Inflammation and Colon Cancer

doi:10.1053/j.gastro.2010.01.058

Gastroenterology

Volume 138, Issue 6, May 2010, Pages 2101-2114.e5

https://doi.org/10.1053/j.gastro.2010.01.058 Get rights and content

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.

Section snippets

Development of CRC Compared with CAC

Development of CRC typically follows several consecutive steps, which were first described in a milestone study by Fearon and Vogelstein¹⁶ (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

Immune System in Colon Cancer

Like 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).⁸ In addition, advanced tumors recruit specific myeloid subsets that represent phenotypically heterogeneous but a functionally similar population of CD11b⁺Gr1⁺ cells, called

Inflammation in CRC and CAC Initiation

It is unlikely that inflammation initiates sporadic CRC because most intratumoral immune cells are recruited after the tumor is formed and so, in this case, chronic inflammation does not precede but follows tumor development. However, after a tumor forms, the localized inflammatory microenvironment can promote accumulation of additional mutations and epigenetic changes. Activated inflammatory cells produce reactive oxygen species (ROS) and reactive nitrogen intermediates that can induce DNA

Inflammation in Promotion of CRC and CAC

Tumor promotion is a process of tumor growth from a single premalignant cell into a fully developed tumor. Initial and continuous tumor growth both depend on a balance between cell death and cell proliferation. Cytokines and chemokines can serve as tumor growth and survival factors and can promote tumor growth by promoting angiogenesis and suppressing immune-mediated tumor elimination15, 72, 73 (Table 2). Other factors in the intestine, such as intestinal microbiota and dietary compounds, can

Role of the Intestinal Microbiota in Cancer Development

If the microbiota is involved in cancer development, the colon must be its major site of action—the human intestine contains >500 different types of micro-organisms and the colon contains >10¹³ bacterial cells.⁷⁴ Studies have shown that CAC development depends qualitatively and quantitatively on the intestinal microflora.75, 76 The intestinal microflora has important homeostatic immune and metabolic functions, affects the proliferation and survival of epithelial cells, and provides protection

Roles for Pattern Recognition Receptors in Colon Cancer

Pattern recognition receptors such as Toll-like receptors (TLR) and Nod-like receptors (NLR) are activated during tumorigenesis by components of bacteria and viruses, products of tissue damage, and necrosis, stress, or other signals.90, 91, 92 However, the overall contribution of pattern recognition receptors to epithelial cells compared with immune or inflammatory cells is not clear; analyses of cell-type specific knockout mice are required. TLRs and receptors for IL-1 family cytokines (IL-1

NF-κB and Colorectal Cancers

Most tumor-promoting cytokines are activated via NF-κB transcription factors or (along with other inflammatory stimuli) activate NF-κB signaling in premalignant cells and immune/inflammatory cells.⁷² NF-κB is likely to have a prominent role in colorectal and colitis-associated tumorigenesis. Aberrant NF-κB activation was detected in >50% of colorectal and colitis-associated tumors and mouse studies have established a role for NF-κB in CAC development.100, 101 The protumorigenic role of NF-κB

Cytokine Signaling and Tumor Promotion

Most, but not all, tumor-promoting cytokines activate receptors on intestinal epithelial cells that activate oncogenic transcription factors and other oncogenic signaling pathways, such as extracellular signal-regulated kinase or Akt/mammalian target of rapamycin (mTOR). Transcription factors NF-κB and STAT3 are particularly important in the development of CAC and CRC.7, 116, 119, 120 (Figure 4). Although the initial evidence for cytokine-regulated tumor promotion came from the studies in the

Prostaglandin Synthesis, Inflammation, and Colorectal Tumorigenesis

COX2 is an inducible mediator of prostaglandin synthesis and an important factor in colorectal tumorigenesis.⁴¹ COX2 expression is upregulated in the colorectal tumors and in experimental models of CAC.165, 166 Selective inhibitors (such as celecoxib) and nonspecific inhibitors (aspirin) of COX reduce CRC incidence.40, 165, 166 The protumorigenic effects of COX2 are mediated by its major end product, PGE₂; and human colorectal tumors have increased levels of PGE₂.167, 168, 169, 170 These

Inflammation in Invasion and Metastasis

The role of immune cells and their products in metastasis of colorectal and colitis-induced tumors has not been examined in details because of the lack of suitable mouse models. Indeed, tumors from classical models (APC^Min and AOM + DSS) rarely metastasize and, therefore, many models for colon cancer metastasis included transplantation of cell lines orthotopically or under the skin, as well as intrasplenic or intravenous injection to further assess metastatic colonization of target organs.

Anticancer and Anti-Inflammatory Agents

Although much has been learned about the molecular connection between inflammation and colon cancer, this knowledge has not been completely translated to the clinic. It is unlikely that anti-inflammatory drugs will be tremendously effective as monotherapies for patients with CRC, but they might be used with chemo- or radiotherapy. Anti-inflammatory agents might be used, alone or with other strategies, to prevent CAC. Therapy for CRC includes surgical resection, radiation, and chemotherapy with

Dietary Compounds that Influence CRC and CAC

Risk factors for CRC include obesity, lack of exercise, alcohol and tobacco consumption, and dietary factors, such the Western diet (large amounts of red meat and fat, low amounts of vegetables, fruit, and fiber).²²³ Several other compounds have been found to reduce CRC risk, including carbohydrates (inulin and oligofructose), unsaturated n-3 fatty acids, vitamins, minerals (calcium and selenium), and phytochemicals (resveratrol, curcumin).²²⁴ Although the molecular mechanisms of these

Conclusions and Perspectives

Inflammation affects every facet of tumor development and might also affect the efficacy of cancer therapies. Anti-inflammatory drugs can reduce CRC risk and clinical trials should indicate the therapeutic efficacy of anti-inflammatory biologics, such as anti-TNF, anti-IL-6, anti-IL-1, and inhibitors of NF-κB and STAT3. Importantly, anti-inflammatory drugs target myeloid and lymphoid cells, which do not carry oncogenic mutations and, therefore, do not undergo rapid evolution and selection. This

Acknowledgments

The authors thank Vanja Nagy for reading the manuscript.

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: Conflicts of interest The authors disclose no conflicts.

: Funding Supported by Terry Fox Run and Croatian Ministry of Science, Technology and Sport grants to Dr Terzić, RFA from Crohn's and Colitis Foundation of America (CCFA #1762) to Dr Grivennikov, and by grants from the National Institutes of Health and the American Association for Cancer Research to Dr M. Karin, who is an American Cancer Society Research Professor.

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Inflammation and Colon Cancer

Section snippets

Development of CRC Compared with CAC

Immune System in Colon Cancer

Inflammation in CRC and CAC Initiation

Inflammation in Promotion of CRC and CAC

Role of the Intestinal Microbiota in Cancer Development

Roles for Pattern Recognition Receptors in Colon Cancer

NF-κB and Colorectal Cancers

Cytokine Signaling and Tumor Promotion

Prostaglandin Synthesis, Inflammation, and Colorectal Tumorigenesis

Inflammation in Invasion and Metastasis

Anticancer and Anti-Inflammatory Agents

Dietary Compounds that Influence CRC and CAC

Conclusions and Perspectives

Acknowledgments

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