MinireviewCytokines as a key component of cancer-related inflammation
Introduction
The link between inflammation and cancer was first postulated in the 19th century based on morphological observations [1], [2]. Several different lines of work, ranging from epidemiology to gene modified mice, have highlighted key aspects of inflammation as a predisposing cause of cancer. Moreover, even tumors for which a firm causal relation to inflammation has not been established (e.g. breast cancer), are characterized by smouldering inflammation at the tumor site. Indeed inflammatory cells and mediators are present in the microenvironment of most, probably all tumours, irrespective of causation. This observation has lead to a search for connections between genetic events causing neoplastic transformation and inflammation. Recent findings suggest that oncogenes representative of different molecular classes orchestrate the production of inflammatory mediators [1]. Here we will briefly review from the cytokine systems representative key component of cancer-related inflammation and highlight targets for pharmacological interventions (Fig. 1).
Section snippets
The primary inflammatory cytokines: TNF and IL-1
Studies on TNF demonstrating enhancement of cancer cell invasion ability, provided early proof for a pro-tumor function of inflammatory cytokines. In addition, the finding of protection of TNF deficient mice against skin carcinogenesis offered genetic evidence linking inflammation and cancer [1].
TNF-mediated tumor promotion can involve different pathways: a direct effect on tumor cells of low concentration of this cytokine; an interplay with the chemokine system with induction of CXCR4;
IL-6 and cancer
IL-6 is a key growth-promoting and antiapoptotic inflammatory cytokine [25], [26], [27] and is also one of the effector signals of activated NF-κB in the promotion of neoplasia.
A clear pro-tumoral role for IL-6 has been demonstrated in multiple myeloma (MM) where both an autocrine loop of IL-6 production as well as a paracrine loop by bone marrow stromal cells have been reported [28]. Accordingly, IL-6 deficient mice were resistant to the development of murine plasmocytoma [29]. More recent
Polarizing cytokines
The tumor microenvironment is generally characterized by high concentration of immunosuppressive cytokines IL-10 and TGF-β. Ιn advanced neoplasia there is usually low levels of IL-12 and defective activation of conventional Th1 immunity. Recent genetic evidence [40] indicates that the IL-12-related cytokine IL-23 promotes skin carcinogenesis. IL-23 promotes the differentiation of Th17 cells which orchestrates neutrophil-initiated resistance to extracellular bacteria and inflammation [41].
In
Angiogenic cytokines
In several studies of human cancer, TAM accumulation has been associated with angiogenesis and with the production of angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PDGF) [1]. TAM accumulate in hypoxic regions of tumors, and hypoxia triggers a pro-angiogenic program in these cells [48], [49], [50]. A number of molecules with possible impact on angiogenesis have been shown to be expressed by macrophages in low oxygen
Chemokines
Chemokines have long been associated with the recruitment of leukocytes in tumors [65], [66], [67]. Recent results with gene targeted mice have provided unequivocal evidence for a role of CC chemokines in carcinogenesis. Mice deficient in D6, a decoy and scavenger receptor for inflammatory CC chemokines, show increased susceptibility to skin carcinogenesis and colitis-associated cancer [68] and unpublished data.
The contribution of chemokines to angiogenesis and tumor promotion has been the
Cytokines as a target of therapies
Cancer-associated inflammation is an attractive target of future anti-tumour therapies. Population-based studies demonstrated that prolonged usage of aspirin or other nonsteroid anti-inflammatory drugs delay the development of pre-malignant adenomas and may also reduce incidence of different forms of neoplasia [71], [72], [73], [74], [75].
Primary inflammatory cytokines (e.g. IL-1 and TNF), expressed by infiltrating leukocytes and tumor cells, are central target of potential anticancer therapy.
Concluding remarks
Cytokines are a key component and orchestrator of the inflammatory microenvironment of tumours. As such they represent a prime target in therapeutic efforts aimed at taming tumor promoting cancer-related inflammation. For many years all efforts to treat cancer have concentrated on the destruction/inhibition of tumor cells. Strategies to modulate the host microenvironment offer additional interesting approaches. Initial results in this direction are encouraging and justify continuing efforts.
Acknowledgments
This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC) Italy; by Ministry of Health and Istituto Superiore Sanita Italy (Project Oncology 2006), G.G. is supported by a fellowship from Fondazione Fabrizio De Andre’, Italy.
References (85)
- et al.
Inflammation and cancer: back to Virchow?
Lancet
(2001) - et al.
Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway
Cell
(2006) - et al.
Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily
Cytokine
(1999) - et al.
The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis
Immunity
(2007) - et al.
TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling
Immunity
(2004) - et al.
IL-6 in autoimmune disease and chronic inflammatory proliferative disease
Cytokine Growth Factor Rev
(2002) - et al.
The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer
Trends Mol Med
(2008) - et al.
Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6
Blood
(1989) - et al.
Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma
Cancer Cell
(2007) - et al.
Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma
Cancer Cell
(2007)
Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes
Trends Immunol
Tolerance, DCs and tryptophan: much ado about IDO
Trends Immunol
TGF-beta and cancer
Cytokine Growth Factor Rev
Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis
Cancer Cell
Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-1alpha
Am J Pathol
Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1
Blood
Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels
Cell
MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis
Cell
Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis
Am J Pathol
Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors
Semin Cancer Biol
The two NF-kappaB activation pathways and their role in innate and adaptive immunity
Trends Immunol
COX-2 inhibition and colorectal cancer
Semin Oncol
Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies
Lancet
Cancer-related inflammation
Nature
Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids
Mol Biol Cell
The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells
Cancer Res
The inflammatory cytokine tumor necrosis factor-alpha regulates chemokine receptor expression on ovarian cancer cells
Cancer Res
Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer
J Clin Oncol
Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose
J Clin Oncol
Interleukin 1-induced augmentation of experimental metastases from a human melanoma in nude mice
Cancer Res
IL-1 is required for tumor invasiveness and angiogenesis
Proc Natl Acad Sci USA
The paradox of pro-inflammatory cytokines in cancer
Cancer Metastasis Rev
The role of interleukin-1 polymorphisms in the pathogenesis of gastric cancer
Nature
The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1beta
Genes Dev
ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance
Nat Immunol
Extracellular and intracellular decoys in the tuning of inflammatory cytokines and Toll-like receptors: the new entry TIR8/SIGIRR
J Leukoc Biol
SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling
Nat Immunol
Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR
Eur Cytokine Netw
Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family
Proc Natl Acad Sci USA
Risk factors and distinguishing features of cancer in IBD
Inflamm Bowel Dis
Increased susceptibility to colitis-associated cancer of mice lacking TIR8, an inhibitory member of the interleukin-1 receptor family
Cancer Res
Cited by (285)
Cancer incidence in Familial Mediterranean Fever: A retrospective analysis
2023, Seminars in Arthritis and RheumatismCell proliferation, apoptosis and inflammation response of Melissa officinalis and Thymus vulgaris in SW480 colon cancer cells
2023, South African Journal of BotanyVaried effect of fortification of kale sprouts with novel organic selenium compounds on the synthesis of sulphur and phenolic compounds in relation to cytotoxic, antioxidant and anti-inflammatory activity
2022, Microchemical JournalCitation Excerpt :Searching for new candidates for prevention of thyroid cancer, even in the form of functional foods, seems to be crucial, in the view of the statement by Rahib et al. [52] that thyroid cancer will replace colorectal cancer as the fourth leading cancer diagnosis by 2030. Inflammation seems to be one of the most important elements of carcinogenesis process [53], enabling cancer progression and decreasing the response to therapy. Searching for new candidates for functional foods with chemopreventive properties should include not only direct cytotoxic activity, but also the effect on cancer co-existing symptoms, like inflammation.
Systemic Inflammation Response Index and weight loss as prognostic factors in metastatic pancreatic cancer: A concept study from the PANTHEIA-SEOM trial
2024, World Journal of Gastrointestinal OncologyNeutrophil-to-lymphocyte ratio and monocyte-to-eosinophil ratio as prognostic indicators for advanced nasopharyngeal carcinoma
2024, European Archives of Oto-Rhino-Laryngology