Inflammation and oncogenesis: a vicious connection
Introduction
Most, if not all, solid tumors are infiltrated with immune and inflammatory cells. This can represent an ongoing anti-tumor response or be a sign of immune system subversion by the tumor for its own benefit. The first possibility has been addressed within the frame of the ‘tumor immunosurveillance’ concept, proposed by Old, Schreiber, and co-workers [1••]. The immune system can play an anti-tumorigenic role in certain cases, especially in blood, chemically and virally induced cancers by eliminating pre-malignant as well as fully transformed cells. This process largely depends on altered immunogenic epitopes expressed by cancer cells as well as on stress, necrosis, and other immunostimulatory signals, which help immune system to recognize tumor antigens as “non-self”. On the effector side, immunosurveillance relies on CD8+ cytotoxic T cells (CTLs) and natural killer (NK) cells as well as help from antigen presenting dendritic cells (DCs) and CD4+ Th1 cells and various cytokines [1••].
However, cancer cells possess a great ability to mutate, evolve and rapidly grow. Hence, the cancer can easily outsmart the immune system through the growth of low-immunogenic or resistant clones or by directly subverting the anti-tumor immune response and use it for tumor promotion. Often referred to as ‘tumor escape’ [2], this situation is very well illuminated by the fact that advanced tumors always exhibit a significant immune infiltrate but are rarely rejected. Tumors also may remain dormant for a long time, reflecting an ‘equilibrium’ between tumor growth (immune dependent or independent) and immune destruction [3••]. Thus, while the host immune system is engaged in tumor detection and destruction, it has become increasingly evident that immune cells and inflammatory processes that either precede or are subsequent to cancer development play a pivotal pro-tumorigenic role [4, 5]. Various immune cells, including T and B lymphocytes, macrophages, DC, neutrophils, mast cells, and other cell types are frequently found to be concentrated in tumors relative to the surrounding tissue [6, 7, 8•, 9]. Therefore, it appears that such cells are actively recruited in response to tumor-derived signals as a result of tumor selection and evolution. However, it is also plausible that such cells may be initially recruited into the tumor as a part of the anti-tumor response, but once present within the tumor microenvironment they are diverted towards pro-tumorigenic responses. For instance, myeloid cells, which can give rise to ‘M1’ macrophages that produce IL-12 and other anti-tumorigenic products, differentiate within the tumor microenvironment into myeloid derived suppressor cells (MDSC) or ‘M2’ macrophages that produce various immunosuppressive and pro-angiogenic molecules [10, 11, 12]. Similarly, various tumor promoting T cells, including Th2, Th17, and Treg cells, can be recruited or differentiated in situ within tumors, while cells important for anti-tumor responses, such as Th1 cells or CD8+ CTLs, are either underrepresented or functionally disarmed [13, 14•, 15, 16]. Importantly, there is no unequivocal correlation between the presence of a T cell infiltrate and tumor prognosis as for sporadic colon cancer it represents better prognosis [17•, 18•], while in breast cancer an infiltrate with a high CD4+ to CD8+ ratio correlates with worse prognosis [19]. Furthermore, tumors can induce and perpetuate tumor-associated inflammation and use it to their own benefit [20•].
What determines the overall contribution of inflammatory processes to tumor development? 1) First, many inflammatory mediators (for instance, cytokines) are also important growth and survival factors that stimulate the survival and proliferation of pre-malignant cells [21]. 2) Inflammatory mediators often activate oncogenic transcription factors, such as NF-κB and STAT3 [22, 23, 24], whereas oncogenes such as Ras and Myc can initiate inflammatory response [25, 26•]. 3) Tumor-associated inflammation can suppress anti-tumor immune response and divert tumor specific immune cells from being anti-tumorigenic to become pro-tumorigenic. 4) Inflammation can stimulate tumor angiogenesis. 5) Inflammation can stimulate tumor invasiveness and metastatic dissemination [27].
Section snippets
Types of tumor-promoting inflammation
Several types of inflammation, which differ by cause, mechanism, outcome and intensity exist [28••], and all of them potentially can promote cancer development and progression. How tumor-promoting inflammation is induced? First, repetitive injury and infections can result in a chronic inflammatory response, for instance, infection with Helicobacter pylori or Hepatitis C virus (HCV) causes gastritis, ulcers, and hepatitis, eventually leading to gastric or liver cancer, respectively [21].
Does inflammation induce tumorigenesis?
Epidemiological, pharmacological, and genetic evidences provide a solid support that inflammation can increase cancer risk and can promote tumor progression [26•]. However, it remains to be determined whether chronic inflammation can cause tumor-initiating genetic alterations or can only act in conjunction with carcinogen exposure. In the case CAC, it was suggested that chronic inflammation and colonic injury can directly cause DNA alterations [45, 46••]. However, chronic inflammation and loss
Inflammation and tumor growth
Tumor growth (often called tumor promotion) is the sum total of malignant cell proliferation vs. malignant cell death. Both processes are strongly impacted by inflammation and inflammatory cytokines produced by tumor infiltrating immune cells, such as IL-6 and TNF-α, can serve as mitogens and survival factors for pre-malignant and fully established cancer cells (Figure 1). Inflammation also contributes to the induction of angiogenesis, which is crucial for supplying the growing tumor with
The interplay between NF-κB and STAT3 in colitis-associated cancer: malignant cooperation between immune and cancer cells
The crucial role of NF-κB in linking inflammation and tumorigenesis was first demonstrated in a mouse model of CAC [62]. Ablation of IKKβ in intestinal epithelial cells largely abolished the development of colonic adenomas. The pro-oncogenic role of NF-κB in CAC is most probably mediated through induction of anti-apoptotic proteins, particularly Bcl-XL [62, 64•, 65•]. NF-κB activation in epithelial cells has no effect on cell proliferation. By contrast, STAT3 in intestinal epithelial cells
Inflammation and metastasis
Ninety percent of cancer deaths are due to metastatic growth. Immune cells are present in all advanced tumors and specifically at the invasive front of the tumor and are involved in various forms of direct and indirect interactions with metastasizing cells and micrometastases [20•, 27]. Indeed, the inflammatory microenvironment was found to influence several key stages of metastatic process [78] (Figure 1). The process of epithelial–mesenchymal transition (EMT), which is crucial for metastasis,
Conclusions and perspective
The connection between inflammatory immune responses and tumorigenesis has been extensively investigated during the past decade and some of the underlying mechanisms have been elucidated. As a result, our view of the role played by the immune system in tumorigenesis has shifted from a strict anti-tumorigenic function to a more balanced view according to which the immune system, while having negative effects on tumor growth at distinct stages of the tumorigenic process, has also a potent
References and recommended reading
Papers of special interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by Research Fellowship Award from Crohn's and Colitis Foundation of America (CCFA #1762) to S.G. and the National Institutes of Health and the American Association for Cancer Research to M.K., who is an American Cancer Society Research Professor. Authors have no competing financial interests.
References (89)
- et al.
The immunobiology of cancer immunosurveillance and immunoediting
Immunity
(2004) - et al.
Paradoxical roles of the immune system during cancer development
Nat Rev Cancer
(2006) - et al.
Immune cells as anti-cancer therapeutic targets and tools
J Cell Biochem
(2007) - et al.
Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability
Carcinogenesis
(2009) - et al.
CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages
Cancer Cell
(2009) - et al.
Effector memory T cells, early metastasis, and survival in colorectal cancer
N Engl J Med
(2005) - Grivennikov SI, Greten FR, Karin M: Immunity, inflammation and cancer: the good, the bad and the ugly. Cell 2010, in...
- et al.
DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice
J Clin Invest
(2008) - et al.
Mucosal barrier and immune mediators
Curr Opin Gastroenterol
(2001) - et al.
A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations
Oncogene
(2009)
IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis
Cell
Inflammation: a driving force speeds cancer metastasis
Cell Cycle
Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis
Dev Cell
Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion
Cancer Cell
Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells
Oncogene
Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin
Nature
Intracellular signals and events activated by cytokines of the tumor necrosis factor superfamily: from simple paradigms to complex mechanisms
Int Rev Cytol
The three Es of cancer immunoediting
Annu Rev Immunol
Adaptive immunity maintains occult cancer in an equilibrium state
Nature
Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes?
Curr Opin Immunol
NF-kappaB and cancer-identifying targets and mechanisms
Curr Opin Genet Dev
De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent
Cancer Cell
Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors
Nat Med
Cancer related inflammation: the macrophage connection
Cancer Lett
Myeloid-derived suppressor cells as regulators of the immune system
Nat Rev Immunol
Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis
Proc Natl Acad Sci U S A
IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway
J Exp Med
Swords into plowshares: IL-23 repurposes tumor immune surveillance
Trends Immunol
Type, density, and location of immune cells within human colorectal tumors predict clinical outcome
Science
Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer
PLoS Med
NF-κB: linking inflammation and immunity to cancer development and progression
Nat Rev Immunol
Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment
Nat Rev Immunol
Nuclear factor-kappaB in cancer development and progression
Nature
Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis
Genes Dev
Cancer-related inflammation
Nature
Immune cells as mediators of solid tumor metastasis
Cancer Metastasis Rev
Origin and physiological roles of inflammation
Nature
A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses
Nat Med
Lung cancer and chronic obstructive pulmonary disease: needs and opportunities for integrated research
J Natl Cancer Inst
Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice
Cancer Sci
Diet-induced hepatocellular carcinoma in genetically predisposed mice
Hum Mol Genet
Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance
Proc Natl Acad Sci U S A
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