A cytokine-mediated link between innate immunity, inflammation, and cancer
Wan-Wan Lin1 and Michael Karin2
1Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Republic of China. 2Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, UCSD, La Jolla, California, USA.
It has been established that cancer can be promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumor-supporting microenvironment that is an indispensable participant in the neoplastic process. The mechanisms that link infection, innate immunity, inflammation, and cancer are being unraveled at a fast pace. Important components in this linkage are the cytokines produced by activated innate immune cells that stimulate tumor growth and progression. In addition, soluble mediators produced by cancer cells recruit and activate inflammatory cells, which further stimulate tumor progression. However, inflammatory cells also produce cytokines that can limit tumor growth. Here we provide an overview of the current understanding of the role of inflammation-induced cytokines in tumor initiation, promotion, and progression.
Mechanisms that link inflammation and cancer Cancer is a hyperproliferative disorder that involves morphological cellular transformation, dysregulation of apoptosis, uncontrolled cellular proliferation, invasion, angiogenesis, and metastasis (1). Clinical and epidemiologic studies have suggested a strong associ- ation between chronic infection, inflammation, and cancer (2–6). For example, there are strong associations between alcohol abuse, which leads to inflammation of the liver and pancreas, and cancers of these organs. Cigarette smoking, asbestos exposure, and silica exposure are each associated with inflammation of the lung and lung carcinoma; inflammatory bowel disease (IBD) is associated with colon cancer; infection with Helicobacter pylori is associated with gastric carcinoma; chronic viral hepatitis is associated with liver cancer; infection with Schistosoma spp. is associated with blad- der and colon carcinoma; infection with some strains of HPV is associated with cervical cancer; and infection with EBV is associ- ated with Burkitt lymphoma and nasopharyngeal carcinoma. Such observations suggest that chronic inflammation is involved in tumor initiation (the process by which normal cells are genetically altered so that they become malignant), promotion (the process by which small clusters of malignant cells are stimulated to grow), and progression (the process by which the growing tumor becomes more aggressive) (2–7). Recent data from mouse models of human cancer have established that inflammation, which orchestrates the tumor microenvironment, is a critical component of both tumor promotion and tumor progression (8–10).
The inflammatory milieu is occupied by cells such as resident and recruited macrophages, DCs, T cells, and NK cells (11). Among these, tumor-associated macrophages (TAMs) and T cells are frequently the prominent leukocytes present in a tumor (12, 13). The infiltrated immune cells can exert rather paradoxical effects during cancer development (Figure 1) (7). Most current
data support the notion that acute inflammation triggered by tumor-infiltrating host leukocytes does not exert normal immu- noprotective mechanisms that lead to eradication of the evolving cancer (antitumor immunity). Instead, excessively and chronically produced proinflammatory mediators are thought to contribute to tumor promotion and progression (2, 8, 14, 15). In the tumor microenvironment, there is a delicate balance between antitumor immunity and tumor-originated proinflammatory activity, which weakens antitumor immunity (14, 16). These activities depend on different mediators that are released by host inflammatory cells, cancer cells, and other types of tumor-associated host cells (such as fibroblasts and endothelial cells). When host-mediated anti- tumor activity is weaker than tumor-mediated immunosuppres- sive activity, tumor cells undergo immune escape and grow rap- idly (17). By contrast, when host-mediated antitumor immunity is stronger than tumor-mediated immunosuppressive activity, tumor cells are eliminated (17). The net outcome of a persistent inflammatory microenvironment is enhanced tumor promotion, accelerated tumor progression, invasion of the surrounding tis- sues, angiogenesis, and often metastasis (2, 6, 9, 10).
A key molecular link between inflammation and tumor promo- tion and progression is provided by the inhibitor of NF-kB kinase/ NF-kB (IKK/NF-kB) signaling pathway, which is activated by many proinflammatory cytokines (9, 10). NF-kB is a transcription factor that regulates the expression of many genes whose products can suppress tumor cell death; stimulate tumor cell cycle progres- sion; enhance epithelial-to-mesenchymal transition, which has an important role in tumor invasiveness; and provide newly emerging tumors with an inflammatory microenvironment that supports their progression, invasion of surrounding tissues, angiogenesis, and metastasis (6, 10, 18–20).
Nonstandard abbreviations used: CAC, colitis-associated colon cancer; HCC, hepatocellular carcinoma; IBD, inflammatory bowel disease; IKK, inhibitor of NF-kB kinase; MM, multiple myeloma; NOD, nucleotide-binding oligomerization domain; NSCLC; non–small cell lung carcinoma; PAMP, pathogen-associated molecular pat- tern; PRR, pattern recognition receptor; TAM, tumor-associated macrophage; TRAIL, TNF-related apoptosis-inducing ligand.
Conflict of interest: The authors have declared that no conflict of interest exists. Citation for this article: J. Clin. Invest. 117:1175–1183 (2007). doi:10.1172/JCI31537.
Infection, innate immunity, and tumorigenesis Chronic inflammation caused by persistent infection with a parasite, bacterium, or virus is a major driving force in tumor development (2, 9) (Figure 1). It was noted that bacterial infec- tion following the surgical removal of primary tumors can pro- mote rapid growth of metastases in mice (21) and humans (22). Infectious organisms trigger inflammation through activation of receptors that recognize pathogen-associated molecular patterns
The Journal of Clinical Investigation