{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T19:41:02Z","timestamp":1787427662105,"version":"build-2736575974"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Cancer\u2010associated fibroblasts (CAFs) are key players in multicellular, stromal\u2010dependent alterations leading to HCC pathogenesis. However, the intricate crosstalk between CAFs and other components in the tumor microenvironment (TME) remains unclear. This study aimed to investigate the cellular crosstalk among CAFs, tumor cells, and tumor\u2010associated neutrophils (TANs) during different stages of HCC pathogenesis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>In the HCC\u2010TME, CAF\u2010derived cardiotrophin\u2010like cytokine factor 1 (CLCF1) increased chemokine (C\u2010X\u2010C motif) ligand 6 (CXCL6) and TGF\u2010\u03b2 secretion in tumor cells, which subsequently promoted tumor cell stemness in an autocrine manner and TAN infiltration and polarization in a paracrine manner. Moreover, CXCL6 and TGF\u2010\u03b2 secreted by HCC cells activated extracellular signal\u2010regulated kinase (ERK) 1\/2 signaling of CAFs to produce more CLCF1, thus forming a positive feedback loop to accelerate HCC progression. Inhibition of ERK1\/2 or CLCF1\/ciliary neurotrophic factor receptor signaling efficiently impaired CLCF1\u2010mediated crosstalk among CAFs, tumor cells, and TANs both <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. In clinical samples, up\u2010regulation of the CLCF1\u2212CXCL6\/TGF\u2010\u03b2 axis exhibited a marked correlation with increased cancer stem cells, \u201cN2\u201d\u2010polarized TANs, tumor stage, and poor prognosis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study reveals a cytokine\u2010mediated cellular crosstalk and clinical network involving the CLCF1\u2212CXCL6\/TGF\u2010\u03b2 axis, which regulates the positive feedback loop among CAFs, tumor stemness, and TANs, HCC progression, and patient prognosis. These results may support the CLCF1 cascade as a potential prognostic biomarker and suggest that selective blockade of CLCF1\/ciliary neurotrophic factor receptor or ERK1\/2 signaling could provide an effective therapeutic target for patients with HCC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31792","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T03:12:49Z","timestamp":1615173169000},"page":"1717-1735","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":319,"title":["Cancer\u2010Associated Fibroblast\u2010Mediated Cellular Crosstalk Supports Hepatocellular Carcinoma Progression"],"prefix":"10.1097","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6399-3412","authenticated-orcid":false,"given":"Mengjia","family":"Song","sequence":"first","affiliation":[{"name":"Department of Biotherapy,Sun Yat\u2010sen University Cancer Center,Guangzhou,P. R. 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