count":35,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cancer-associated fibroblasts (CAFs), the major constituent of the tumor microenvironment, are considered the most active cells and key contributors to tumor resistance, recurrence, and metastasis. Therefore, we have investigated here the potential normalization of the active features of breast CAFs with decorin (DCN), a small leucine-rich proteoglycan that acts as an oncogene suppressor. We have first shown that rhDCN modulates the expression of a plethora of proteins involved in different signaling pathways, including STAT3\/NF-\u03baB and ERK. Consequently, rhDCN repressed the important active CAF biomarkers \u03b1-SMA, IL-6, and SDF-1 through inhibition of the STAT3\/AUF-1 pathway, in cells grown as 2D and 3D cultures. Furthermore, rhDCN had a strong downregulation effect on FAP-\u03b1, a key biomarker of active CAFs, and suppressed their proliferative and invasive capacities through upregulation of p16 and p21, and downregulation of MMP-2 and MMP-9. Furthermore, rhDCN suppressed the paracrine effects of active CAFs in promoting epithelial-to-mesenchymal transition (EMT) and cancer stem cells in breast cancer cells, both in vitro and in orthotopic tumor xenografts. Importantly, rhDCN-related normalization of active CAFs features was persistent through cellular passaging, and was not accompanied by cytotoxicity. Together, these findings have revealed rhDCN as a promising anti-breast cancer therapeutic cytokine through suppression of the non-cell-autonomous cancer-promoting effects of active CAFs.<\/jats:p>","DOI":"10.3390\/cells15030311","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T16:32:59Z","timestamp":1770395579000},"page":"311","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Recombinant Human Decorin Normalizes the Active Features of Breast Cancer-Associated Fibroblasts"],"prefix":"10.3390","volume":"15","author":[{"given":"Wafaa A.","family":"Aljagthmi","sequence":"first","affiliation":[{"name":"Research Laboratories, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"},{"name":"Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayodele A.","family":"Alaiya","sequence":"additional","affiliation":[{"name":"Research Laboratories, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maha","family":"Daghestani","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2426-0945","authenticated-orcid":false,"given":"Falah H.","family":"Al-Mohanna","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdelilah","family":"Aboussekhra","sequence":"additional","affiliation":[{"name":"Research Laboratories, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104389","DOI":"10.1016\/j.critrevonc.2024.104389","article-title":"A review concerning the breast cancer-related tumour microenvironment","volume":"199","author":"Patarroyo","year":"2024","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41420-023-01306-3","article-title":"Cancer-associated fibroblasts induce growth and radioresistance of breast cancer cells through paracrine IL-6","volume":"9","author":"Guo","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s12967-025-06071-8","article-title":"Cancer-associated fibroblasts in carcinogenesis","volume":"23","author":"Zhou","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41568-019-0238-1","article-title":"A framework for advancing our understanding of cancer-associated fibroblasts","volume":"20","author":"Sahai","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.cell.2005.02.034","article-title":"Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1\/CXCL12 secretion","volume":"121","author":"Orimo","year":"2005","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/cac2.12291","article-title":"Cancer-associated fibroblasts in breast cancer: Challenges and opportunities","volume":"42","author":"Hu","year":"2022","journal-title":"Cancer Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/s41571-021-00588-9","article-title":"Harnessing cytokines and chemokines for cancer therapy","volume":"19","author":"Propper","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41573-022-00557-6","article-title":"Emerging principles of cytokine pharmacology and therapeutics","volume":"22","author":"Saxton","year":"2023","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Morris, R.M., Mortimer, T.O., and O\u2019Neill, K.L. (2022). Cytokines: Can Cancer Get the Message?. Cancers, 14.","DOI":"10.3390\/cancers14092178"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Aljagthmi, W.A., Alasmari, M.A., Daghestani, M.H., Al-Kharashi, L.A., Al-Mohanna, F.H., and Aboussekhra, A. (2024). Decorin (DCN) Downregulation Activates Breast Stromal Fibroblasts and Promotes Their Pro-Carcinogenic Effects through the IL-6\/STAT3\/AUF1 Signaling. Cells, 13.","DOI":"10.3390\/cells13080680"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5480","DOI":"10.18632\/oncotarget.23869","article-title":"Decorin is a pivotal effector in the extracellular matrix and tumour microenvironment","volume":"9","author":"Zhang","year":"2018","journal-title":"Oncotarget"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1007\/s11010-025-05224-z","article-title":"Decorin: Matrix-based pan-cancer tumor suppressor","volume":"480","author":"Appunni","year":"2025","journal-title":"Mol. Cell. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3688","DOI":"10.1038\/sj.onc.1205470","article-title":"Suppression of tumorigenicity by adenovirus-mediated gene transfer of decorin","volume":"21","author":"Reed","year":"2002","journal-title":"Oncogene"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1038\/sj.onc.1208329","article-title":"Decorin prevents metastatic spreading of breast cancer","volume":"24","author":"Reed","year":"2005","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Diehl, V., Huber, L.S., Trebicka, J., Wygrecka, M., Iozzo, R.V., and Schaefer, L. (2021). The Role of Decorin and Biglycan Signaling in Tumorigenesis. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.801801"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"C554","DOI":"10.1152\/ajpcell.00016.2022","article-title":"Oncosuppressive roles of decorin through regulation of multiple receptors and diverse signaling pathways","volume":"322","author":"Xie","year":"2022","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2020.10.001","article-title":"Decorin deficiency promotes epithelial-mesenchymal transition and colon cancer metastasis","volume":"95","author":"Mao","year":"2021","journal-title":"Matrix Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/346281a0","article-title":"Negative regulation of transforming growth factor-beta by the proteoglycan decorin","volume":"346","author":"Yamaguchi","year":"1990","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e975645","DOI":"10.4161\/23723556.2014.975645","article-title":"Oncosuppressive functions of decorin","volume":"2","author":"Neill","year":"2015","journal-title":"Mol. Cell. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1158\/0008-5472.CAN-08-0192","article-title":"Breast carcinoma-associated fibroblasts and their counterparts display neoplastic-specific changes","volume":"68","author":"Hawsawi","year":"2008","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30962","DOI":"10.1074\/jbc.M114.594044","article-title":"The Cytokine IL-6 Reactivates Breast Stromal Fibroblasts through Transcription Factor STAT3-dependent Up-regulation of the RNA-binding Protein AUF1","volume":"289","author":"Hendrayani","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Jiang, H., and Li, H. (2021). Prognostic values of tumoral MMP2 and MMP9 overexpression in breast cancer: A systematic review and meta-analysis. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-07860-2"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ccell.2024.11.011","article-title":"Cytokines in cancer","volume":"43","author":"Kureshi","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1089\/jir.2018.0019","article-title":"Cytokines in the Treatment of Cancer","volume":"39","author":"Conlon","year":"2019","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.burns.2006.08.018","article-title":"Recombinant human decorin inhibits cell proliferation and downregulates TGF-beta1 production in hypertrophic scar fibroblasts","volume":"33","author":"Zhang","year":"2007","journal-title":"Burns"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Quintero-Fabian, S., Arreola, R., Becerril-Villanueva, E., Torres-Romero, J.C., Arana-Argaez, V., Lara-Riegos, J., Ramirez-Camacho, M.A., and Alvarez-Sanchez, M.E. (2019). Role of Matrix Metalloproteinases in Angiogenesis and Cancer. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01370"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1002\/ijc.23930","article-title":"Tumor microenvironment: Modulation by decorin and related molecules harboring leucine-rich tandem motifs","volume":"123","author":"Goldoni","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1002\/ijc.21606","article-title":"Osteoprotegerin (OPG)\u2014A potential new role in the regulation of endothelial cell phenotype and tumour angiogenesis?","volume":"118","author":"Cross","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1593\/neo.13478","article-title":"Curcumin triggers p16-dependent senescence in active breast cancer-associated fibroblasts and suppresses their paracrine procarcinogenic effects","volume":"15","author":"Hendrayani","year":"2013","journal-title":"Neoplasia"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Al-Ansari, M.M., and Aboussekhra, A. (2014). Caffeine mediates sustained inactivation of breast cancer-associated myofibroblasts via up-regulation of tumor suppressor genes. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090907"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1200\/JCO.1995.13.3.688","article-title":"Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy","volume":"13","author":"Fyfe","year":"1995","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13046-018-1001-2","article-title":"RANKL\/RANK\/OPG system beyond bone remodeling: Involvement in breast cancer and clinical perspectives","volume":"38","author":"Infante","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41416-018-0328-y","article-title":"Cytokines in clinical cancer immunotherapy","volume":"120","author":"Berraondo","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/bs.ircmb.2022.05.002","article-title":"Overcoming the limitations of cytokines to improve cancer therapy","volume":"369","author":"Cirella","year":"2022","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13","DOI":"10.4062\/biomolther.2023.196","article-title":"Current Development Status of Cytokines for Cancer Immunotherapy","volume":"32","author":"Song","year":"2024","journal-title":"Biomol. Ther."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/311\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T05:15:14Z","timestamp":1770786914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/311"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,6]]},"references-count":35,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cells15030311"],"URL":"https:\/\/doi.org\/10.3390\/cells15030311","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,6]]}}}