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• W2085852125 abstract "The connection between inflammation and tumorigenesis is well-established and in the last decade has received a great deal of supporting evidence from genetic, pharmacological, and epidemiological data. Inflammatory bowel disease is an important risk factor for the development of colon cancer. Inflammation is also likely to be involved with other forms of sporadic as well as heritable colon cancer. The molecular mechanisms by which inflammation promotes cancer development are still being uncovered and could differ between colitis-associated and other forms of colorectal cancer. Recent work has elucidated the role of distinct immune cells, cytokines, and other immune mediators in virtually all steps of colon tumorigenesis, including initiation, promotion, progression, and metastasis. These mechanisms, as well as new approaches to prevention and therapy, are discussed in this review. The connection between inflammation and tumorigenesis is well-established and in the last decade has received a great deal of supporting evidence from genetic, pharmacological, and epidemiological data. Inflammatory bowel disease is an important risk factor for the development of colon cancer. Inflammation is also likely to be involved with other forms of sporadic as well as heritable colon cancer. The molecular mechanisms by which inflammation promotes cancer development are still being uncovered and could differ between colitis-associated and other forms of colorectal cancer. Recent work has elucidated the role of distinct immune cells, cytokines, and other immune mediators in virtually all steps of colon tumorigenesis, including initiation, promotion, progression, and metastasis. These mechanisms, as well as new approaches to prevention and therapy, are discussed in this review. Sergei Grivennikov*View Large Image Figure ViewerDownload Hi-res image Download (PPT)Eliad Karin*,§View Large Image Figure ViewerDownload Hi-res image Download (PPT)Michael Karin*View Large Image Figure ViewerDownload Hi-res image Download (PPT)Colitis-associated cancer (CAC) is the CRC subtype that is associated with inflammatory bowel disease (IBD), is difficult to treat, and has high mortality.5Feagins L.A. Souza R.F. Spechler S.J. Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer.Nat Rev Gastroenterol Hepatol. 2009; 6: 297-305Crossref PubMed Scopus (53) Google Scholar More than 20% of IBD patients develop CAC within 30 years of disease onset, and >50% of these will die from CAC.6Lakatos P.L. Lakatos L. Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies.World J Gastroenterol. 2008; 14: 3937-3947Crossref PubMed Scopus (69) Google Scholar Although immune-mediated mechanisms link IBD and CAC,7Greten F.R. Eckmann L. Greten T.F. et al.IKKb links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.Cell. 2004; 118: 285-296Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar, 8Atreya I. Neurath M.F. Immune cells in colorectal cancer: prognostic relevance and therapeutic strategies.Expert Rev Anticancer Ther. 2008; 8: 561-572Crossref PubMed Scopus (28) Google Scholar there are similarities between CAC and other types of CRC that develop without any signs of overt inflammatory disease (Figure 1). Some of the essential stages of cancer development, including formation of aberrant crypt foci, polyps, adenomas, and carcinomas, are similar between noninflammatory CRC and CAC. However, some different pathogenic sequences have been proposed for CAC, including chronic inflammation and injury-dysplasia carcinoma, which arises without the formation of well-defined adenoma. Nonetheless, common genetic and signaling pathways, such as those involving Wnt, β-catenin, K-ras, p53, transforming growth factor (TGF)-β, and the DNA mismatch repair (MMR) proteins, are altered in sporadic CRC and CAC, although the timing of p53 and adenomatous polyposis coli (APC) inactivation and K-Ras activation can differ between CRC and CAC.6Lakatos P.L. Lakatos L. Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies.World J Gastroenterol. 2008; 14: 3937-3947Crossref PubMed Scopus (69) Google Scholar, 9Sheng H. Shao J. Williams C.S. et al.Nuclear translocation of beta-catenin in hereditary and carcinogen-induced intestinal adenomas.Carcinogenesis. 1998; 19: 543-549Crossref PubMed Scopus (57) Google Scholar Importantly, development of both sporadic CRC and CAC is influenced by the intestinal microflora (at least, in animal models). Finally, even colorectal tumors that are not associated with clinically detectable IBD display robust inflammatory infiltration and increased expression of proinflammatory cytokines.8Atreya I. Neurath M.F. Immune cells in colorectal cancer: prognostic relevance and therapeutic strategies.Expert Rev Anticancer Ther. 2008; 8: 561-572Crossref PubMed Scopus (28) Google Scholar, 10Atreya I. Atreya R. Neurath M.F. NF-kappaB in inflammatory bowel disease.J Intern Med. 2008; 263: 591-596Crossref PubMed Scopus (119) Google Scholar, 11Waldner M.J. Neurath M.F. Cytokines in colitis associated cancer: potential drug targets?.Inflamm Allergy Drug Targets. 2008; 7: 187-194Crossref PubMed Scopus (17) Google Scholar, 12Clevers H. At the crossroads of inflammation and cancer.Cell. 2004; 118: 671-674Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar IBD patients with family history of CRC have >2-fold higher risk13Askling J. Dickman P.W. Karlen P. et al.Family history as a risk factor for colorectal cancer in inflammatory bowel disease.Gastroenterology. 2001; 120: 1356-1362Abstract Full Text Full Text PDF PubMed Google Scholar for colon cancer development, suggesting overlap in mechanisms driving CRC and CAC. Moreover, a large fraction of CRC tumors and cell lines exhibit constitutive activation of transcription factors that are essential components of multiple inflammatory pathways, namely nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3)14Sakamoto K. Maeda S. Hikiba Y. et al.Constitutive NF-kappaB activation in colorectal carcinoma plays a key role in angiogenesis, promoting tumor growth.Clin Cancer Res. 2009; 15: 2248-2258Crossref PubMed Scopus (41) Google Scholar, 15Yu H. Pardoll D. Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3.Nat Rev Cancer. 2009; 9: 798-809Crossref PubMed Scopus (557) Google Scholar (Table 1). It is therefore possible that immune cells and inflammatory cytokines act through similar yet distinct mechanisms in the pathogenesis of CAC and sporadic CRC. We discuss these mechanisms in this review.Figure 1Mechanisms of colorectal cancer (CRC) and colitis-associated cancer (CAC) development. CRC is caused by accumulation of mutations in oncogenes and tumor suppressor genes; some of these lead to aberrant activation of β-catenin signaling. Mutations in adenomatous polyposis coli (APC), β-catenin, or other components of this pathway mediate the transition of single preneoplastic cells to aberrant crypt foci (ACF) and then to adenoma and colorectal carcinoma. Chronic inflammation, which leads to CAC, is characterized by production of proinflammatory cytokines that can induce mutations in oncogenes and tumor suppressor genes (APC, p53, K-ras) and genomic instability via various mechanisms. Persistent inflammation facilitates tumor promotion by activating proliferation and antiapoptotic properties of premalignant cells, as well as tumor progression and metastasis. There is considerable overlap in mechanisms of CRC and CAC pathogenesis. GSK-β, glycogen synthase kinase-β; RNI, reactive nitrogen intermediates; TGF, transforming growth factor.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Main Features of Colitis-Associated Cancer and Colorectal CancerUp to 20% of IBD (UC) patients develop CAC within 30 years of disease onset.High overall mortality rate (>50%).NSAID use reduces the risk of CRC and therefore underlines the importance of inflammation in otherwise “non-inflammatory” CRC. Potential role for anticytokine therapy.Can either develop through the classic adenoma to carcinoma sequence or through a sequence of chronic inflammation, injury, dysplasia, and colorectal carcinoma.Common genetic and signaling pathways are altered in sporadic CRC and CAC, including those that involve β-catenin, p53, K-ras, and B-raf.Colorectal tumors display robust inflammatory infiltration with multiple cell type infiltrates. These immune cells are important sources of protumorigenic inflammatory cytokines and chemokines. Most colorectal tumors and almost all colitis-associated tumors have constitutive activation of transcription factors, such as NF-κB and/or STAT3, which mediate the immune response and oncogenesis.Growth and progression of colorectal tumors and colitis-associated tumors depend on the quality and quantity of intestinal microflora.CAC, colitis-associated cancer; CRC, colorectal cancer; IBD, inflammatory bowel disease; NF-κB, nuclear factor-κB; NSAID, nonsteroidal anti-inflammatory drug; STAT3, signal transducer and activator of transcription 3; UC, ulcerative colitis. Open table in a new tab Development of CRC Compared with CACDevelopment of CRC typically follows several consecutive steps, which were first described in a milestone study by Fearon and Vogelstein16Fearon E.R. Vogelstein B. A genetic model for colorectal tumorigenesis.Cell. 1990; 61: 759-767Abstract Full Text PDF PubMed Scopus (5434) Google Scholar (Figure 1). Although initiating mutations in normal epithelial or stem cells occur at random and at low rates, cells that contain activating mutations in Wnt or β-catenin are the most likely to form tumors. Mutations in APC, which has 15 exons and encodes a huge protein with molecular weight that is >300 kDa, are typically early events in the tumorigenic pathway. The APC protein is an inhibitor of β-catenin, sequestering it in the cytoplasm.17Korinek V. Barker N. Morin P.J. et al.Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma.Science. 1997; 275: 1784-1787Crossref PubMed Scopus (2159) Google Scholar, 18Morin P.J. Sparks A.B. Korinek V. et al.Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.Science. 1997; 275: 1787-1790Crossref PubMed Scopus (2410) Google Scholar, 19Bienz M. Clevers H. Linking colorectal cancer to Wnt signaling.Cell. 2000; 103: 311-320Abstract Full Text Full Text PDF PubMed Google Scholar Wnt-dependent signaling results in the proteolytic degradation of APC, β-catenin activation and translocation to the nucleus.17Korinek V. Barker N. Morin P.J. et al.Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma.Science. 1997; 275: 1784-1787Crossref PubMed Scopus (2159) Google Scholar Therefore, APC encodes a tumor suppressor; both alleles must be disrupted for transformation to occur.Individuals with familial adenomatous polyposis carry a mutation in one APC allele; the 2nd allele is typically inactivated through loss of heterozygosity within the first 30 years of life, resulting in formation of multiple and aggressive tumors in the colon.20Taketo M.M. Edelmann W. Mouse models of colon cancer.Gastroenterology. 2009; 136: 780-798Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar APC mutations are required for the transition of preneoplastic cells to aberrant crypt foci and toward development of microadenoma and adenoma.16Fearon E.R. Vogelstein B. A genetic model for colorectal tumorigenesis.Cell. 1990; 61: 759-767Abstract Full Text PDF PubMed Scopus (5434) Google Scholar, 18Morin P.J. Sparks A.B. Korinek V. et al.Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.Science. 1997; 275: 1787-1790Crossref PubMed Scopus (2410) Google Scholar Inactivation of APC stops the migration and differentiation of premalignant cells and their subsequent shedding at the edge of the crypt.21Barker N. Ridgway R.A. van Es J.H. et al.Crypt stem cells as the cells-of-origin of intestinal cancer.Nature. 2009; 457: 608-611Crossref PubMed Scopus (455) Google Scholar, 22Sansom O.J. Reed K.R. Hayes A.J. et al.Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration.Genes Dev. 2004; 18: 1385-1390Crossref PubMed Scopus (315) Google Scholar Thus, cells with APC mutations, which would be otherwise shed into the intestinal lumen, have enough time to acquire the second and third mutations required for subsequent malignant conversion. Therefore, APC inactivation (or β-catenin activation) are essential for formation of adenomas—recent studies showed that APC inactivation must occur in intestinal stem cells, rather than epithelial cells.21Barker N. Ridgway R.A. van Es J.H. et al.Crypt stem cells as the cells-of-origin of intestinal cancer.Nature. 2009; 457: 608-611Crossref PubMed Scopus (455) Google Scholar, 23Zhu L. Gibson P. Currle D.S. et al.Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation.Nature. 2009; 457: 603-607Crossref PubMed Scopus (249) Google Scholar Recent study suggests that loss of APC and activation of CtBP1 are needed for adenoma development, while subsequent KRAS activation and β-catenin nuclear localization promote CRC.24Phelps R.A. Chidester S. Dehghanizadeh S. et al.A two-step model for colon adenoma initiation and progression caused by APC loss.Cell. 2009; 137: 623-634Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Although a very large gene such as APC can be easily inactivated by mutations, these are not the only mutations that lead to β-catenin activation. Mutations in glycogen synthase kinase-β, β-catenin itself, and other components of this pathway are found in 10% of colon tumors.25Schneikert J. Behrens J. The canonical Wnt signalling pathway and its APC partner in colon cancer development.Gut. 2007; 56: 417-425Crossref PubMed Scopus (78) Google Scholar Interestingly, in Helicobacter pylori–induced gastric tumors, proinflammatory signaling by tumor necrosis factor (TNF)-α can induce β-catenin nuclear accumulation even without the presence of APC mutations.26Oguma K. Oshima H. Aoki M. et al.Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells.EMBO J. 2008; 27: 1671-1681Crossref PubMed Scopus (94) Google Scholar Similarly, activation of the receptor EP2 by prostaglandin E2 (PGE2), which is produced during acute and chronic inflammation, also increases β-catenin nuclear accumulation and transcriptional activity.27Castellone M.D. Teramoto H. Williams B.O. Druey K.M. Gutkind J.S. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis.Science. 2005; 310: 1504-1510Crossref PubMed Scopus (386) Google Scholar Other inflammatory signaling pathways converge at the point of glycogen synthase kinase-β and casein kinases 1 and 2, the protein kinases that control β-catenin activation.28Gao Y. Wang H.Y. Casein kinase 2 Is activated and essential for Wnt/beta-catenin signaling.J Biol Chem. 2006; 281: 18394-18400Crossref PubMed Scopus (42) Google Scholar, 29Sakanaka C. Phosphorylation and regulation of beta-catenin by casein kinase I epsilon.J Biochem. 2002; 132: 697-703Crossref PubMed Google Scholar, 30Umar S. Sarkar S. Wang Y. Singh P. Functional cross-talk between {beta}-catenin and nf{kappa}b signaling pathways in colonic crypts of mice in response to progastrin.J Biol Chem. 2009; 284: 22274-22284Crossref PubMed Scopus (20) Google Scholar, 31Umar S. Wang Y. Morris A.P. Sellin J.H. Dual alterations in casein kinase I-epsilon and GSK-3beta modulate beta-catenin stability in hyperproliferating colonic epithelia.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G599-G607Crossref PubMed Scopus (13) Google Scholar To the same end, activation of NF-κB and Akt pathways by proinflammatory signaling promotes β-catenin activation.32Kaler P. Augenlicht L. Klampfer L. Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3.Oncogene. 2009; 28: 3892-3902Crossref PubMed Scopus (38) Google Scholar, 33Kaler P. Godasi B.N. Augenlicht L. Klampfer L. The NF-kappaB/AKT-dependent Induction of Wnt Signaling in Colon Cancer Cells by Macrophages and IL-1beta.Cancer Microenviron. 2009; 2: 69-80Crossref Scopus (18) Google Scholar Interestingly, conventionally raised, Helicobacter-infected, interleukin (IL)-10–deficient mice develop spontaneous inflammation and colon tumors,34Berg D.J. Davidson N. Kuhn R. et al.Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses.J Clin Invest. 1996; 98: 1010-1020Crossref PubMed Google Scholar but tumor cells do not contain APC or even p53 mutations, indicating a possible role for inflammation in APC-inactivation–independent activation of β-catenin signaling.34Berg D.J. Davidson N. Kuhn R. et al.Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses.J Clin Invest. 1996; 98: 1010-1020Crossref PubMed Google Scholar, 35Sturlan S. Oberhuber G. Beinhauer B.G. et al.Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development.Carcinogenesis. 2001; 22: 665-671Crossref PubMed Google Scholar In a mouse model of CAC, mutations in exon 3 of the β-catenin gene are frequently detected, which result in nuclear localization of β-catenin.7Greten F.R. Eckmann L. Greten T.F. et al.IKKb links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.Cell. 2004; 118: 285-296Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar There are, therefore, several different mechanisms of β-catenin activation, one of the key events in colorectal tumorigenesis.Several additional pathways must be deregulated for early-stage adenomas to progress to carcinoma in situ and invasive metastatic carcinoma. This progression includes activation of the oncogenes K-ras and B-Raf, as well as inactivation of tumor suppressors, such as the TGF-β receptor (R)II (and other components of this signaling pathway), activin receptors, p53, and the proapoptotic protein Bax.36Takaku K. Oshima M. Miyoshi H. Matsui M. Seldin M.F. Taketo M.M. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes.Cell. 1998; 92: 645-656Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, 37Biswas S. Chytil A. Washington K. et al.Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer.Cancer Res. 2004; 64: 4687-4692Crossref PubMed Scopus (72) Google Scholar, 38Grady W.M. Carethers J.M. Genomic and epigenetic instability in colorectal cancer pathogenesis.Gastroenterology. 2008; 135: 1079-1099Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar The adenoma to carcinoma transition also requires increased expression of cyclooxygenase 2 (COX2), the rate-limiting enzyme in prostaglandin biosynthesis.39Oshima M. Dinchuk J.E. Kargman S.L. et al.Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2).Cell. 1996; 87: 803-809Abstract Full Text Full Text PDF PubMed Scopus (1921) Google Scholar, 40Gupta R.A. Dubois R.N. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2.Nat Rev Cancer. 2001; 1: 11-21Crossref PubMed Google Scholar, 41Koehne C.H. Dubois R.N. COX-2 inhibition and colorectal cancer.Semin Oncol. 2004; 31: 12-21Abstract Full Text Full Text PDF PubMed Google Scholar “Gatekeeper” mutations in DNA integrity checkpoint genes also occur at this (or an earlier) point, resulting in microsatellite instability in 15% of colorectal tumors and/or chromosome instability in 80% of late-stage colorectal tumors.38Grady W.M. Carethers J.M. Genomic and epigenetic instability in colorectal cancer pathogenesis.Gastroenterology. 2008; 135: 1079-1099Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar Genetic instability results in the great variation in mutations detected in colorectal tumors and is responsible for their capacity to evolve, grow, progress, escape host control, and rapidly become resistant to therapy.Immune System in Colon CancerLike other solid malignancies, colorectal and colitis-associated tumors are infiltrated by various types of immune cells. Cells of the innate immune system, such as neutrophils, mast cells, natural killer (NK) cells, dendritic cells (DC), and tumor-associated macrophages can be easily detected in these tumors (Table 2).8Atreya I. Neurath M.F. Immune cells in colorectal cancer: prognostic relevance and therapeutic strategies.Expert Rev Anticancer Ther. 2008; 8: 561-572Crossref PubMed Scopus (28) Google Scholar In addition, advanced tumors recruit specific myeloid subsets that represent phenotypically heterogeneous but a functionally similar population of CD11b+Gr1+ cells, called myeloid-derived suppressor cells.42Gabrilovich D.I. Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system.Nat Rev Immunol. 2009; 9: 162-174Crossref PubMed Scopus (959) Google Scholar These cells share some characteristic with monocytes, macrophages, neutrophils, and DC and help suppress antitumor immune responses and tumor angiogenesis.42Gabrilovich D.I. Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system.Nat Rev Immunol. 2009; 9: 162-174Crossref PubMed Scopus (959) Google Scholar Cells of the adaptive immune system are also recruited into colorectal and colitis-associated tumors, where they have either pro- or antitumorigenic roles. T cells, for instance, are required for inflammation, cancer development, and tumor progression, as well as for anticancer immunity.43Erdman S.E. Sohn J.J. Rao V.P. et al.CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice.Cancer Res. 2005; 65: 3998-4004Crossref PubMed Scopus (92) Google Scholar, 44Izcue A. Coombes J.L. Powrie F. Regulatory lymphocytes and intestinal inflammation.Annu Rev Immunol. 2009; 27: 313-338Crossref PubMed Scopus (177) Google Scholar, 45Dunn G.P. Old L.J. Schreiber R.D. The three Es of cancer immunoediting.Annu Rev Immunol. 2004; 22: 329-360Crossref PubMed Scopus (686) Google ScholarTable 2Tumor-Promoting Immune Cells and Cytokines in Colon CancerCell typeFunction or mechanismT cells (CD4 and CD8)Cytokine production (IL-6, IL-10, TNF, IL-21, IL-17, IL-22, IFN-γ, lymphotoxin, RANKL)Direct cytotoxicity or T-cell helpTreg cellsCytokine production (IL-10, TGF-β)ImmunosuppressionSuppress inflammationMacrophages, DC, MDSC, neutrophilsCytokine production (IL-6, IL-1,VEGF, IL-23, TNF)Chemokine productionMMP productionAngiogenesisImmunosuppression (arginase)NK cellsCytokine production (IFN-γ, IL-22, IL-17)Direct cytotoxicityB cellsCytokine production?Antibody response?Epithelial and tumor cellsIL-1, IL-6, TNF, EGFCytokineMechanisms/pathways in cancer and immune cellsTNF-αSurvival, activation, recruitment, growth. AP-1, MAPK and NF-κB activationIL-6Survival, growth, T-cell survival and differentiation, myeloid cell recruitment. STAT3, ERK, and AktIL-11Survival, growth. STAT3, STAT1, ERKIL-23T-cell differentiation (Th17) and interference with Tregs, production of IL-17 and IL-22 by immune cells.No direct effect on cancer cells? STAT3.IL-1α, IL-βSurvival, growth, cytokines, chemokines, T-cell activation and differentiation. NF-κB, MAPKIL-22Survival, mucosal integrity, chemokines. STAT3IL-17A,FSurvival, chemokines, T-cell regulation, monocytes, and neutrophil recruitment. MAPK, NF-κBEGFSurvival, proliferation. MAPK, STAT3IL-10Anti-inflammatory, Treg stimulation. Unknown effects on cancer cells. STAT3, MAPKDC, dendritic cells; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; IL, interleukin; MAPK, mitogen-activated protein kinase; MDSC, myeloid-derived suppressor cells; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; NK, natural killer; STAT3, signal transducer and activator of transcription 3; TGF, transforming growth factor; TNF, tumor necrosis factor; Treg, regulatory T cells; VEGF, vascular endothelial growth factor. Open table in a new tab What is the contribution of tumor immunosurveillance vs tumor-promoting inflammation in CRC and CAC? In CAC, the immune system seems to have a mostly protumorigenic role. In sporadic CRC, there seems to be a well-defined balance between immunosurveillance (executed by CD8+ T cells, NK cells, and CD4+ T cells) and tumor-promoting inflammation (executed by innate immune cells, B cells, and various subtypes of T cells) (Figure 2). In CRC and CAC, immunosurveillance could mediate the early detection and elimination of transformed cells and aberrant crypt foci, and also keep small tumors at dormant state. Immunosurveillance may be also important during metastasis, when small numbers or single metastatic cells travel and can be attacked by antitumor immune cells that are not inhibited by factors in the tumor microenvironment. In many other stages of colorectal and colitis-associated tumorigenesis, inflammation counteracts and outcompetes antitumor immunity by direct immunosuppressive effects, as well as by regulation of tumor-cell survival, proliferation, angiogenesis, and other hallmarks of tumorigenesis. Lymphocyte infiltration into sporadic colorectal tumors is generally associated with good prognosis.46Guidoboni M. Gafa R. 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• W2085852125 date "2010-05-01" @default.
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• W2085852125 title "Inflammation and Colon Cancer" @default.
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