{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T14:51:12Z","timestamp":1783695072738,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T00:00:00Z","timestamp":1636502400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI15\/00974"],"award-info":[{"award-number":["PI15\/00974"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI18\/00708"],"award-info":[{"award-number":["PI18\/00708"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>As an important component of tumor microenvironment, cancer-associated fibroblasts (CAFs) have lately gained prominence owing to their crucial role in the resistance to therapies. Photodynamic therapy (PDT) stands out as a successful therapeutic strategy to treat cutaneous squamous cell carcinoma. In this study, we demonstrate that the transforming growth factor \u03b21 (TGF\u03b21) cytokine secreted by CAFs isolated from patients with SCC can drive resistance to PDT in epithelial SCC cells. To this end, CAFs obtained from patients with in situ cSCC were firstly characterized based on the expression levels of paramount markers as well as the levels of TGF\u03b21 secreted to the extracellular environment. On a step forward, two established human cSCC cell lines (A431 and SCC13) were pre-treated with conditioned medium obtained from the selected CAF cultures. The CAF-derived conditioned medium effectively induced resistance to PDT in A431 cells through a reduction in the cell proliferation rate. This resistance effect was recapitulated by treating with recombinant TGF\u03b21 and abolished by using the SB525334 TGF\u03b21 receptor inhibitor, providing robust evidence of the role of TGF\u03b21 secreted by CAFs in the development of resistance to PDT in this cell line. Conversely, higher levels of recombinant TGF\u03b21 were needed to reduce cell proliferation in SCC13 cells, and no induction of resistance to PDT was observed in this cell line in response to CAF-derived conditioned medium. Interestingly, we probed that the comparatively higher intrinsic resistance to PDT of SCC13 cells was mediated by the elevated levels of TGF\u03b21 secreted by this cell line. Our results point at this feature as a promising biomarker to predict both the suitability of PDT and the chances to optimize the treatment by targeting CAF-derived TGF\u03b21 in the road to a more personalized treatment of particular cSCC tumors.<\/jats:p>","DOI":"10.3390\/cancers13225613","type":"journal-article","created":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T09:19:21Z","timestamp":1636535961000},"page":"5613","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["TGF\u03b21 Secreted by Cancer-Associated Fibroblasts as an Inductor of Resistance to Photodynamic Therapy in Squamous Cell Carcinoma Cells"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5767-4258","authenticated-orcid":false,"given":"Mar\u00eda","family":"Gallego-Rentero","sequence":"first","affiliation":[{"name":"Departamento de Biolog\u00eda, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5868-8790","authenticated-orcid":false,"given":"Mar\u00eda","family":"Guti\u00e9rrez-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Fern\u00e1ndez-Guarino","sequence":"additional","affiliation":[{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, IRYCIS, 28034 Madrid, Spain"},{"name":"Dermatology Service, Hospital Ram\u00f3n y Cajal, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9677-921X","authenticated-orcid":false,"given":"Marta","family":"Mascaraque","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0830-7237","authenticated-orcid":false,"given":"Mikel","family":"Portillo-Esnaola","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Gilaberte","sequence":"additional","affiliation":[{"name":"Servicio de Dermatolog\u00eda, Hospital Miguel Servet, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0817-1627","authenticated-orcid":false,"given":"Elisa","family":"Carrasco","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6574-2887","authenticated-orcid":false,"given":"\u00c1ngeles","family":"Juarranz","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, IRYCIS, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.hoc.2018.08.001","article-title":"Cutaneous Squamous Cell Carcinoma","volume":"33","author":"Waldman","year":"2018","journal-title":"Hematol. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.jaad.2017.08.059","article-title":"Cutaneous squamous cell carcinoma. Incidence, risk factors, diagnosis and staging","volume":"78","author":"Que","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.cll.2017.06.003","article-title":"Cutaneous Squamous Cell Carcinoma","volume":"37","author":"Parekh","year":"2017","journal-title":"Clin. Lab. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.mayocp.2015.12.017","article-title":"Head and Neck Squamous Cell Carcinoma: Update on Epidemiology, Diagnosis, and Treatment","volume":"91","author":"Marur","year":"2016","journal-title":"Mayo Clin. Proc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.pdpdt.2018.09.009","article-title":"Photodynamic therapy for Bowen\u2019s Disease (squamous cell carcinoma in situ) current review and update","volume":"24","author":"Okhovat","year":"2018","journal-title":"Photodiagn. Photodyn. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1111\/ijd.12553","article-title":"Squamous cell carcinoma of the skin: Epidemiology, classification, management, and novel trends","volume":"54","author":"Kallini","year":"2014","journal-title":"Int. J. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.jaad.2018.10.042","article-title":"Present and future perspectives of photodynamic therapy for cutaneous squamous cell carcinoma","volume":"80","author":"Keyal","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1111\/bjd.16838","article-title":"Conventional and combination topical photodynamic therapy for basal cell carcinoma: Systematic review and meta-analysis","volume":"179","author":"Collier","year":"2018","journal-title":"Br. J. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/den.13353","article-title":"Role of photodynamic therapy in the treatment of esophageal cancer","volume":"31","author":"Wu","year":"2019","journal-title":"Dig. Endosc."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mascaraque, M., Delgado-Wicke, P., Nuevo-Tapioles, C., Gracia-Caza\u00f1a, T., Abarca-Lachen, E., Gonz\u00e1lez, S., Cuezva, J.M., Gilaberte, Y., and Juarranz, \u00c1. (2020). Metformin as an Adjuvant to Photodynamic Therapy in Resistant Basal Cell Carcinoma Cells. Cancers, 12.","DOI":"10.3390\/cancers12030668"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1038\/jid.2015.248","article-title":"Photoactivation of ROS Production In situ Transiently Activates Cell Proliferation in Mouse Skin and in the Hair Follicle Stem Cell Niche Promoting Hair Growth and Wound Healing","volume":"135","author":"Carrasco","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ejmech.2014.12.025","article-title":"Photodynamic effects induced by meso-tris(pentafluorophenyl)corrole and its cyclodextrin conjugates on cytoskeletal components of HeLa cells","volume":"92","author":"Barata","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1016\/j.biopha.2018.07.049","article-title":"Photodynamic therapy\u2014mechanisms, photosensitizers and combinations","volume":"106","author":"Kwiatkowski","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1002\/lsm.22802","article-title":"Photodynamic therapy in patients with head and neck squamous cell carcinoma","volume":"50","author":"Hosokawa","year":"2018","journal-title":"Lasers Surg. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1365-2133.2008.08593.x","article-title":"Methylaminolaevulinate-based photodynamic therapy of Bowen\u2019s disease and squamous cell carcinoma","volume":"159","author":"Venturini","year":"2008","journal-title":"Br. J. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/j.1529-8019.2010.01381.x","article-title":"MAL-PDT for difficult to treat nonmelanoma skin cancer","volume":"24","author":"Stebbins","year":"2011","journal-title":"Dermatol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.det.2006.09.008","article-title":"Methyl Aminolevulinate-photodynamic Therapy for Basal Cell Carcinoma","volume":"25","author":"Szeimies","year":"2007","journal-title":"Dermatol. Clin."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1111\/bjd.13036","article-title":"Development of squamous cell carcinoma after photodynamic therapy with methyl aminoleuvulinate","volume":"171","author":"Calista","year":"2014","journal-title":"Br. J. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.7150\/ijbs.25720","article-title":"Effect of Stromal Cells in Tumor Microenvironment on Metastasis Initiation","volume":"14","author":"Guo","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12943-019-0983-5","article-title":"Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: A systematic review","volume":"18","author":"Peltanova","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"761","DOI":"10.7150\/jca.17648","article-title":"Role of tumor microenvironment in tumorigenesis","volume":"8","author":"Wang","year":"2017","journal-title":"J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/j.cell.2015.01.043","article-title":"TGF-\u03b2 Promotes Heterogeneity and Drug Resistance in Squamous Cell Carcinoma","volume":"160","author":"Oshimori","year":"2015","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.semcancer.2013.12.008","article-title":"TGF-beta in CAF-mediated tumor growth and metastasis","volume":"25","author":"Calon","year":"2014","journal-title":"Semin. Cancer Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1002\/ijc.32193","article-title":"In search of definitions: Cancer-associated fibroblasts and their markers","volume":"146","author":"Nurmik","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/nrc.2016.73","article-title":"The biology and function of fibroblasts in cancer","volume":"16","author":"Kalluri","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8334","DOI":"10.1038\/srep08334","article-title":"Stretching Fibroblasts Remodels Fibronectin and Alters Cancer Cell Migration","volume":"5","author":"Ao","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1007\/s00018-011-0735-1","article-title":"Vimentin in cancer and its potential as a molecular target for cancer therapy","volume":"68","author":"Satelli","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sharma, P., Alsharif, S., Fallatah, A., and Chung, B.M. (2019). Intermediate Filaments as Effectors of Cancer Development and Metastasis: A Focus on Keratins, Vimentin, and Nestin. Cells, 8.","DOI":"10.3390\/cells8050497"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1111\/his.13657","article-title":"High expression of CD10 in anaplastic thyroid carcinomas","volume":"73","author":"Nakazawa","year":"2018","journal-title":"Histopathology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.0303-6987.2006.00283.x","article-title":"CD10 expression in trichoepithelioma and basal cell carcinoma","volume":"33","author":"Pham","year":"2006","journal-title":"J. Cutan. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3799","DOI":"10.1083\/jcb.201704053","article-title":"Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin","volume":"216","author":"Erdogan","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1042\/BST20160387","article-title":"Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis","volume":"45","author":"Erdogan","year":"2017","journal-title":"Biochem. Soc. Trans."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1093\/abbs\/gmx127","article-title":"Paradoxical roles of TGF-\u03b2 signaling in suppressing and promoting squamous cell carcinoma","volume":"50","author":"Wu","year":"2017","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1042\/BST20160065","article-title":"Dichotomous roles of TGF-\u03b2 in human cancer","volume":"44","author":"Huang","year":"2016","journal-title":"Biochem. Soc. Trans."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"a022301","DOI":"10.1101\/cshperspect.a022301","article-title":"Targeting TGF-\u03b2 Signaling for Therapeutic Gain","volume":"9","author":"Akhurst","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Schoonderwoerd, M.J., Goumans, M.-J.T., and Hawinkels, L.J. (2020). Endoglin: Beyond the Endothelium. Biomolecules, 10.","DOI":"10.3390\/biom10020289"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.stem.2017.10.001","article-title":"TGF-\u03b2-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma","volume":"21","author":"Brown","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_38","first-page":"1657","article-title":"Tumorigenic keratinocyte lines requiring anchorage and fibroblast support cultured from hu-man squamous cell carcinomas","volume":"41","author":"Rheinwald","year":"1981","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.ceca.2007.08.005","article-title":"TRPC channels determine human keratinocyte differentiation: New insight into basal cell carcinoma","volume":"43","author":"Beck","year":"2008","journal-title":"Cell Calcium."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/j.1365-4632.2010.04700.x","article-title":"Photodamaging effects of porphyrins and chitosan on primary human keratinocytes and carcinoma cell cultures","volume":"50","author":"Susan","year":"2011","journal-title":"Int. J. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1242\/jcs.023283","article-title":"L- and S-endoglin differentially modulate TGF\u03b21 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts","volume":"121","author":"Velasco","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8693","DOI":"10.3390\/ijms21228693","article-title":"Effects of Tenascin C on the Integrity of Extra-cellular Matrix and Skin Aging","volume":"21","author":"Young","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s10495-005-6075-6","article-title":"Morphological criteria to distinguish cell death induced by apoptotic and necrotic treatments","volume":"10","author":"Stockert","year":"2005","journal-title":"Apoptosis"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Shen, H., Cai, S., Wu, C., Yang, W., Yu, H., and Liu, L. (2021). Recent Advances in Three-Dimensional Multicellular Spheroid Culture and Future Development. Micromachines, 12.","DOI":"10.3390\/mi12010096"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1007\/s10495-006-0016-x","article-title":"Induction of heme-oxygenase 1 requires the p38MAPK and PI3K pathways and suppresses apoptotic cell death following hypericin-mediated photodynamic therapy","volume":"12","author":"Kocanova","year":"2007","journal-title":"Apoptosis"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ejphar.2007.01.025","article-title":"Transforming growth factor-\u03b21 stimulates heme oxygenase-1 expression via the PI3K\/Akt and NF-\u03baB pathways in human lung epithelial cells","volume":"560","author":"Lin","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_47","first-page":"1539","article-title":"Inhibition of heme oxygenase-1 increases responsiveness of melanoma cells to ALA-based photodynamic therapy","volume":"31","author":"Frank","year":"2007","journal-title":"Int. J. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.1111\/cas.14578","article-title":"Functional diversity of cancer-associated fibroblasts in modulating drug resistance","volume":"111","author":"Bu","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/(SICI)1097-4652(200007)184:1<70::AID-JCP7>3.0.CO;2-U","article-title":"Generation of active TGF-beta by prostatic cell cocultures using novel basal and luminal prostatic epithelial cell lines","volume":"184","author":"Salm","year":"2000","journal-title":"J. Cell Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Liarte, S., Bernab\u00e9-Garc\u00eda, \u00c1., and Nicol\u00e1s, F.J. (2020). Human Skin Keratinocytes on Sustained TGF-\u03b2 Stimulation Reveal Partial EMT Features and Weaken Growth Arrest Responses. Cells, 9.","DOI":"10.3390\/cells9010255"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"40237","DOI":"10.1074\/jbc.M401665200","article-title":"Autocrine and Exogenous Transforming Growth Factor \u03b2 Control Cell Cycle Inhibition through Pathways with Different Sensitivity","volume":"279","author":"Wang","year":"2004","journal-title":"J. Biol. Chem."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/22\/5613\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:28:33Z","timestamp":1760167713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/22\/5613"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,10]]},"references-count":51,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cancers13225613"],"URL":"https:\/\/doi.org\/10.3390\/cancers13225613","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,10]]}}}