{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T01:41:43Z","timestamp":1781919703288,"version":"3.54.5"},"reference-count":110,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T00:00:00Z","timestamp":1612310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal carcinoma (CRC) is the third most common cancer. Likewise, it is a disease that has a long survival if it is prematurely detected. However, more than 50% of patients will develop metastases, mainly in the liver (LM-CRC), throughout the evolution of their disease, which accounts for most CRC-related deaths. Treatment it is certainly a controversial issue, since it has not been shown to increase overall survival in the adjuvant setting, although it does improve disease free survival (DFS). Moreover, current chemotherapy combinations are administered based on data extrapolated from primary tumors (PT), not considering that LM-CRC present a very particular tumor microenvironment that can radically condition the effectiveness of treatments designed for a PT. The liver has a particular histology and microenvironment that can determine tumor growth and response to treatments: double blood supply, vascularization through fenestrated sinusoids and the presence of different mesenchymal cell types, among other particularities. Likewise, the liver presents a peculiar immune response against tumor cells, a fact that correlates with the poor response to immunotherapy. All these aspects will be addressed in this review, putting them in the context of the histological growth patterns of LM-CRC, a particular pathologic feature with both prognostic and predictive repercussions.<\/jats:p>","DOI":"10.3390\/ijms22041544","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T20:31:51Z","timestamp":1612384311000},"page":"1544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The Tumor Microenvironment in Liver Metastases from Colorectal Carcinoma in the Context of the Histologic Growth Patterns"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6428-1847","authenticated-orcid":false,"given":"Gemma","family":"Garcia-Vici\u00e9n","sequence":"first","affiliation":[{"name":"Tumoral and Stromal Chemoresistance Group, Molecular Mechanisms and Experimental Therapy in Oncology Program (ONCOBELL), Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge\u2014IDIBELL, 08908 L\u2019Hospitalet de Llobregat, Spain"},{"name":"Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 08908 L\u2019Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4394-2634","authenticated-orcid":false,"given":"Artur","family":"Mezheyeuski","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, 752 37 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Ba\u00f1uls","sequence":"additional","affiliation":[{"name":"Tumoral and Stromal Chemoresistance Group, Molecular Mechanisms and Experimental Therapy in Oncology Program (ONCOBELL), Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge\u2014IDIBELL, 08908 L\u2019Hospitalet de Llobregat, Spain"},{"name":"Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 08908 L\u2019Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00faria","family":"Ruiz-Roig","sequence":"additional","affiliation":[{"name":"Tumoral and Stromal Chemoresistance Group, Molecular Mechanisms and Experimental Therapy in Oncology Program (ONCOBELL), Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge\u2014IDIBELL, 08908 L\u2019Hospitalet de Llobregat, Spain"},{"name":"Department of Pathology, Hospital Universitari de Bellvitge, 08908 L\u2019Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9110-518X","authenticated-orcid":false,"given":"David G.","family":"Mollev\u00ed","sequence":"additional","affiliation":[{"name":"Tumoral and Stromal Chemoresistance Group, Molecular Mechanisms and Experimental Therapy in Oncology Program (ONCOBELL), Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge\u2014IDIBELL, 08908 L\u2019Hospitalet de Llobregat, Spain"},{"name":"Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 08908 L\u2019Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,3]]},"reference":[{"key":"ref_1","unstructured":"(2020, November 20). (GLOBOSCAN). IA for R on CWHO. Cancer Today. Available online: http:\/\/gco.iarc.fr\/today\/data\/pdf\/fact-sheets\/cancers\/cancer-fact-sheets-6.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3109","DOI":"10.1200\/JCO.2008.20.6771","article-title":"Improved overall survival with oxaliplatin.; fluorouracil.; and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial","volume":"27","author":"Boni","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1634\/theoncologist.2012-0121","article-title":"The oncosurgery approach to managing liver metastases from colorectal cancer: A multidisciplinary international consensus","volume":"17","author":"Adam","year":"2012","journal-title":"Oncologist"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3393\/ac.2016.32.3.92","article-title":"Prognostic factors in terms of the number of metastatic nodules in patients with colorectal cancer liver metastases","volume":"32","author":"Jang","year":"2016","journal-title":"Ann. Coloproctol."},{"key":"ref_5","first-page":"1","article-title":"Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis","volume":"10","author":"Liu","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1371\/journal.pgen.0020119","article-title":"Anatomic demarcation by positional variation in fibroblast gene expression programs","volume":"2","author":"Rinn","year":"2006","journal-title":"PLoS Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1158\/1541-7786.MCR-14-0121","article-title":"A monotonic and prognostic genomic signature from fibroblasts for colorectal cancer initiation, progression, and metastasis","volume":"12","author":"Cuadras","year":"2014","journal-title":"Mol. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6437","DOI":"10.18632\/oncotarget.2237","article-title":"A 5-gene classifier from the carcinoma-associated fibroblast transcriptomic profile and clinical outcome in colorectal cancer","volume":"5","author":"Berenguer","year":"2014","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1038\/bjc.2017.334","article-title":"International consensus guidelines for scoring the histopathological growth patterns of liver metastasis","volume":"117","author":"Teuwen","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s10456-019-09661-5","article-title":"Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases","volume":"22","author":"Galjart","year":"2019","journal-title":"Angiogenesis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s10585-020-10048-w","article-title":"Histopathological growth patterns as biomarker for adjuvant systemic chemotherapy in patients with resected colorectal liver metastases","volume":"37","author":"Buisman","year":"2020","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1038\/nm.4197","article-title":"Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases","volume":"22","author":"Frentzas","year":"2017","journal-title":"Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1093\/oxfordjournals.jjco.a023174","article-title":"Histologic growth patterns of metastatic carcinomas of the liver","volume":"26","author":"Terayama","year":"1996","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1002\/path.966","article-title":"Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia","volume":"195","author":"Vermeulen","year":"2001","journal-title":"J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kurebayashi, Y., Kubota, N., and Sakamoto, M. (2020). Immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: Relationship with histopathological and molecular classifications. Hepatol. Res.","DOI":"10.1111\/hepr.13539"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s10585-012-9469-1","article-title":"The histological growth pattern of colorectal cancer liver metastases has prognostic value","volume":"29","author":"Bird","year":"2012","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s10585-015-9715-4","article-title":"Growth pattern of colorectal liver metastasis as a marker of recurrence risk","volume":"32","author":"Eefsen","year":"2015","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1038\/modpathol.2014.4","article-title":"The morphological growth patterns of colorectal liver metastases are prognostic for overall survival","volume":"27","author":"Nielsen","year":"2014","journal-title":"Mod. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s10585-019-09975-0","article-title":"Histopathological growth patterns of colorectal liver metastasis exhibit little heterogeneity and can be determined with a high diagnostic accuracy","volume":"36","author":"Nierop","year":"2019","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/1097-0142(20000715)89:2<267::AID-CNCR10>3.0.CO;2-1","article-title":"Fibrous pseudocapsule of metastatic liver tumors from colorectal carcinoma: Clinicopathologic study of 152 first resection cases","volume":"89","author":"Okano","year":"2000","journal-title":"Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Oliveira, R.C., Alexandrino, H., Cipriano, M.A., Alves, F.C., and Tralh\u00e3o, J.G. (2020). Predicting liver metastases growth patterns: Current status and future possibilities. Semin. Cancer Biol.","DOI":"10.1016\/j.semcancer.2020.07.007"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.ophtha.2017.09.029","article-title":"Radiologic and Histopathologic Correlation of Different Growth Patterns of Metastatic Uveal Melanoma to the Liver","volume":"125","author":"Liao","year":"2018","journal-title":"Ophthalmology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/cjp2.105","article-title":"Replacement and desmoplastic histopathological growth patterns: A pilot study of prediction of outcome in patients with uveal melanoma liver metastases","volume":"4","author":"Barnhill","year":"2018","journal-title":"J. Pathol. Clin. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11689","DOI":"10.2147\/CMAR.S264586","article-title":"Prognostic factors after hepatectomy for gastric adenocarcinoma liver metastases: Desmoplastic growth pattern as the key to improved overall survival","volume":"12","author":"Temido","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1038\/sj.bjc.6601727","article-title":"Breast adenocarcinoma liver metastases.; in contrast to colorectal cancer liver metastases.; display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia","volume":"90","author":"Stessels","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1093\/ejcts\/ezx063","article-title":"Growth patterns of pulmonary metastases: Should we adjust resection techniques to primary histology and size?","volume":"52","author":"Welter","year":"2017","journal-title":"Eur. J. Cardio Thorac. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.semcancer.2018.01.009","article-title":"Histopathological growth patterns as a candidate biomarker for immunomodulatory therapy","volume":"52","author":"Daelemans","year":"2018","journal-title":"Semin. Cancer Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"209","DOI":"10.4103\/2152-7806.111298","article-title":"Imaging of brain metastases","volume":"4","author":"Fink","year":"2013","journal-title":"Surg. Neurol. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s12307-015-0172-z","article-title":"Inflammation and uPAR-Expression in Colorectal Liver Metastases in Relation to Growth Pattern and Neo-adjuvant Therapy","volume":"8","author":"Eefsen","year":"2015","journal-title":"Cancer Microenviron"},{"key":"ref_30","unstructured":"Brodt, P. (2011). The Tumor microenvironment at different stages of hepatic metastasis. Liver Metastasis: Biology and Clinical Managemen, Springer. [1st ed.]."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1158\/0008-5472.CAN-12-3931","article-title":"The multifaceted role of the microenvironment in liver metastasis: Biology and clinical implications","volume":"73","author":"Majeed","year":"2013","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5971","DOI":"10.1158\/1078-0432.CCR-16-0460","article-title":"Role of the microenvironment in liver metastasis: From pre- to prometastatic niches","volume":"22","author":"Brodt","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s12307-008-0011-6","article-title":"The prometastatic microenvironment of the liver","volume":"1","year":"2008","journal-title":"Cancer Microenviron."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"821","DOI":"10.3748\/wjg.v13.i6.821","article-title":"The hepatic sinusoidal endothelial lining and colorectal liver metastases","volume":"13","author":"Braet","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1093\/carcin\/bgu090","article-title":"Endothelial cell-derived-fibronectin extra domain A promotes colorectal cancer metastasis via inducing epithelialmesenchymal transition","volume":"35","author":"Ou","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"22410","DOI":"10.18632\/oncotarget.4198","article-title":"MIF, secreted by human hepatic sinusoidal endothelial cells.; promotes chemotaxis and outgrowth of colorectal cancer in liver prometastasis","volume":"6","author":"Hu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1158\/0008-5472.CAN-14-1493","article-title":"Notch suppresses angiogenesis and progression of hepatic metastases","volume":"75","author":"Banerjee","year":"2015","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/ijc.27677","article-title":"G-CSF rescues tumor growth and neo-angiogenesis during liver metastasis under host angiopoietin-2 deficiency","volume":"132","author":"Im","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1053\/jhep.2002.32528","article-title":"Endostatin inhibits murine colon carcinoma sinusoidal-type metastases by preferential targeting of hepatic sinusoidal endothelium","volume":"35","author":"Solaun","year":"2002","journal-title":"Hepatology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1002\/hep.23590","article-title":"Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice","volume":"51","author":"Arteta","year":"2010","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.semcancer.2014.02.006","article-title":"Prognostic relevance of cancer-associated fibroblasts in human cance","volume":"25","author":"Paulsson","year":"2014","journal-title":"Semin. Cancer Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"27","DOI":"10.5146\/tjpath.2013.01144","article-title":"The prognostic value of tumor-stroma proportion in laryngeal squamous cell carcinoma","volume":"29","author":"Ecevit","year":"2013","journal-title":"Turk. Patoloji Derg.\/Turk. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1111\/his.13396","article-title":"In reply to Hynes et al.: Back to the future: Routine morphological assessment of the tumour microenvironment is prognostic in stages II\/III colon cancer in a large population-based study","volume":"72","author":"Huijbers","year":"2018","journal-title":"Histopathology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1093\/annonc\/mds246","article-title":"The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients: Validation in the victor trial","volume":"24","author":"Huijbers","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/j.cgh.2008.05.006","article-title":"The Activated Stroma Index Is a Novel and Independent Prognostic Marker in Pancreatic Ductal Adenocarcinoma","volume":"6","author":"Erkan","year":"2008","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/ng.3225","article-title":"Stromal gene expression defines poor-prognosis subtypes in colorectal cancer","volume":"47","author":"Calon","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s10549-013-2571-5","article-title":"Prognostic significance of the tumor-stroma ratio: Validation study in node-negative premenopausal breast cancer patients from the EORTC perioperative chemotherapy (POP) trial (10854)","volume":"139","author":"Dekker","year":"2013","journal-title":"Breast Cancer Res. Treat"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1016\/j.molonc.2014.04.006","article-title":"Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs, providing prognostic information","volume":"8","author":"Calon","year":"2014","journal-title":"Mol. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"59766","DOI":"10.18632\/oncotarget.11121","article-title":"Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells","volume":"7","author":"Soriano","year":"2016","journal-title":"Oncotarget"},{"key":"ref_50","first-page":"665","article-title":"Minimal Residual Disease \u2606","volume":"9","author":"Sabath","year":"2018","journal-title":"Ref. Modul. Biomed. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.bcp.2013.01.018","article-title":"Fibroblast-mediated drug resistance in cancer","volume":"85","author":"Paraiso","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nrc2714","article-title":"Environment-mediated drug resistance: A major contributor to minimal residual disease","volume":"9","author":"Mark","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5914","DOI":"10.1158\/1078-0432.CCR-13-0694","article-title":"Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature","volume":"19","author":"Herrera","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1097\/PAS.0000000000000232","article-title":"Histologic categorization of fibrotic cancer stroma in the primary tumor is an independent prognostic index in resectable colorectal liver metastasis","volume":"38","author":"Ueno","year":"2014","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4466","DOI":"10.1158\/1078-0432.CCR-18-3957","article-title":"Noncanonical TGFb pathway relieves the blockade of IL1B\/TGFb-mediated crosstalk between tumor and stroma: TGFBR1 and TAK1 inhibition in colorectal cancer","volume":"25","author":"Cimas","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/path.5224","article-title":"Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma","volume":"248","author":"Neuzillet","year":"2019","journal-title":"J. Pathol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.ccell.2018.01.011","article-title":"Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer","volume":"33","author":"Costa","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.cell.2018.01.009","article-title":"CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness","volume":"172","author":"Su","year":"2018","journal-title":"Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13058-020-01311-9","article-title":"A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer","volume":"22","author":"Bonneau","year":"2020","journal-title":"Breast Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1084\/jem.20162024","article-title":"Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cance","volume":"214","author":"Biffi","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4663","DOI":"10.3748\/wjg.v24.i41.4663","article-title":"Typing of pancreatic cancer-associated fibroblasts identifies different subpopulations","volume":"24","author":"Nielsen","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s004320000199","article-title":"Clinicopathological significance of fibrotic capsule formation around liver metastasis from colorectal cancer","volume":"127","author":"Lunevicius","year":"2001","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1002\/ijc.24166","article-title":"Two distinct expression patterns of urokinase.; urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases","volume":"124","author":"Illemann","year":"2009","journal-title":"Int. J. Cance"},{"key":"ref_64","first-page":"765","article-title":"Phenotypic modulation of perisinusoidal cells following acute liver injury: A quantitative analysis","volume":"73","author":"Johnson","year":"1992","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/nature12783","article-title":"Distinct fibroblast lineages determine dermal architecture in skin development and repair","volume":"504","author":"Driskell","year":"2013","journal-title":"Nature"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1186\/1755-1536-5-S1-S17","article-title":"Origin of myofibroblasts in liver fibrosis","volume":"5","author":"Brenner","year":"2012","journal-title":"Fibrogenes Tissue Repair"},{"key":"ref_67","first-page":"135","article-title":"Hepatic fibrosis and cirrhosis: The (myo)fibroblastic cell subpopulations involved","volume":"38","author":"Guyot","year":"2006","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S0168-8278(02)00263-5","article-title":"Beauty is in the eye of the beholder: Emerging concepts and pitfalls in hepatic stellate cell research","volume":"37","author":"Cassiman","year":"2002","journal-title":"J. Hepatol."},{"key":"ref_69","first-page":"125","article-title":"Temperature dependent I-V characteristics of plasma hydrogenated Poly-Si TFTs in the low voltage region","volume":"30","author":"Jang","year":"1997","journal-title":"J. Korean Phys. Soc."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.2353\/ajpath.2007.060661","article-title":"Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment","volume":"171","author":"Mueller","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1053\/jhep.2003.50068","article-title":"Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis","volume":"37","author":"Olaso","year":"2003","journal-title":"Hepatology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"E3297","DOI":"10.1073\/pnas.1400062111","article-title":"Origin of myofibroblasts in the fibrotic liver in mice","volume":"111","author":"Iwaisako","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s00418-008-0503-y","article-title":"Thy-1 is expressed in myofibroblasts but not found in hepatic stellate cells following liver injury","volume":"131","author":"Dudas","year":"2009","journal-title":"Histochem. Cell Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/labinvest.2013.135","article-title":"Cytoglobin is expressed in hepatic stellate cells.; but not in myofibroblasts.; in normal and fibrotic human liver","volume":"94","author":"Motoyama","year":"2014","journal-title":"Lab. Investig."},{"key":"ref_75","first-page":"926","article-title":"Morphological aspects of angiogenesis in experimental liver metastases","volume":"143","author":"Paku","year":"1993","journal-title":"Am. J. Pathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1002\/ijc.20886","article-title":"Development of the vasculature in \u201cpushing-type\u201d liver metastases of an experimental colorectal cancer","volume":"115","author":"Paku","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1016\/S0140-6736(18)30789-X","article-title":"International validation of the consensus Immunoscore for the classification of colon cancer: A prognostic and accuracy study","volume":"391","author":"Mlecnik","year":"2018","journal-title":"Lancet"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/2162402X.2017.1286436","article-title":"Detailed resolution analysis reveals spatial T cell heterogeneity in the invasive margin of colorectal cancer liver metastases associated with improved survival","volume":"6","author":"Berthel","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1002\/bjs.9627","article-title":"Prognosis according to histochemical analysis of liver metastases removed at liver resection","volume":"101","author":"Brunner","year":"2014","journal-title":"Br. J. Surg."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/jnci\/djx123","article-title":"Comprehensive intrametastatic immune quantification and major impact of immunoscore on survival","volume":"110","author":"Mlecnik","year":"2018","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.ccell.2018.11.003","article-title":"The Link between the Multiverse of Immune Microenvironments in Metastases and the Survival of Colorectal Cancer Patients","volume":"34","author":"Mlecnik","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1007\/s11605-017-3446-6","article-title":"Increased Infiltration of Natural Killer and T Cells in Colorectal Liver Metastases Improves Patient Overall Survival","volume":"21","author":"Donadon","year":"2017","journal-title":"J. Gastrointest Surg."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41416-020-0881-z","article-title":"Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis","volume":"123","author":"Nierop","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature21349","article-title":"Mellman Elements of cancer immunity and the cancer-immune set point","volume":"541","author":"Chen","year":"2017","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Latacz, E., van Dam, P.J., Vanhove, C., Llado, L., Descamps, B., Ruiz, N., Joye, I., Gr\u00fcnhagen, D., Van Laere, S., and Dirix, P. (2020). Can medical imaging identify the histopathological growth patterns of liver metastases?. Semin. Cancer Biol.","DOI":"10.1016\/j.semcancer.2020.07.002"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Stremitzer, S., Vermeulen, P., Graver, S., Kockx, M., Dirix, L., Yang, D., Zhang, W., Stift, J., Wrba, F., and Gruenberger, T. (2020). Immune phenotype and histopathological growth pattern in patients with colorectal liver metastases. Br. J. Cancer.","DOI":"10.1038\/s41416-020-0812-z"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.lungcan.2019.09.013","article-title":"Clinical significance of PD-L1-positive cancer-associated fibroblasts in pN0M0 non-small cell lung cancer","volume":"137","author":"Koji","year":"2019","journal-title":"Lung Cancer"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Inoue, C., Miki, Y., Saito, R., Hata, S., Abe, J., Sato, I., Okada, Y., and Sasano, H. (2019). PD-L1 induction by cancer-associated fibroblast-derived factors in lung adenocarcinoma cells. Cancers, 11.","DOI":"10.3390\/cancers11091257"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1002\/ijc.32278","article-title":"Cancer-associated fibroblasts promote PD-L1 expression in mice cancer cells via secreting CXCL5","volume":"145","author":"Li","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/s41419-018-0458-4","article-title":"Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma","volume":"9","author":"Cheng","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1158\/2159-8290.CD-19-1384","article-title":"Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer","volume":"10","author":"Kieffer","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.4049\/jimmunol.169.5.2407","article-title":"Immunomodulatory Effects of the Liver: Deletion of Activated CD4 + Effector Cells and Suppression of IFN-\u03b3-Producing Cells After Intravenous Protein Immunization","volume":"169","author":"Klugewitz","year":"2002","journal-title":"J. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.jaut.2015.08.020","article-title":"Immunity, tolerance and autoimmunity in the liver: A comprehensive review","volume":"66","author":"Doherty","year":"2016","journal-title":"J. Autoimmun."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fonc.2019.00148","article-title":"Systematic review of the prognostic role of the immune system after surgery of colorectal liver metastases","volume":"9","author":"Hof","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1056\/NEJMc1510353","article-title":"PD-1 Blockade in Tumors with Mismatch-Repair Deficiency","volume":"373","author":"Diaz","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/S1470-2045(17)30422-9","article-title":"Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, phase 2 study","volume":"18","author":"Overman","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"327ra26","DOI":"10.1126\/scitranslmed.aad6352","article-title":"The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis","volume":"8","author":"Mlecnik","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.cell.2018.09.018","article-title":"Evolution of Metastases in Space and Time under Immune Selection","volume":"175","author":"Angelova","year":"2018","journal-title":"Cell"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Ciner, A.T., Jones, K., Muschel, R.J., and Brodt, P. (2020). The unique immune microenvironment of liver metastases: Challenges and opportunities. Semin. Cancer Biol.","DOI":"10.1016\/j.semcancer.2020.06.003"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"7253","DOI":"10.1158\/1078-0432.CCR-17-1038","article-title":"Radiomics analysis for evaluation of pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer","volume":"23","author":"Liu","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1007\/s00330-017-5146-8","article-title":"Can CT-based radiomics signature predict KRAS\/NRAS\/BRAF mutations in colorectal cancer?","volume":"28","author":"Yang","year":"2018","journal-title":"Eur. Radiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"4587","DOI":"10.1245\/s10434-019-07910-x","article-title":"Prediction of Histopathologic Growth Patterns of Colorectal Liver Metastases with a Noninvasive Imaging Method","volume":"26","author":"Cheng","year":"2019","journal-title":"Ann. Surg. Oncol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"12624","DOI":"10.1038\/ncomms12624","article-title":"Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma","volume":"7","author":"Wallin","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-06922-5","article-title":"Thy-1+ Cancer-associated Fibroblasts Adversely Impact Lung Cancer Prognosis","volume":"7","author":"Schliekelman","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Pretzsch, E., B\u00f6sch, F., Neumann, J., Ganschow, P., Bazhin, A., Guba, M., Werner, J., and Angele, M. (2019). Mechanisms of Metastasiss in Colorectal Cancer and Metastatic Organotropism: Hematogenous versus Peritoneal Spread. J. Oncol., 2019.","DOI":"10.1155\/2019\/7407190"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"20212","DOI":"10.1073\/pnas.1320318110","article-title":"Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cance","volume":"110","author":"Feig","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1126\/science.1195300","article-title":"Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-\u03b1","volume":"330","author":"Kraman","year":"2010","journal-title":"Science"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.ccr.2014.04.005","article-title":"Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival","volume":"25","author":"Carstens","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.cell.2014.08.007","article-title":"Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy","volume":"159","author":"Sherman","year":"2014","journal-title":"Cell"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"12630","DOI":"10.1038\/ncomms12630","article-title":"ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion","volume":"7","author":"Chronopoulos","year":"2016","journal-title":"Nat. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1544\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:19:46Z","timestamp":1760159986000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1544"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,3]]},"references-count":110,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22041544"],"URL":"https:\/\/doi.org\/10.3390\/ijms22041544","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,3]]}}}