The systemic hallmarks of cancer

Abstract

Cancer is not just a lump of cells that divide, invade, and spread randomly, but rather a multi-layered precisely tuned process that requires the participation of the whole organism. There is an urgent need to zoom-out from the cellular and the local stromal view and broaden our perspective by including the whole organism level. Geographically separated cancer tissues communicate between themselves, forming a system that interacts with the rest of the organism through cancer induced systemic pathogenic networks. In the present paper, I introduce six systemic hallmarks of cancer that emerge as a result of these interactions. I also describe several potential therapeutic approaches that can be developed using the cancer system concept. Overall, I argue that the tumoricentric paradigm should be replaced with a broader approach that brings into focus the “cancerized” organism.

Keywords

Cancer system / metastasis / cancer hallmarks / organism / tissue / system of cancer / systemic networks / system biology

References

[1] Noble D.A theory of biological relativity: no privileged level of causation..Interface Focus2012;2:55-64 PMCID:PMC3262309

[2] Noble D.A biological relativity view of the relationships between genomes and phenotypes..Prog Biophys Mol Biol2013;111:59-65

[3] Noble D.The music of life.2006;Oxford

[4] Egeblad M,Werb Z.Tumors as organs: complex tissues that interface with the entire organism..Dev Cell2010;18:884-901 PMCID:PMC2905377

[5] McAllister SS.Tumor-host interactions: a far-reaching relationship..J Clin Oncol2010;28:4022-8

[6] Al-Zoughbi W,Paramasivan GS,Pichler M.Tumor macroenvironment and metabolism..Semin Oncol2014;41:281-95 PMCID:PMC4012137

[7] McAllister SS.The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis..Nat Cell Biol2014;16:717-27 PMCID:PMC6220424

[8] Borniger JC.Central regulation of breast cancer growth and metastasis..J Cancer Metastasis Treat2019;5: PMCID:PMC6879058

[9] Borniger JC,Surbhi,Zhang N.A role for hypocretin/orexin in metabolic and sleep abnormalities in a mouse model of non-metastatic breast cancer..Cell Metab2018;28:118-29.e5 PMCID:PMC6031468

[10] Paul D.Cancer the big picture: seeing the forest beyond the trees..Oncolog-Hematolog2015;1:28-30

[11] Udrişte O.Gena ancestrală şi originea cancerului (in Romanian).1978;Bucharest, RomaniaEditura ştiinţifică şi enciclopedică

[12] Arechaga J.On the boundary between development and neoplasia. An interview with Professor G. Barry Pierce..Int J Dev Biol1993;37:5-16

[13] Dongre A.New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer..Nat Rev Mol Cell Biol2019;20:69-84

[14] Gallik KL,Nacke LM,Rocha M.Neural crest and cancer: divergent travelers on similar paths..Mech Dev2017;148:89-99 PMCID:PMC5811199

[15] Vincent MD.The animal within: carcinogenesis and the clonal evolution of cancer cells are speciation events sensu stricto..Evolution2010;64:1173-83

[16] Vincent MD.Cancer: beyond speciation..Adv Cancer Res2011;112:283-350

[17] Vincent M.Cancer: a de-repression of a default survival program common to all cells? a life-history perspective on the nature of cancer..Bioessays2012;34:72-82

[18] Hanahan D.The hallmarks of cancer..Cell2000;100:57-70

[19] Hanahan D.Hallmarks of cancer: the next generation..Cell2011;144:646-74

[20] Nguyen DX.Genetic determinants of cancer metastasis..Nat Rev Genet2007;8:341-52

[21] Chiang AC.Molecular basis of metastasis..N Engl J Med2008;359:2814-23 PMCID:PMC4189180

[22] Vogelstein B,Velculescu VE,Diaz LA Jr.Cancer genome landscapes..Science2013;339:1546-58 PMCID:PMC3749880

[23] Paget S.The distribution of secondary growths in cancer of the breast..Lancet1889;1:571-3

[24] Sugarbaker EV.Cancer metastasis: a product of tumor-host interactions..Curr Probl Cancer1979;3:1-59

[25] Fidler IJ.Metastasis results from preexisting variant cells within a malignant tumor..Science1977;197:893-5

[26] Price JE,Fidler IJ.Growth in an organ microenvironment as a selective process in metastasis..Clin Exp Metastasis1988;96:91-102

[27] McDonald OG,Saunders T,Mentch SJ.Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis..Nat Genet2017;49:367-76

[28] Aytes A,Mitrofanova A,Cyrta J.NSD2 is a conserved driver of metastatic prostate cancer progression..Nat Commun2018;9:5201

[29] Lambert AW,Weinberg RA.Emerging biological principles of metastasis..Cell2017;168:670-91 PMCID:PMC5308465

[30] Hendrix MJC,Seftor REB,Kulesa PM.Reprogramming metastatic tumour cells with embryonic microenvironments..Nat Rev Cancer2007;7:246-55

[31] Telerman A.The molecular programme of tumour reversion: the steps beyond malignant transformation..Nat Rev Cancer2009;9:206-16

[32] Bissell MJ.Putting tumours in context..Nat Rev Cancer2001;1:46-54 PMCID:PMC2975572

[33] Orimo A.Stromal fibroblasts in cancer: a novel tumor-promoting cell type..Cell Cycle2006;5:1597-601

[34] Caon I,Parnigoni A,Moretto P.Revisiting the hallmarks of cancer: the role of hyaluronan..Semin Cancer Biol2020;62:9-19

[35] Amson R,Telerman A.Lessons from tumor reversion for cancer treatment..Curr Opin Oncol2013;25:59-65

[36] Sun Y.The emerging molecular machinery and therapeutic targets of metastasis..Trends Pharmacol Sci2015;36:349-59 PMCID:PMC4461477

[37] Scheel C,Karnoub A.Adaptation versus selection: the origins of metastatic behavior..Cancer Res2007;67:11476-9discussion 9-80

[38] Ruan K,Ouyang G.MicroRNAs: novel regulators in the hallmarks of human cancer..Cancer Lett2009;285:116-26

[39] Nath S,Das P.Transcriptional control of mitosis: deregulation and cancer..Front Endocrinol (Lausanne)2015;6:60 PMCID:PMC4419714

[40] Chiaretti S.Role of liprins in the regulation of tumor cell motility and invasion..Curr Cancer Drug Targets2016;16:238-48

[41] Saini P.Tks adaptor proteins at a glance..J Cell Sci2018;131: PMCID:PMC5818055

[42] Anfossi S,Nagvekar R.MicroRNAs, regulatory messengers inside and outside cancer cells..Adv Exp Med Biol2018;1056:87-108

[43] Hoshino A,Bojmar L,Cioffi C.Extracellular vesicle and particle biomarkers define multiple human cancers..Cell2020;182:1-18

[44] Wortzel I,Kenific CM.Exosome-mediated metastasis: communication from a distance..Dev Cell2019;49:347-60

[45] Schwarzenbach H.MicroRNA shuttle from cell-to-cell by exosomes and its impact in cancer..Noncoding RNA2019;5: PMCID:PMC6468647

[46] Hoshino A,Shen TL,Hashimoto A.Tumour exosome integrins determine organotropic metastasis..Nature2015;527:329-35 PMCID:PMC4788391

[47] Rodrigues G,Kenific CM,Steiner L.Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis..Nat Cell Biol2019;21:1403-12 PMCID:PMC7354005

[48] Tomasetti C.Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions..Science2015;347:78-81 PMCID:PMC4446723

[49] Lau EY,Lee TK.Cancer stem cells and their microenvironment: biology and therapeutic implications..Stem Cells Int2017;2017:3714190 PMCID:PMC5346399

[50] Brabletz T,Spaderna S,Kirchner T.Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression..Nat Rev Cancer2005;5:744-9

[51] Ganesh K,Kaygusuz Y,He L.L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer..Nature Cancer2020;20-45 PMCID:PMC7351134

[52] Brennan MF,Moraco N.Lessons learned from the study of 10,000 patients with soft tissue sarcoma..Ann Surg2014;260:416-21discussion 21-2 PMCID:PMC4170654

[53] Fearon ER.A genetic model for colorectal tumorigenesis..Cell1990;61:759-67

[54] Guizard AN,Launay LC,Lapotre-Ledoux BM.Diagnosis and management of head and neck cancers in a high-incidence area in France: a population-based study..Medicine (Baltimore)2017;96:e7285 PMCID:PMC5500046

[55] Olson E,Wolfe KM,Silberstein PT.Epidemiology of thyroid cancer: a review of the national cancer database, 2000-2013..Cureus2019;11:e4127 PMCID:PMC6483114

[56] Welch DR.Defining the Hallmarks of Metastasis..Cancer Res2019;79:3011-27 PMCID:PMC6571042

[57] Flanigan RC.The role of radical nephrectomy in metastatic renal cell carcinoma..Semin Urol Oncol2001;19:98-102

[58] O’Reilly MS,Shing Y,Vasios G.Endostatin: an endogenous inhibitor of angiogenesis and tumor growth..Cell1997;88:277-85

[59] Kisker O,Banyard J,Becker CM.Generation of multiple angiogenesis inhibitors by human pancreatic cancer..Cancer Res2001;61:7298-304

[60] Kaplan RN,Zacharoulis S,Vincent L.VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche..Nature2005;438:820-7 PMCID:PMC2945882

[61] Mareel M,Madani I.Cancer invasion and metastasis: interacting ecosystems..Virchows Arch2009;454:599-622

[62] Kano Y,Konno M,Miyata H.Cells of origin of squamous epithelium, dysplasia and cancer in the head and neck region after bone marrow transplantation..Int J Oncol2014;44:443-50

[63] Houghton J,Nomura S,Carlson J.Gastric cancer originating from bone marrow-derived cells..Science2004;306:1568-71

[64] Guest I,Ma J,Glinsky G.Direct and indirect contribution of bone marrow-derived cells to cancer..Int J Cancer2010;126:2308-18 PMCID:PMC3051419

[65] Kaplan RN,Lyden D.Preparing the "soil": the premetastatic niche..Cancer Res2006;66:11089-93

[66] Kim S,Lin WW,Grivennikov S.Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis..Nature2009;457:102-6 PMCID:PMC2746432

[67] Spano D.Tumor microenvironment: a main actor in the metastasis process..Clin Exp Metastasis2012;29:381-95

[68] Costa-Silva B,Ocean AJ,Zhang H.Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver..Nat Cell Biol2015;17:816-26 PMCID:PMC5769922

[69] Liu Y.Characteristics and significance of the pre-metastatic niche..Cancer Cell2016;30:668-81

[70] Norton JD,Craggs G.Id helix-loop-helix proteins in cell growth and differentiation..Trends Cell Biol1998;8:58-65

[71] Guo L.Exosomes: potent regulators of tumor malignancy and potential bio-tools in clinical application..Crit Rev Oncol Hematol2015;95:346-58

[72] Karamanos NK,Theocharis AD,Franchi M.Proteoglycan chemical diversity drives multifunctional cell regulation and therapeutics..Chem Rev2018;118:9152-232

[73] Baietti MF,Mortier E,Degeest G.Syndecan-syntenin-ALIX regulates the biogenesis of exosomes..Nat Cell Biol2012;14:677-85

[74] Mu W,Zoller M.Host matrix modulation by tumor exosomes promotes motility and invasiveness..Neoplasia2013;15:875-87 PMCID:PMC3730040

[75] Peinado H,Lavotshkin S,Costa-Silva B.Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET..Nat Med2012;18:883-91 PMCID:PMC3645291

[76] Hessvik NP.Current knowledge on exosome biogenesis and release..Cell Mol Life Sci2018;75:193-208 PMCID:PMC5756260

[77] Cha DJ,Dou Y,Higginbotham JN.KRAS-dependent sorting of miRNA to exosomes..Elife2015;4:e07197 PMCID:PMC4510696

[78] Redig AJ.Breast cancer as a systemic disease: a view of metastasis..J Intern Med2013;274:113-26 PMCID:PMC3711134

[79] Engblom C,Zilionis R,Bos SA.Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF(high) neutrophils..Science2017;358: PMCID:PMC6343476

[80] Orimo A,Sgroi DC,Delaunay T.Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion..Cell2005;121:335-48

[81] Hattori K,Tashiro K,Tateno M.Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells..Blood2001;97:3354-60

[82] Kidd S,Watson K,Lu H.Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma..PLoS One2012;7:e30563 PMCID:PMC3282707

[83] LeBleu VS.A peek into cancer-associated fibroblasts: origins, functions and translational impact..Dis Model Mech2018;11: PMCID:PMC5963854

[84] Allavena P,Mantovani A.Molecular links between inflammation and cancer.2015;Systems Biology of CancerCambridge University Press273-81

[85] Colotta F,Sica A,Mantovani A.Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability..Carcinogenesis2009;30:1073-81

[86] Grivennikov SI,Karin M.Immunity, inflammation, and cancer..Cell2010;140:883-99 PMCID:PMC2866629

[87] Kundu JK.Inflammation: gearing the journey to cancer..Mutat Res2008;659:15-30

[88] Terlizzi M,Pinto A.Inflammasome: cancer's friend or foe?.Pharmacol Ther2014;143:24-33

[89] Setrerrahmane S.Tumor-related interleukins: old validated targets for new anti-cancer drug development..Mol Cancer2017;16:153 PMCID:PMC5606116

[90] Elaraj DM,Varghese S,Hewitt SM.The role of interleukin 1 in growth and metastasis of human cancer xenografts..Clin Cancer Res2006;12:1088-96

[91] Tuomisto AE,Vayrynen JP.Systemic inflammation in colorectal cancer: Underlying factors, effects, and prognostic significance..World J Gastroenterol2019;25:4383-404 PMCID:PMC6710177

[92] Becker A,Weiss JM,Peinado H.Extracellular vesicles in cancer: cell-to-cell mediators of metastasis..Cancer Cell2016;30:836-48 PMCID:PMC5157696

[93] Manning S.The immunomodulatory role of tumor-derived extracellular vesicles in colorectal cancer..Immunol Cell Biol2018;

[94] Jain S,Naseem S.Acute-phase proteins: as diagnostic tool..J Pharm Bioallied Sci2011;3:118-27 PMCID:PMC3053509

[95] Bankey PE.Hepatic reagulation of systemic inflammation following acute injury..Curr Opin Crit Care1996;2:280-6

[96] Nieuwenhuijzen GA,Lu Q,van Rooijen N.Macrophage elimination increases bacterial translocation and gut-origin septicemia but attenuates symptoms and mortality rate in a model of systemic inflammation..Ann Surg1993;218:791-9 PMCID:PMC1243076

[97] Iida N,Stewart CA,Bouladoux N.Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment..Science2013;342:967-70 PMCID:PMC6709532

[98] Viaud S,Mignot G,Daillere R.The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide..Science2013;342:971-6 PMCID:PMC4048947

[99] Gorjifard S.Microbiota-myeloid cell crosstalk beyond the gut..J Leukoc Biol2016;100:865-79 PMCID:PMC6608064

[100] Kostic AD,Meyerson M.Microbes and inflammation in colorectal cancer..Cancer Immunol Res2013;1:150-7

[101] Rutkowski MR.TLR5 signaling, commensal microbiota and systemic tumor promoting inflammation: the three parcae of malignant progression..Oncoimmunology2015;4:e1021542 PMCID:PMC4570098

[102] Hui D.Prognostication of survival in patients with advanced cancer: predicting the unpredictable?.Cancer Control2015;22:489-97 PMCID:PMC4769860

[103] Wang C,Xu S.High systemic immune-inflammation index (SII) represents an unfavorable prognostic factor for small cell lung cancer treated with etoposide and platinum-based chemotherapy..Lung2020;198:405-14

[104] Dupréa A.Inflammation and cancer: what a surgical oncologist should know..Eur J Surg Oncol2018;44:566-70

[105] Nakamura K.Targeting cancer-related inflammation in the era of immunotherapy..Immunol Cell Biol2017;95:325-32

[106] Dinarello CA.Why not treat human cancer with interleukin-1 blockade?.Cancer Metastasis Rev2010;29:317-29 PMCID:PMC2865633

[107] Crusz SM.Inflammation and cancer: advances and new agents..Nat Rev Clin Oncol2015;12:584-96

[108] Chen G,Zhang W,Wu M.Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response..Nature2018;560:382-6 PMCID:PMC6095740

[109] Zhou M,Zhou L,Ding G.Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203..Cell Immunol2014;292:65-9

[110] Liu Y,Cao X.The exosomes in tumor immunity..Oncoimmunology2015;4:e1027472 PMCID:PMC4570093

[111] Whiteside TL.Exosomes and tumor-mediated immune suppression..J Clin Invest2016;126:1216-23 PMCID:PMC4811135

[112] Yin Y,Chen X,Zhang Y.Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth..Cell Res2014;24:1164-80 PMCID:PMC4185347

[113] Berchem G,Bosseler M,Baconnais S.Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-beta and miR23a transfer..Oncoimmunology2016;5:e1062968 PMCID:PMC4839360

[114] Belkaid Y.Homeostatic Immunity and the Microbiota..Immunity2017;46:562-76 PMCID:PMC5604871

[115] Honda K.The microbiota in adaptive immune homeostasis and disease..Nature2016;535:75-84

[116] Matson V,Bao R,Zha Y.The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients..Science2018;359:104-8 PMCID:PMC6707353

[117] Routy B,Derosa L,Alou MT.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors..Science2018;359:91-7

[118] Tamura R,Yamamoto Y,Sasaki H.Dual role of macrophage in tumor immunity..Immunotherapy2018;10:899-909

[119] Shitara K.Regulatory T cells: a potential target in cancer immunotherapy..Ann N Y Acad Sci2018;1417:104-15

[120] Whiteside TL.The role of regulatory T cells in cancer immunology..Immunotargets Ther2015;4:159-71 PMCID:PMC4918255

[121] Zamarron BF.Dual roles of immune cells and their factors in cancer development and progression..Int J Biol Sci2011;7:651-8 PMCID:PMC3107473

[122] Shalapour S.Immunity, inflammation, and cancer: an eternal fight between good and evil..J Clin Invest2015;125:3347-55 PMCID:PMC4588298

[123] Labelle M,Hynes RO.Platelets guide the formation of early metastatic niches..Proc Natl Acad Sci U S A2014;111:E3053-61 PMCID:PMC4121772

[124] Ocana A,Pandiella A.Neutrophils in cancer: prognostic role and therapeutic strategies..Mol Cancer2017;16:137 PMCID:PMC5558711

[125] Mouchemore KA,Hamilton JA.Neutrophils, G-CSF and their contribution to breast cancer metastasis..FEBS J2018;285:665-79

[126] Cools-Lartigue J,Najmeh S.Neutrophil extracellular traps in cancer progression..Cell Mol Life Sci2014;71:4179-94 PMCID:PMC7096049

[127] Park J,Amoozgar Z,Fein MR.Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps..Sci Transl Med2016;8:361ra138 PMCID:PMC5550900

[128] Lieffers JR,Hall KD,Prado CM.A viscerally driven cachexia syndrome in patients with advanced colorectal cancer: contributions of organ and tumor mass to whole-body energy demands..Am J Clin Nutr2009;89:1173-9 PMCID:PMC2667460

[129] Warburg O.On the origin of cancer cells..Science1956;123:309-14

[130] Vaupel P.Availability, not respiratory capacity governs oxygen consumption of solid tumors..Int J Biochem Cell Biol2012;44:1477-81

[131] Davidson SM,Olenchock BA,Keibler MA.Environment impacts the metabolic dependencies of ras-driven non-small cell lung cancer..Cell Metab2016;23:517-28 PMCID:PMC4785096

[132] Tisdale MJ.Mechanisms of cancer cachexia..Physiol Rev2009;89:381-410

[133] Fearon KC,Guttridge DC.Cancer cachexia: mediators, signaling, and metabolic pathways..Cell Metab2012;16:153-66

[134] Porporato PE.Understanding cachexia as a cancer metabolism syndrome..Oncogenesis2016;5:e200 PMCID:PMC5154342

[135] Vander Heiden MG.Understanding the Intersections between Metabolism and Cancer Biology..Cell2017;168:657-69 PMCID:PMC5329766

[136] Alam MM,FitzGerald KE.A holistic view of cancer bioenergetics: mitochondrial function and respiration play fundamental roles in the development and progression of diverse tumors..Clin Transl Med2016;5:3 PMCID:PMC4728164

[137] Martinez-Outschoorn UE,Howell A,Tanowitz HB.Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment..Int J Biochem Cell Biol2011;43:1045-51 PMCID:PMC3102770

[138] Pavlides S,Migneco G,Chiavarina B.The autophagic tumor stroma model of cancer: role of oxidative stress and ketone production in fueling tumor cell metabolism..Cell Cycle2010;9:3485-505 PMCID:PMC3047615

[139] Pavlides S,Vera I,Frank PG.Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the “reverse Warburg effect”: a transcriptional informatics analysis with validation..Cell Cycle2010;9:2201-19

[140] Tsoli M.Cancer cachexia: malignant inflammation, tumorkines, and metabolic mayhem..Trends Endocrinol Metab2013;24:174-83

[141] Flint TR,Connell CM,Denton AE.Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity..Cell Metab2016;24:672-84 PMCID:PMC5106372

[142] Lee YM,Ma WL.Hypothesis: solid tumours behave as systemic metabolic dictators..J Cell Mol Med2016;20:1076-85 PMCID:PMC4882994

[143] Argiles JM,Lopez-Soriano FJ.Inter-tissue communication in cancer cachexia..Nat Rev Endocrinol2018;15:9-20

[144] Argiles JM,Stemmler B.Cancer cachexia: understanding the molecular basis..Nat Rev Cancer2014;14:754-62

[145] George J,Lai V,Zanation A.Cancer cachexia syndrome in head and neck cancer patients: Part II. pathophysiology..Head Neck2007;29:497-507

[146] Roxburgh CS.Cancer and systemic inflammation: treat the tumour and treat the host..Br J Cancer2014;110:1409-12 PMCID:PMC3960633

[147] Payen VL,Baselet B.Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway..Cell Mol Life Sci2016;73:1333-48

[148] Porporato PE,Baselet B.Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism..Cell Mol Life Sci2016;73:1349-63

[149] Chasen M,Hirschman S.Immunomodulatory agents for the treatment of cachexia..Curr Opin Support Palliat Care2014;8:328-33

[150] Das SK,Schauer S,Temmel H.Adipose triglyceride lipase contributes to cancer-associated cachexia..Science2011;333:233-8

[151] Mantovani G,Mura L,Mudu MC.Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites..J Mol Med (Berl)2000;78:554-61

[152] Kir S,Kleiner S,Cohen P.Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia..Nature2014;513:100-4 PMCID:PMC4224962

[153] Petruzzelli M,Schreiber R,Tsoli M.A switch from white to brown fat increases energy expenditure in cancer-associated cachexia..Cell Metab2014;20:433-47

[154] Tomasin R,Cominetti MR.Metastasis and cachexia: alongside in clinics, but not so in animal models..J Cachexia Sarcopenia Muscle2019;10:1183-94 PMCID:PMC6903449

[155] Zhang G,Ding H,Doan HA.Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90..Nat Commun2017;8:589 PMCID:PMC5605540

[156] Lazar I,Dauvillier S,Ducoux-Petit M.Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: a novel mechanism linking obesity and cancer..Cancer Res2016;76:4051-7

[157] Tomasetti M,Santarelli L.Exosome-derived microRNAs in cancer metabolism: possible implications in cancer diagnostics and therapy..Exp Mol Med2017;49:e285 PMCID:PMC5291842

[158] Marinho R,Ottoch JP.Role of exosomal microRNAs and myomiRs in the development of cancer cachexia-associated muscle wasting..Front Nutr2017;4:69 PMCID:PMC5767254

[159] He WA,Londhe P,Guttridge DC.Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7..Proc Natl Acad Sci U S A2014;111:4525-9 PMCID:PMC3970508

[160] Masri S,Kinouchi K,Cervantes M.Lung adenocarcinoma distally rewires hepatic circadian homeostasis..Cell2016;165:896-909 PMCID:PMC5373476

[161] Goncalves MD,Pauli C,Cheng Z.Fenofibrate prevents skeletal muscle loss in mice with lung cancer..Proc Natl Acad Sci U S A2018;115:E743-52 PMCID:PMC5789923

[162] Bruning PF,van Noord PA,de Jong-Bakker M.Insulin resistance and breast-cancer risk..Int J Cancer1992;52:511-6

[163] Maloney EK,Dagdigian NE,Connors KM.An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation..Cancer Res2003;63:5073-83

[164] Hartl WH,Jauch KW,Schildberg FW.Effect of glucagon on protein synthesis in human rectal cancer in situ..Ann Surgery1998;227:390-7 PMCID:PMC1191277

[165] Mayers JR,Danai LV,Davidson SM.Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers..Science2016;353:1161-5 PMCID:PMC5245791

[166] Mayers JR,Clish CB,Torrence ME.Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development..Nat Med2014;20:1193-8 PMCID:PMC4191991

[167] Bindels LB.Muscle wasting: the gut microbiota as a new therapeutic target?.Int J Biochem Cell Biol2013;45:2186-90

[168] Nieuwdorp M,Pai N.Role of the microbiome in energy regulation and metabolism..Gastroenterology2014;146:1525-33

[169] Argiles JM,Almendro V,Lopez-Soriano FJ.Cross-talk between skeletal muscle and adipose tissue: a link with obesity?.Med Res Rev2005;25:49-65

[170] Hellerstein MK,Meydani M,Dinarello CA.Interleukin-1-induced anorexia in the Rat - influence of prostaglandins..J Clin Invest1989;84:228-35 PMCID:PMC303974

[171] Chauhan A,Manderson C,Wasley D.Exploring autonomic nervous system dysfunction in patients with cancer cachexia: a pilot study..Auton Neurosci2012;166:93-5

[172] Chrousos GP.The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation..N Engl J Med1995;332:1351-62

[173] Murphy KT.The pathogenesis and treatment of cardiac atrophy in cancer cachexia..Am J Physiol Heart Circ Physiol2016;310:H466-77

[174] Belloum Y,Favier FB.Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity (Review)..Oncol Rep2017;37:2543-52

[175] Anker SD.The syndrome of cardiac cachexia..Int J Cardiol2002;85:51-66

[176] Israel M.The metabolic advantage of tumor cells..Mol Cancer2011;10:70 PMCID:PMC3118193

[177] Israël M.A primary cause of cancer: GABA deficiency in endocrine pancreas..Cancer Therapy2012;8:171-83

[178] Cancer metabolism: an alteration of the anabolic–catabolic selection switch..OA Cancer2014;2:1

[179] Israël M.Metabolic rewiring of stem cells and differentiated cells in cancer: the hypothetical consequences of a GABA deficiency in endocrine pancreas..J Cancer Metastasis Treat2019;5:

[180] Kuhn T,Sookthai D,Rolle-Kampczyk U.Higher plasma levels of lysophosphatidylcholine 18:0 are related to a lower risk of common cancers in a prospective metabolomics study..BMC Med2016;14:13 PMCID:PMC4730724

[181] Beleva E.From Virchow's triad to metastasis: circulating hemostatic factors as predictors of risk for metastasis in solid tumors..J BUON2013;18:25-33

[182] Karikoski M,Elima K,Hollmen M.Clever-1/stabilin-1 controls cancer growth and metastasis..Clin Cancer Res2014;20:6452-64

[183] Khorana AA,Culakova E,Lyman GH.Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy..J Thromb Haemost2007;5:632-4

[184] Falanga A,Milesi V.Mechanisms and risk factors of thrombosis in cancer..Crit Rev Oncol Hematol2017;118:79-83

[185] van den Berg YW,Reitsma PH.The relationship between tissue factor and cancer progression: insights from bench and bedside..Blood2012;119:924-32

[186] Magnus N,Meehan B,Lee TH.Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations..Proc Natl Acad Sci U S A2014;111:3544-9 PMCID:PMC3948265

[187] Versteeg HH,Kerver M,Ahamed J.Inhibition of tissue factor signaling suppresses tumor growth..Blood2008;111:190-9 PMCID:PMC2200804

[188] Labelle M.The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination..Cancer Discov2012;2:1091-9 PMCID:PMC3540992

[189] Labelle M,Hynes RO.Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis..Cancer Cell2011;20:576-90 PMCID:PMC3487108

[190] Laubli H.Selectins promote tumor metastasis..Semin Cancer Biol2010;20:169-77

[191] Becker KA,Adams C,Kramer M.Melanoma cell metastasis via P-selectin-mediated activation of acid sphingomyelinase in platelets..Clin Exp Metastasis2017;34:25-35

[192] Lavergne M,Schaff M,Mangin PH.Platelet integrins in tumor metastasis: do they represent a therapeutic target?.Cancers (Basel)2017;9: PMCID:PMC5664072

[193] Mege D,Ouaissi M,Sielezneff I.The origin and concentration of circulating microparticles differ according to cancer type and evolution: a prospective single-center study..Int J Cancer2016;138:939-48

[194] Mezouar S,Darbousset R,Crescence L.Role of platelets in cancer and cancer-associated thrombosis: experimental and clinical evidences..Thromb Res2016;139:65-76

[195] Dvorak HF,Orenstein NS,Hahn P.Tumor shedding and coagulation..Science1981;212:923-4

[196] Del Conde I,Dietzen DJ,Thiagarajan P.Microvesicle-associated tissue factor and Trousseau’s syndrome..J Thromb Haemost2007;5:70-4 PMCID:PMC3410746

[197] Geddings JE.Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients..Blood2013;122:1873-80 PMCID:PMC3772497

[198] Magnon C.Role of the autonomic nervous system in tumorigenesis and metastasis..Mol Cell Oncol2015;2:e975643 PMCID:PMC4904882

[199] Elenkov IJ,Chrousos GP.The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system..Pharmacol Rev2000;52:595-638

[200] Li T,Tamada K,Nomoto K.Repeated restraint stress impairs the antitumor T cell response through its suppressive effect on Th1-type CD4+ T cells..Anticancer Res1997;17:4259-68

[201] Cao L,Lin EJ,Choi EY.Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition..Cell2010;142:52-64 PMCID:PMC3784009

[202] Burfeind KG,Marks DL.The central role of hypothalamic inflammation in the acute illness response and cachexia..Semin Cell Dev Biol2016;54:42-52 PMCID:PMC4872506

[203] Braun TP,Szumowski M,Grossberg AJ.Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis..J Exp Med2011;208:2449-63 PMCID:PMC3256966

[204] Burfeind KG,Levasseur PR,Norgard MA.TRIF is a key inflammatory mediator of acute sickness behavior and cancer cachexia..Brain Behav Immun2018;73:364-74 PMCID:PMC6129432

[205] Mravec B,Cernackova A.Hypothalamic inflammation at a crossroad of somatic diseases..Cell Mol Neurobiol2019;39:11-29

[206] Molfino A,Colaiacomo MC,Emiliani A.Cancer anorexia: hypothalamic activity and its association with inflammation and appetite-regulating peptides in lung cancer..J Cachexia Sarcopenia Muscle2017;8:40-7 PMCID:PMC5326827

[207] Mauffrey P,Barroca V,Firlej V.Progenitors from the central nervous system drive neurogenesis in cancer..Nature2019;569:672-8

[208] Cole SW,Lutgendorf SK,Sood AK.Sympathetic nervous system regulation of the tumour microenvironment..Nat Rev Cancer2015;15:563-72 PMCID:PMC4828959

[209] Jones DH,Sanchez OH,Komarova SV.Regulation of cancer cell migration and bone metastasis by RANKL..Nature2006;440:692-6

[210] Katayama Y,Kao WM,Peired AJ.Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow..Cell2006;124:407-21

[211] Elefteriou F.Role of sympathetic nerves in the establishment of metastatic breast cancer cells in bone..J Bone Oncol2016;5:132-4 PMCID:PMC5063226

[212] Magnon C,Lin J,Gerber L.Autonomic nerve development contributes to prostate cancer progression..Science2013;341:1236361

[213] Grytli HH,Fossa SD,Haheim LL.Use of beta-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy..Prostate2013;73:250-60

[214] Lemeshow S,Phillips G,Antonsen S.Beta-blockers and survival among Danish patients with malignant melanoma: a population-based cohort study..Cancer Epidemiol Biomarkers Prev2011;20:2273-9 PMCID:PMC3652234

[215] Melhem-Bertrandt A,Lei X,Lee RT.Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer..J Clin Oncol2011;29:2645-52 PMCID:PMC3139371

[216] Pavlov VA.The vagus nerve and the inflammatory reflex--linking immunity and metabolism..Nat Rev Endocrinol2012;8:743-54 PMCID:PMC4082307

[217] Fujii T,Moriwaki Y,Ono S.Expression and function of the cholinergic system in immune cells..Front Immunol2017;8:1085 PMCID:PMC5592202

[218] Yu H,Tang Q,Wei G.Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation..Sci Rep2017;7:40802 PMCID:PMC5244394

[219] Zhao CM,Kodama Y,Westphalen CB.Denervation suppresses gastric tumorigenesis..Sci Transl Med2014;6:250ra115 PMCID:PMC4374618

[220] Jobling P,Oliveira SM,Walker MM.Nerve-cancer cell cross-talk: a novel promoter of tumor progression..Cancer Res2015;75:1777-81

[221] Pelosof LC.Paraneoplastic syndromes: an approach to diagnosis and treatment..Mayo Clin Proc2010;85:838-54 PMCID:PMC2931619

[222] DeLellis RA.Paraneoplastic endocrine syndromes: a review..Endocr Pathol2003;14:303-17

[223] Castellone MD,Teramoto H,Ali G.Cross talk between the bombesin neuropeptide receptor and Sonic hedgehog pathways in small cell lung carcinoma..Oncogene2015;34:1679-87 PMCID:PMC4539617

[224] Sherbet GV.Hormonal influences on cancer progression and prognosis..Vitam Horm2005;71:147-200

[225] Mousa SA,Lin HY,Hercbergs A.Contributions of thyroid hormone to cancer metastasis..Biomedicines2018;6:89 PMCID:PMC6165185

[226] Su SC,Yang WE,Reiter RJ.Cancer metastasis: mechanisms of inhibition by melatonin..J Pineal Res2017;62:

[227] Zaki NF,Farouk O,Spence DW.Depressive symptoms, sleep profiles and serum melatonin levels in a sample of breast cancer patients..Nat Sci Sleep2020;12:135-49 PMCID:PMC7025675

[228] Yu B,Temprosa M,Appel N.The consortium of metabolomics studies (COMETS): metabolomics in 47 prospective cohort studies..Am J Epidemiol2019;188:991-1012 PMCID:PMC6545286

[229] Dean DC,Hornicek FJ.From genomics to metabolomics: emerging metastatic biomarkers in osteosarcoma..Cancer Metastasis Rev2018;37:719-31

[230] Xiao S.Gastric cancer: metabolic and metabolomics perspectives (Review)..Int J Oncol2017;51:5-17

[231] Peng X,Farshidfar F,Lorenzi PL.Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers..Cell Rep2018;23:255-69.e4 PMCID:PMC5916795

[232] Cieslik M,Baranova N,Kumar M.Epigenetic coordination of signaling pathways during the epithelial-mesenchymal transition..Epigenetics Chromatin2013;6:28 PMCID:PMC3847279

[233] Hong D,Tye CE,Fritz AJ.Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition..Oncotarget2017;8:17610-27 PMCID:PMC5392273

[234] Vincent MD.Cancer: towards a general theory of the target: all successful cancer therapies, actual or potential, are reducible to either (or both) of two fundamental strategies..Bioessays2017;39:

[235] Dai S,Wu Z,Wei X.Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer..Mol Ther2008;16:782-90 PMCID:PMC7106337

[236] Que RS,Ding GP,Cao LP.Increasing the immune activity of exosomes: the effect of miRNA-depleted exosome proteins on activating dendritic cell/cytokine-induced killer cells against pancreatic cancer..J Zhejiang Univ Sci B2016;17:352-60 PMCID:PMC4868825

[237] Tauro BJ,Mathias RA,Ji H.Two distinct populations of exosomes are released from LIM1863 colon carcinoma cell-derived organoids..Mol Cell Proteomics2013;12:587-98 PMCID:PMC3591653

[238] Kitano H.Biological robustness..Nat Rev Genet2004;5:826-37

[239] Tyson JJ,Novak B.Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell..Curr Opin Cell Biol2003;15:221-31

[240] Chen JC,Talos F,Rieckhof GE.Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks..Cell2014;159:402-14 PMCID:PMC4194029

[241] Archetti M.Cooperation among cancer cells: applying game theory to cancer..Nat Rev Cancer2019;19:110-7

[242] Csermely P.Cancer-related networks: a help to understand, predict and change malignant transformation..Semin Cancer Biol2013;23:209-12

[243] Antonia SJ,Ramalingam SS,De Castro Carpeno J.Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis..Lancet Oncol2019;20:1395-408 PMCID:PMC7193685

[244] Garon EB,Rizvi NA,Leighl NB.Five-year overall survival for patients with advanced nonsmall-cell lung cancer treated with pembrolizumab: results from the phase I keynote-001 study..J Clin Oncol2019;37:2518-27 PMCID:PMC6768611

[245] Larkin J,Gonzalez R,Rutkowski P.Five-year survival with combined nivolumab and ipilimumab in advanced melanoma..N Engl J Med2019;381:1535-46

[246] Rosenzweig SA.Acquired resistance to drugs targeting tyrosine kinases..Adv Cancer Res2018;138:71-98 PMCID:PMC5985159

[247] Liu X,Xiao R,Huang W.Hypothalamic gene transfer of BDNF inhibits breast cancer progression and metastasis in middle age obese mice..Mol Ther2014;22:1275-84 PMCID:PMC4089014

[248] Bucsek MJ,MacDonald CR,Evans L.Beta-adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8(+) T cells and undermines checkpoint inhibitor therapy..Cancer Res2017;77:5639-51

[249] Kokolus KM,Sivik JM,Zhu J.Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice..Oncoimmunology2018;7:e1405205 PMCID:PMC5790362

[250] Springer J,Haghikia A,Lal H.Prevention of liver cancer cachexia-induced cardiac wasting and heart failure..Eur Heart J2014;35:932-41 PMCID:PMC3977133

[251] Saada-Bouzid E,Karabajakian A,Servois V.Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma..Ann Oncol2017;28:1605-11