{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:39:26Z","timestamp":1790807966456,"version":"4.1.0"},"reference-count":185,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"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>Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause of death in cancer patients. In colorectal cancer (CRC), cachexia affects around 50\u201361% of patients, but remains overlooked, understudied, and uncured. The mechanisms driving CC are not fully understood but are related, at least in part, to the local and systemic immune response to the tumor. Accumulating evidence demonstrates a significant role of tumor microenvironment (TME) cells (e.g., macrophages, neutrophils, and fibroblasts) in both cancer progression and tumor-induced cachexia, through the production of multiple procachectic factors. The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor \u03b1 (TNF\u03b1), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called \u201ccachexokines\u201d. The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis. This review summarizes the current knowledge on the role of TME cellular components in CRC-associated cachexia, as well as discusses the potential role of selected mediators secreted by colorectal cancer cells in cooperation with tumor-associated immune and non-immune cells of tumor microenvironment in inducing or potentiating cancer cachexia. This knowledge serves to aid the understanding of the mechanisms of this process, as well as prevent its consequences.<\/jats:p>","DOI":"10.3390\/ijms22041565","type":"journal-article","created":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T12:02:10Z","timestamp":1612440130000},"page":"1565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":176,"title":["The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1773-3038","authenticated-orcid":false,"given":"Aldona","family":"Kasprzak","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, University of Medical Sciences, \u015awi\u0119cicki Street 6, 60-781 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1007\/s00520-017-4022-z","article-title":"A cross-sectional study examining the prevalence of cachexia and areas of unmet need in patients with cancer","volume":"26","author":"Vagnildhaug","year":"2018","journal-title":"Support Care Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.21037\/apm.2018.08.07","article-title":"Measuring cachexia-diagnostic criteria","volume":"8","author":"Dev","year":"2019","journal-title":"Ann. Palliat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Roy, A., and Kumar, A. (2019). ER Stress and Unfolded Protein Response in Cancer Cachexia. Cancers, 11.","DOI":"10.3390\/cancers11121929"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/nm.4093","article-title":"Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia","volume":"22","author":"Fukawa","year":"2016","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.lfs.2016.11.033","article-title":"TNF-\u03b1 and cancer cachexia: Molecular insights and clinical implications","volume":"170","author":"Patel","year":"2017","journal-title":"Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"dmm043166","DOI":"10.1242\/dmm.043166","article-title":"HCT116 colorectal liver metastases exacerbate muscle wasting in a mouse model for the study of colorectal cancer cachexia","volume":"13","author":"Huot","year":"2020","journal-title":"Dis. Model. Mech."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1002\/jcsm.12528","article-title":"Cancer cachexia and its pathophysiology: Links with sarcopenia, anorexia and asthenia","volume":"11","author":"Santos","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1152\/physiolgenomics.00128.2014","article-title":"Cardiac and skeletal muscles show molecularly distinct responses to cancer cachexia","volume":"47","author":"Shum","year":"2015","journal-title":"Physiol. Genom."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.3892\/or.2017.5542","article-title":"Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity (Review)","volume":"37","author":"Belloum","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/jcp.26811","article-title":"Adipose tissue dysfunction in cancer cachexia","volume":"234","author":"Daas","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/s41575-019-0189-8","article-title":"Global burden of colorectal cancer: Emerging trends, risk factors and prevention strategies","volume":"16","author":"Keum","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1002\/jcsm.12449","article-title":"Cancer cachexia induces morphological and inflammatory changes in the intestinal mucosa","volume":"10","author":"Costa","year":"2019","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/jcsm.12402","article-title":"Orphan disease status of cancer cachexia in the USA and in the European Union: A systematic review","volume":"10","author":"Anker","year":"2019","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5597","DOI":"10.2147\/CMAR.S261585","article-title":"Cancer Cachexia: Definition, Staging, and Emerging Treatments","volume":"12","author":"Ni","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/bjs.10075","article-title":"Influence of body composition profile on outcomes following colorectal cancer surgery","volume":"103","author":"Malietzis","year":"2016","journal-title":"Br. J. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1097\/DCR.0000000000000958","article-title":"Impact of Low Muscularity and Myosteatosis on Long-term Outcome After Curative Colorectal Cancer Surgery: A Propensity Score-Matched Analysis","volume":"61","author":"Sueda","year":"2018","journal-title":"Dis. Colon Rectum"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.semcancer.2013.08.007","article-title":"Tumor and its microenvironment: A synergistic interplay","volume":"23","author":"Catalano","year":"2013","journal-title":"Semin. Cancer Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5829","DOI":"10.3748\/wjg.v23.i32.5829","article-title":"Role of tissue microenvironment resident adipocytes in colon cancer","volume":"23","author":"Tabuso","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Roma-Rodrigues, C., Mendes, R., Baptista, P.V., and Fernandes, A.R. (2019). Targeting Tumor Microenvironment for Cancer Therapy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040840"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3892\/ijo.2013.2180","article-title":"The importance of tissue environment surrounding the tumor on the development of cancer cachexia","volume":"44","author":"Chiba","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1159\/000502097","article-title":"Tumor Macroenvironment: An Update","volume":"87","author":"Hoefler","year":"2020","journal-title":"Pathobiology"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mizuno, R., Kawada, K., Itatani, Y., Ogawa, R., Kiyasu, Y., and Sakai, Y. (2019). The Role of Tumor-Associated Neutrophils in Colorectal Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030529"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mizuno, R., Kawada, K., and Sakai, Y. (2019). Prostaglandin E2\/EP Signaling in the Tumor Microenvironment of Colorectal Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246254"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/nature06916","article-title":"Mining the plasma proteome for cancer biomarkers","volume":"452","author":"Hanash","year":"2008","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1152\/physrev.00016.2008","article-title":"Mechanisms of cancer cachexia","volume":"89","author":"Tisdale","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.cmet.2012.06.011","article-title":"Cancer cachexia: Mediators, signaling, and metabolic pathways","volume":"16","author":"Fearon","year":"2012","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"791060","DOI":"10.1155\/2015\/791060","article-title":"Cancer as a Pro-inflammatory Environment: Metastasis and Cachexia","volume":"2015","author":"Carnier","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1002\/jcsm.12565","article-title":"The expression landscape of cachexia-inducing factors in human cancers","volume":"11","author":"Freire","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Alves, M.J., Figuer\u00eado, R.G., Azevedo, F.F., Cavallaro, D.A., Neto, N.I., Lima, J.D., Matos-Neto, E., Radloff, K., Riccardi, D.M., and Camargo, R.G. (2017). Adipose tissue fibrosis in human cancer cachexia: The role of TGF\u03b2 pathway. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3178-8"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1002\/jcsm.12441","article-title":"Tumour-derived transforming growth factor-\u03b2 signalling contributes to fibrosis in patients with cancer cachexia","volume":"10","author":"Lima","year":"2019","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.canlet.2019.10.016","article-title":"Single-cell transcriptome analysis reveals tumor immune microenvironment heterogenicity and granulocytes enrichment in colorectal cancer liver metastases","volume":"470","author":"Zhang","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.2217\/fon-2017-0145","article-title":"The colorectal cancer immune microenvironment and approach to immunotherapies","volume":"13","author":"Koi","year":"2017","journal-title":"Future Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1177\/0148607108325076","article-title":"Defining and classifying cancer cachexia: A proposal by the SCRINIO Working Group","volume":"33","author":"Bozzetti","year":"2009","journal-title":"JPEN J. Parenter. Enter. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S1470-2045(10)70218-7","article-title":"Definition and classification of cancer cachexia: An international consensus","volume":"12","author":"Fearon","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1002\/jcsm.12275","article-title":"Development and validation of a clinically applicable score to classify cachexia stages in advanced cancer patients","volume":"9","author":"Zhou","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.3945\/ajcn.116.140434","article-title":"Relation between hypermetabolism, cachexia, and survival in cancer patients: A prospective study in 390 cancer patients before initiation of anticancer therapy","volume":"105","author":"Vazeille","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.clnu.2012.05.009","article-title":"Nutritional status, cachexia and survival in patients with advanced colorectal carcinoma. Different assessment criteria for nutritional status provide unequal results","volume":"32","author":"Thoresen","year":"2013","journal-title":"Clin. Nutr."},{"key":"ref_38","first-page":"412","article-title":"Nutritional status assessment in colorectal cancer patients","volume":"28","author":"Lopes","year":"2013","journal-title":"Nutr. Hosp."},{"key":"ref_39","first-page":"157","article-title":"Nutritional status assessment in colorectal cancer patients qualified to systemic treatment","volume":"21","author":"Kraj","year":"2017","journal-title":"Contemp. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1002\/jpen.1459","article-title":"Close Relationship Between Immunological\/Inflammatory Markers and Myopenia and Myosteatosis in Patients with Colorectal Cancer: A Propensity Score Matching Analysis","volume":"43","author":"Okugawa","year":"2019","journal-title":"JPEN J. Parenter. Enter. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1097\/SPC.0b013e328319d7fa","article-title":"Catabolic mediators of cancer cachexia","volume":"2","author":"Tisdale","year":"2008","journal-title":"Curr. Opin. Support Palliat. Care"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"168407","DOI":"10.1155\/2014\/168407","article-title":"Inflammation based regulation of cancer cachexia","volume":"2014","author":"Onesti","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/320584a0","article-title":"Cachectin and tumour necrosis factor as two sides of the same biological coin","volume":"320","author":"Beutler","year":"1986","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1172\/JCI200420174","article-title":"Cancer cachexia is regulated by selective targeting of skeletal muscle gene products","volume":"114","author":"Acharyya","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1016\/j.cellsig.2012.07.016","article-title":"Role of Ca2+ in proteolysis-inducing factor (PIF)-induced atrophy of skeletal muscle","volume":"24","author":"Mirza","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1097\/SPC.0000000000000398","article-title":"Targeting IL-1\u03b1 in cancer cachexia: A narrative review","volume":"12","author":"McDonald","year":"2018","journal-title":"Curr. Opin. Support Palliat. Care"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-030-38315-2_1","article-title":"IL-1 Signaling in Tumor Microenvironment","volume":"1240","author":"Zhang","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4893","DOI":"10.2174\/1381612823666170613080919","article-title":"Targeting the Tumor Microenvironment by Intervention in Interleukin-1 Biology","volume":"23","author":"Voronov","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1189\/jlb.3MR1216-523R","article-title":"Immunotherapeutic approaches of IL-1 neutralization in the tumor microenvironment","volume":"102","author":"Apte","year":"2017","journal-title":"J. Leukoc. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"C706","DOI":"10.1152\/ajpcell.00626.2008","article-title":"Interleukin-1 stimulates catabolism in C2C12 myotubes","volume":"297","author":"Li","year":"2009","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.cyto.2016.02.015","article-title":"White adipose tissue IFN-\u03b3 expression and signalling along the progression of rodent cancer cachexia","volume":"89","author":"Yamashita","year":"2017","journal-title":"Cytokine"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"597675","DOI":"10.3389\/fphys.2020.597675","article-title":"Inflammation and Skeletal Muscle Wasting During Cachexia","volume":"11","author":"Webster","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"E410","DOI":"10.1152\/ajpendo.00039.2012","article-title":"JAK\/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia","volume":"303","author":"Bonetto","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_54","first-page":"54893","article-title":"The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia","volume":"117","author":"Bonetto","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4131","DOI":"10.1111\/febs.12338","article-title":"Interleukin-6 myokine signaling in skeletal muscle: A double-edged sword?","volume":"280","author":"Scheele","year":"2013","journal-title":"FEBS J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/2044-5040-2-14","article-title":"IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the ApcMin\/+ mouse","volume":"2","author":"White","year":"2012","journal-title":"Skelet. Muscle"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s13539-011-0047-1","article-title":"The effect of exercise on IL-6-induced cachexia in the Apc (Min\/+) mouse","volume":"3","author":"Puppa","year":"2012","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8018197","DOI":"10.1155\/2017\/8018197","article-title":"Linking Cancer Cachexia-Induced Anabolic Resistance to Skeletal Muscle Oxidative Metabolism","volume":"2017","author":"Hardee","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.cmet.2014.06.011","article-title":"A switch from white to brown fat increases energy expenditure in cancer-associated cachexia","volume":"20","author":"Petruzzelli","year":"2014","journal-title":"Cell Metab."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12944-018-0657-0","article-title":"Interleukin-6 induces fat loss in cancer cachexia by promoting white adipose tissue lipolysis and browning","volume":"17","author":"Han","year":"2018","journal-title":"Lipids Health Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fnut.2020.00004","article-title":"Plasma Lipid Profile and Systemic Inflammation in Patients with Cancer Cachexia","volume":"7","author":"Riccardi","year":"2020","journal-title":"Front. Nutr."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.clnu.2011.07.010","article-title":"Is IL-6 the best pro-inflammatory biomarker of clinical outcomes of cancer cachexia?","volume":"31","author":"Watt","year":"2012","journal-title":"Clin. Nutr."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/jcsm.12251","article-title":"Circulating monocyte chemoattractant protein-1 (MCP-1) is associated with cachexia in treatment-na\u00efve pancreatic cancer patients","volume":"9","author":"Talbert","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"113877","DOI":"10.1016\/j.ab.2020.113877","article-title":"Generation of reporter cell lines for factors inducing muscle wasting in cancer cachexia","volume":"606","author":"Cao","year":"2020","journal-title":"Anal. Biochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.jamda.2013.05.009","article-title":"Pro-inflammatory cytokines, aging, and age-related diseases","volume":"14","author":"Michaud","year":"2013","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/s41416-018-0357-6","article-title":"Alterations in serum amino-acid profile in the progression of colorectal cancer: Associations with systemic inflammation, tumour stage and patient survival","volume":"120","author":"Klintrup","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1159\/000503037","article-title":"Evaluation of Parameters for Cancer-Induced Sarcopenia in Patients Autopsied after Death from Colorectal Cancer","volume":"86","author":"Ohmori","year":"2019","journal-title":"Pathobiology"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Richards, C.H., Roxburgh, C.S., MacMillan, M.T., Isswiasi, S., Robertson, E.G., Guthrie, G.K., Horgan, P.G., and McMillan, D.C. (2012). The relationships between body composition and the systemic inflammatory response in patients with primary operable colorectal cancer. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041883"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1097\/SLA.0000000000001113","article-title":"Low Muscularity and Myosteatosis Is Related to the Host Systemic Inflammatory Response in Patients Undergoing Surgery for Colorectal Cancer","volume":"263","author":"Malietzis","year":"2016","journal-title":"Ann. Surg."},{"key":"ref_70","first-page":"140","article-title":"The influence of nutritional status and disease on adiponectin and TNF-\u03b1; levels in colorectal cancer patients","volume":"30","year":"2014","journal-title":"Nutr. Hosp."},{"key":"ref_71","first-page":"347","article-title":"Cardiac alterations in cancer-induced cachexia in mice","volume":"37","author":"Tian","year":"2010","journal-title":"Int. J. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3674","DOI":"10.4049\/jimmunol.148.11.3674","article-title":"Mechanisms of experimental cancer cachexia. Interaction between mononuclear phagocytes and colon-26 carcinoma and its relevance to IL-6-mediated cancer cachexia","volume":"148","author":"Strassmann","year":"1992","journal-title":"J. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Tsoli, M., Schweiger, M., Vanniasinghe, A.S., Painter, A., Zechner, R., Clarke, S., and Robertson, G. (2014). Depletion of white adipose tissue in cancer cachexia syndrome is associated with inflammatory signaling and disrupted circadian regulation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092966"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/rco2.24","article-title":"JAK Inhibitors Suppress Cancer Cachexia-Associated Anorexia and Adipose Wasting in Mice","volume":"3","author":"Arora","year":"2020","journal-title":"JCSM Rapid Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"E995","DOI":"10.1152\/ajpendo.90217.2008","article-title":"Spermidine\/spermine-N(1)-acetyltransferase: A key metabolic regulator","volume":"294","author":"Pegg","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_76","first-page":"1105","article-title":"Decrease in malonyl-CoA and its background metabolic alterations in murine model of cancer cachexia","volume":"21","author":"Celik","year":"2009","journal-title":"Oncol. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.lfs.2019.04.041","article-title":"Abnormality of hepatic triglyceride metabolism in ApcMin\/+ mice with colon cancer cachexia","volume":"227","author":"Yu","year":"2019","journal-title":"Life Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1038\/bjc.2012.211","article-title":"The relationships between cellular components of the peritumoural inflammatory response, clinicopathological characteristics and survival in patients with primary operable colorectal cancer","volume":"106","author":"Richards","year":"2012","journal-title":"Br. J. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.3389\/fimmu.2019.02368","article-title":"Tumor-Infiltrating Immune Cells Act as a Marker for Prognosis in Colorectal Cancer","volume":"10","author":"Ye","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Biasi, F., Guina, T., Maina, M., Nano, M., Falcone, A., Aroasio, E., Saracco, G.M., Papotti, M., Leonarduzzi, G., and Poli, G. (2012). Progressive increase of matrix metalloprotease-9 and interleukin-8 serum levels during carcinogenic process in human colorectal tract. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041839"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1159\/000486816","article-title":"The Role of Tumor-Associated Macrophages in Colorectal Carcinoma Progression","volume":"45","author":"Zhong","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Edin, S., Wikberg, M.L., Dahlin, A.M., Ruteg\u00e5rd, J., \u00d6berg, \u00c5., Oldenborg, P.A., and Palmqvist, R. (2012). The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0047045"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/eji.201141825","article-title":"Macrophages in human colorectal cancer are pro-inflammatory and prime T cells towards an anti-tumour type-1 inflammatory response","volume":"42","author":"Ong","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s00005-017-0463-9","article-title":"Tumor-Associated Macrophages and Regulatory T Cells Infiltration and the Clinical Outcome in Colorectal Cancer","volume":"65","author":"Waniczek","year":"2017","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12943-019-0976-4","article-title":"Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis","volume":"18","author":"Wei","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7375","DOI":"10.1158\/1078-0432.CCR-17-1283","article-title":"The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-Derived IL6","volume":"23","author":"Yin","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.3892\/ijo.2014.2259","article-title":"The IL-6\/JAK\/STAT3 pathway: Potential therapeutic strategies in treating colorectal cancer (Review)","volume":"44","author":"Wang","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.4049\/jimmunol.150.6.2341","article-title":"Mechanisms of experimental cancer cachexia. Local involvement of IL-1 in colon-26 tumor","volume":"150","author":"Strassmann","year":"1993","journal-title":"J. Immunol."},{"key":"ref_89","first-page":"334","article-title":"Conditioned Medium from Cultured Colorectal Cancer Cells Affects Peripheral Blood Mononuclear Cells Inflammatory Phenotype in Vitro","volume":"44","author":"Mohebbi","year":"2019","journal-title":"Iran. J. Med. Sci."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Inaba, S., Hinohara, A., Tachibana, M., Tsujikawa, K., and Fukada, S.I. (2018). Muscle regeneration is disrupted by cancer cachexia without loss of muscle stem cell potential. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205467"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"526","DOI":"10.3389\/fgene.2018.00526","article-title":"Macrophage Depletion in Elderly Mice Improves Response to Tumor Immunotherapy, Increases Anti-tumor T Cell Activity and Reduces Treatment-Induced Cachexia","volume":"9","author":"Duong","year":"2018","journal-title":"Front. Genet."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1172\/JCI74894","article-title":"Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis","volume":"125","author":"Reissfelder","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13059-015-0620-6","article-title":"Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy","volume":"16","author":"Angelova","year":"2015","journal-title":"Genome Biol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e1078058","DOI":"10.1080\/2162402X.2015.1078058","article-title":"The colorectal cancer immune paradox revisited","volume":"5","author":"Angelova","year":"2015","journal-title":"Oncoimmunology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ejca.2013.09.008","article-title":"The clinical utility of the local inflammatory response in colorectal cancer","volume":"50","author":"Richards","year":"2014","journal-title":"Eur. J. Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1093\/abbs\/gmw002","article-title":"Leukocyte populations and IL-6 in the tumor microenvironment of an orthotopic colorectal cancer model","volume":"48","author":"Miller","year":"2016","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"5501","DOI":"10.12659\/MSM.907439","article-title":"Targeting Interleukin-6 (IL-6) Sensitizes Anti-PD-L1 Treatment in a Colorectal Cancer Preclinical Model","volume":"24","author":"Li","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1097\/00004836-200204000-00006","article-title":"Decreased production of interleukin-12 and type 2 immune responses are marked in cachectic patients with colorectal and gastric cancer","volume":"34","author":"Shibata","year":"2002","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1369\/0022155416672418","article-title":"Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer","volume":"64","author":"Tanner","year":"2016","journal-title":"J. Histochem. Cytochem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1189\/jlb.5MR1216-508R","article-title":"Neutrophils as active regulators of the immune system in the tumor microenvironment","volume":"102","author":"Shaul","year":"2017","journal-title":"J. Leukoc. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"4316","DOI":"10.1111\/febs.14524","article-title":"Cancer-related circulating and tumor-associated neutrophils\u2014Subtypes, sources and function","volume":"285","author":"Shaul","year":"2018","journal-title":"FEBS J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.1158\/0008-5472.CAN-15-0125","article-title":"Definition of Prostaglandin E2-EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth","volume":"75","author":"Ma","year":"2015","journal-title":"Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Rao, H.L., Chen, J.W., Li, M., Xiao, Y.B., Fu, J., Zeng, Y.X., Cai, M.Y., and Xie, D. (2012). Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients\u2019 adverse prognosis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030806"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3847","DOI":"10.1158\/1078-0432.CCR-16-2047","article-title":"The Interplay Between Neutrophils and CD8+ T Cells Improves Survival in Human Colorectal Cancer","volume":"23","author":"Governa","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Shen, M., Hu, P., Donskov, F., Wang, G., Liu, Q., and Du, J. (2014). Tumor-associated neutrophils as a new prognostic factor in cancer: A systematic review and meta-analysis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098259"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.cyto.2005.10.002","article-title":"Erythropoietin attenuates cachectic events and decreases production of interleukin-6, a cachexia-inducing cytokine","volume":"32","author":"Kanzaki","year":"2005","journal-title":"Cytokine"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.3389\/fimmu.2020.01526","article-title":"Myeloid-Derived Suppressor Cells in Colorectal Cancer","volume":"11","author":"Sieminska","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1177\/0148607108325075","article-title":"Myeloid-derived suppressor cells in cancer cachexia syndrome: A new explanation for an old problem","volume":"32","author":"Winfield","year":"2008","journal-title":"JPEN J. Parenter. Enteral. Nutr."},{"key":"ref_109","first-page":"7","article-title":"The role of hypoxia in shaping the recruitment of proangiogenic and immunosuppressive cells in the tumor microenvironment","volume":"22","author":"Chouaib","year":"2018","journal-title":"Contemp. Oncol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1084\/jem.20100587","article-title":"HIF-1\u03b1 regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment","volume":"207","author":"Corzo","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1901278","DOI":"10.1002\/advs.201901278","article-title":"Granulocytic Myeloid-Derived Suppressor Cells Promote the Stemness of Colorectal Cancer Cells through Exosomal S100A9","volume":"6","author":"Wang","year":"2019","journal-title":"Adv. Sci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"453","DOI":"10.3892\/or.2012.1812","article-title":"Circulating myeloid-derived suppressor cells are increased and correlate to immune suppression, inflammation and hypoproteinemia in patients with cancer","volume":"28","author":"Ohki","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_113","first-page":"158","article-title":"Serum Soluble Interleukin-2 Receptor is Increased in Malnourished and Immunosuppressed Patients with Gastric and Colorectal Cancer: Possible Influence of Myeloid-Derived Suppressor Cells","volume":"3","author":"Gonda","year":"2012","journal-title":"World J. Oncol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.3892\/ol.2013.1231","article-title":"Serum levels of vascular endothelial growth factor are increased and correlate with malnutrition, immunosuppression involving MDSCs and systemic inflammation in patients with cancer of the digestive system","volume":"5","author":"Nakamura","year":"2013","journal-title":"Oncol. Lett."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1016\/j.bbalip.2013.02.010","article-title":"Adipose tissue and adipocytes support tumorigenesis and metastasis","volume":"1831","author":"Nieman","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.cyto.2012.10.023","article-title":"Adipose tissue-derived factors as potential biomarkers in cachectic cancer patients","volume":"61","author":"Batista","year":"2013","journal-title":"Cytokine"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1002\/jcsm.12345","article-title":"Peritumoural adipose tissue pro-inflammatory cytokines are associated with tumoural growth factors in cancer cachexia patients","volume":"9","author":"Neto","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_118","first-page":"629","article-title":"Systemic Inflammation in Cachexia\u2014Is Tumor Cytokine Expression Profile the Culprit?","volume":"6","author":"Lima","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Chang, M.L., Yang, Z., and Yang, S.S. (2020). Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218308"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s12944-017-0547-x","article-title":"Lipases and lipid droplet-associated protein expression in subcutaneous white adipose tissue of cachectic patients with cancer","volume":"16","author":"Lira","year":"2017","journal-title":"Lipids Health Dis."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/jcsm.12037","article-title":"Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients","volume":"7","author":"Batista","year":"2016","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"164","DOI":"10.3389\/fonc.2014.00164","article-title":"Putative role of adipose tissue in growth and metabolism of colon cancer cells","volume":"4","author":"Schwartz","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1158\/1940-6207.CAPR-16-0322","article-title":"Signals from the Adipose Microenvironment and the Obesity-Cancer Link-A Systematic Review","volume":"10","author":"Himbert","year":"2017","journal-title":"Cancer Prev. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"11674","DOI":"10.1038\/ncomms11674","article-title":"CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment","volume":"7","author":"Zhang","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1002\/mc.20854","article-title":"Interleukin-8 derived from local tissue-resident stromal cells promotes tumor cell invasion","volume":"51","author":"Welte","year":"2012","journal-title":"Mol. Carcinog."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1093\/carcin\/bgl018","article-title":"Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min\/+) colon epithelial cell line","volume":"27","author":"Fenton","year":"2006","journal-title":"Carcinogenesis"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.semcancer.2014.01.005","article-title":"Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth","volume":"25","author":"Lisanti","year":"2014","journal-title":"Semin. Cancer Biol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/978-3-319-78127-3_6","article-title":"Stromal Cells in the Tumor Microenvironment","volume":"1060","author":"Denton","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_129","first-page":"3055","article-title":"Cancer-associated fibroblast regulation of tumor neo-angiogenesis as a therapeutic target in cancer","volume":"17","author":"Wang","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"dmm029447","DOI":"10.1242\/dmm.029447","article-title":"A peek into cancer-associated fibroblasts: Origins, functions and translational impact","volume":"11","author":"LeBleu","year":"2018","journal-title":"Dis. Model. Mech."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ceb.2017.05.006","article-title":"Metabolism shapes the tumor microenvironment","volume":"48","author":"Moscat","year":"2017","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"6006","DOI":"10.1158\/1078-0432.CCR-13-1130","article-title":"Proteome profiling of cancer-associated fibroblasts identifies novel pro-inflammatory signatures and prognostic markers for colorectal cancer","volume":"19","author":"Torres","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_133","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_134","doi-asserted-by":"crossref","first-page":"26323","DOI":"10.18632\/oncotarget.15461","article-title":"Tumor necrosis factor receptor 2\/AKT and ERK signaling pathways contribute to the switch from fibroblasts to CAFs by progranulin in microenvironment of colorectal cancer","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/bjc.2013.748","article-title":"Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: Anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction","volume":"110","author":"Nagasaki","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"8032187","DOI":"10.1155\/2020\/8032187","article-title":"Interleukin-6 Promotes Epithelial-Mesenchymal Transition and Cell Invasion through Integrin \u03b26 Upregulation in Colorectal Cancer","volume":"2020","author":"Sun","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1159\/000504087","article-title":"Expression and Function of a Disintegrin and Metalloproteinases in Cancer-Associated Fibroblasts of Colorectal Cancer","volume":"101","author":"Mochizuki","year":"2020","journal-title":"Digestion"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s12032-013-0663-z","article-title":"Colorectal carcinoma-derived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity","volume":"30","author":"Li","year":"2013","journal-title":"Med. Oncol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1054\/bjoc.2001.1830","article-title":"Proteolysis-inducing factor is expressed in tumours of patients with gastrointestinal cancers and correlates with weight loss","volume":"84","author":"Bhargava","year":"2001","journal-title":"Br. J. Cancer"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/379739a0","article-title":"Characterization of a cancer cachectic factor","volume":"379","author":"Todorov","year":"1996","journal-title":"Nature"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1097\/SPC.0b013e3283186be2","article-title":"Cachexia, survival and the acute phase response","volume":"2","author":"Stephens","year":"2008","journal-title":"Curr. Opin. Support Palliat. Care"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.prp.2018.05.011","article-title":"IL-1\u03b2\/IL-6 network in the tumor microenvironment of human colorectal cancer","volume":"214","author":"Cui","year":"2018","journal-title":"Pathol. Res. Pract."},{"key":"ref_143","first-page":"921","article-title":"Molecular analysis of the cytokine network involved in cachexia in colon 26 adenocarcinoma-bearing mice","volume":"55","author":"Yasumoto","year":"1995","journal-title":"Cancer Res."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1158\/2326-6066.CIR-18-0766","article-title":"IL6 Modulates the Immune Status of the Tumor Microenvironment to Facilitate Metastatic Colonization of Colorectal Cancer Cells","volume":"7","author":"Toyoshima","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1158\/2326-6066.CIR-17-0443","article-title":"Stromal Cell PD-L1 Inhibits CD8+ T-cell Antitumor Immune Responses and Promotes Colon Cancer","volume":"6","author":"Treacy","year":"2018","journal-title":"Cancer Immunol. Res."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/j.cell.2015.08.031","article-title":"Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival","volume":"162","author":"Johnston","year":"2015","journal-title":"Cell"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1002\/jcsm.12561","article-title":"Targeting RAGE prevents muscle wasting and prolongs survival in cancer cachexia","volume":"11","author":"Chiappalupi","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_148","first-page":"67","article-title":"Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia","volume":"5","author":"Oeing","year":"2015","journal-title":"Mol. Metab."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"19976","DOI":"10.1074\/jbc.M115.638411","article-title":"A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia","volume":"290","author":"Seto","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1002\/jcsm.12346","article-title":"Tumour-derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour-bearing mice","volume":"9","author":"Kandarian","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Li, J., Eu, J.Q., Kong, L.R., Wang, L., Lim, Y.C., Goh, B.C., and Wong, A.L.A. (2020). Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy. Molecules, 25.","DOI":"10.3390\/molecules25204831"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"95","DOI":"10.4240\/wjgs.v10.i9.95","article-title":"Molecular therapeutic strategies targeting pancreatic cancer induced cachexia","volume":"10","author":"Yakovenko","year":"2018","journal-title":"World J. Gastrointest. Surg."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.canlet.2020.07.025","article-title":"JNK signaling contributes to skeletal muscle wasting and protein turnover in pancreatic cancer cachexia","volume":"491","author":"Mulder","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.semcdb.2016.02.009","article-title":"STAT3 in the systemic inflammation of cancer cachexia","volume":"54","author":"Zimmers","year":"2016","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.3748\/wjg.v9.i7.1567","article-title":"Role of NF-kappaB and cytokine in experimental cancer cachexia","volume":"9","author":"Zhou","year":"2003","journal-title":"World J. Gastroenterol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"113066","DOI":"10.1016\/j.jep.2020.113066","article-title":"Cryptotanshinone prevents muscle wasting in CT26-induced cancer cachexia through inhibiting STAT3 signaling pathway","volume":"260","author":"Chen","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/j.1365-2796.2007.01854.x","article-title":"Tumour necrosis factor-alpha in human adipose tissue\u2014From signalling mechanisms to clinical implications","volume":"262","author":"Arner","year":"2007","journal-title":"J. Intern. Med."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/j.ajpath.2012.12.023","article-title":"Autophagic degradation contributes to muscle wasting in cancer cachexia","volume":"182","author":"Penna","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1016\/j.jmb.2019.05.032","article-title":"Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function","volume":"431","author":"Penna","year":"2019","journal-title":"J. Mol. Biol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: Renovation of cells and tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"C542","DOI":"10.1152\/ajpcell.00192.2009","article-title":"p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting","volume":"298","author":"McClung","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.3892\/ijo.2013.1893","article-title":"Altered cardiac muscle mTOR regulation during the progression of cancer cachexia in the ApcMin\/+ mouse","volume":"42","author":"Manne","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"De Castro, G.S., Simoes, E., Lima, J.D.C.C., Ortiz-Silva, M., Festuccia, W.T., Tokeshi, F., Alc\u00e2ntara, P.S., Otoch, J.P., Coletti, D., and Seelaender, M. (2019). Human Cachexia Induces Changes in Mitochondria, Autophagy and Apoptosis in the Skeletal Muscle. Cancers, 11.","DOI":"10.3390\/cancers11091264"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"578418","DOI":"10.3389\/fonc.2020.578418","article-title":"The Double-Edge Sword of Autophagy in Cancer: From Tumor Suppression to Pro-tumor Activity","volume":"10","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.canlet.2020.06.015","article-title":"Autophagy in the crosstalk between tumor and microenvironment","volume":"490","author":"Camuzard","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"4297","DOI":"10.4161\/cc.9.21.13817","article-title":"The autophagic tumor stroma model of cancer or \u201cbattery-operated tumor growth\u201d: A simple solution to the autophagy paradox","volume":"9","author":"Pavlides","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.biocel.2011.01.023","article-title":"Stromal-epithelial metabolic coupling in cancer: Integrating autophagy and metabolism in the tumor microenvironment","volume":"43","author":"Pavlides","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"S81","DOI":"10.1016\/j.ejphar.2011.07.007","article-title":"Anti-inflammatory therapies in cancer cachexia","volume":"668","author":"Busquets","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1615\/CritRevOncog.v17.i3.30","article-title":"Counteracting inflammation: A promising therapy in cachexia","volume":"17","author":"Argiles","year":"2012","journal-title":"Crit. Rev. Oncog."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s13539-012-0061-y","article-title":"Recent developments in the treatment of cachexia: Highlights from the 6th Cachexia Conference","volume":"3","author":"Ebner","year":"2012","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"67","DOI":"10.21037\/apm.2018.07.06","article-title":"Anti-cytokines in the treatment of cancer cachexia","volume":"8","author":"Prado","year":"2019","journal-title":"Ann. Palliat. Med."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1677\/JOE-10-0341","article-title":"Combined treatment with GH, insulin, and indomethacin alleviates cancer cachexia in a mouse model","volume":"208","author":"Chen","year":"2011","journal-title":"J. Endocrinol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1080\/14712598.2016.1208168","article-title":"Novel therapeutic options for cachexia and sarcopenia","volume":"16","author":"Molfino","year":"2016","journal-title":"Expert. Opin. Biol. Ther."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S1470-2045(17)30006-2","article-title":"MABp1 as a novel antibody treatment for advanced colorectal cancer: A randomised, double-blind, placebo-controlled, phase 3 study","volume":"18","author":"Hickish","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1080\/14712598.2017.1347631","article-title":"MABp1 for the treatment of colorectal cancer","volume":"17","author":"Burotto","year":"2017","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1159\/000346446","article-title":"Clinical studies on the treatment of cancer cachexia with megestrol acetate plus thalidomide","volume":"58","author":"Wen","year":"2012","journal-title":"Chemotherapy"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1016\/j.biocel.2013.07.016","article-title":"Control of food intake and muscle wasting in cachexia","volume":"45","author":"Amitani","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_178","first-page":"200","article-title":"Unidentified cachexia patients in the oncologic setting: Cachexia UFOs do exist","volume":"63\u201364","author":"Demol","year":"2019","journal-title":"Nutrition"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1007\/s00520-019-04999-4","article-title":"A systematic review examining nutrition support interventions in patients with incurable cancer","volume":"28","author":"Blackwood","year":"2020","journal-title":"Support Care Cancer"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"601329","DOI":"10.3389\/fnut.2020.601329","article-title":"Nutritional Interventions in Cancer Cachexia: Evidence and Perspectives from Experimental Models","volume":"7","author":"Schols","year":"2020","journal-title":"Front. Nutr."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.1002\/cncr.32406","article-title":"A multicenter, open-label, single-arm study of anamorelin (ONO-7643) in advanced gastrointestinal cancer patients with cancer cachexia","volume":"125","author":"Hamauchi","year":"2019","journal-title":"Cancer"},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Wakabayashi, H., Arai, H., and Inui, A. (2020). The regulatory approval of anamorelin for treatment of cachexia in patients with non-small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer in Japan: Facts and numbers. J. Cachexia Sarcopenia Muscle.","DOI":"10.1002\/jcsm.12675"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13395-016-0098-2","article-title":"ActRII blockade protects mice from cancer cachexia and prolongs survival in the presence of anti-cancer treatments","volume":"6","author":"Hatakeyama","year":"2016","journal-title":"Skelet. Muscle"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"111929","DOI":"10.1016\/j.jep.2019.111929","article-title":"Improvement of chemotherapy through reducing of cachexia by using Citrus unshiu peel extract","volume":"242","author":"Ebrahimzadeh","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1080\/01635581.2011.563032","article-title":"Oral resveratrol therapy inhibits cancer-induced skeletal muscle and cardiac atrophy in vivo","volume":"63","author":"Shadfar","year":"2011","journal-title":"Nutr. 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