Inflammation and oncogenesis: a vicious connection

https://doi.org/10.1016/j.gde.2009.11.004Get rights and content

Epidemiological and experimental data suggest a close connection between inflammation and tumorigenesis. Solid tumors are typically infiltrated with immune cells and inflammation impacts most, if not all, stages of tumorigenesis. Molecular and cellular pathways, which connect inflammation and cancer, have emerged as attractive targets for prevention and therapy. In this review we discuss general mechanisms and concepts of cancer promoting inflammation.

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.

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