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Figure 1 The diagram shows two outcomes of inter- actions between tumor cells and infiltrating inflammatory and/or immune cells in the tumor microenvironment. Cytokines secret- ed by tumor and inflammatory/immune cells can either promote tumor development and tumor cell survival or exert antitumor effects. Chronic inflammation develops through the action of various inflammatory mediators, including TNF-α, IL-6, and IL-17, leading to eradication of antitumor immunity and accel- erated tumor progression. However, TRAIL, through direct induction of tumor cell apopto- sis, IL-10, through antiinflammatory effects, and IL-12, through activation of CTLs and NK cells and expression of cytotoxic mediators, can lead to tumor suppression. The multiple actions of TGF-β (cytotoxic in colon cancer cells, and having both positive and negative effects on the tumor microenvironment) and IL-23 (see Figure 3) explain their dual roles in tumor development.

(PAMPs), such as cell wall components and nucleic acids (23). At least four families of mammalian innate immune receptors that recognize PAMPs have been identified; these are known as pattern recognition receptors (PRRs) and include TLRs, nucleotide-bind- ing oligomerization domain–like (NOD-like) receptors (NLRs), C-type lectin receptors (CLRs), and triggering receptors expressed on myeloid cells (TREMs) (24–27). The interaction between PAMPs and PRRs results in the activation of inflammatory cells and ini- tiation of host responses whose major purpose is to eliminate and kill invading organisms (9). However, inadequate pathogen eradication, prolonged inflammatory signaling, and defects in anti- inflammatory mechanisms can all lead to chronic inflammation and benefit tumor development (28).

In addition to epidemiological data linking chronic infections to increased cancer risk (2, 3, 29), genetic links between PRRs and can- cer also exist. Polymorphisms in a gene cluster encoding TLR6 and TLR10 have been linked to an increased risk of prostate cancer (30), and mutations in the NOD2 locus have been linked to an increased risk for developing Crohn disease (31), an IBD associated with a modestly increased risk of developing colorectal cancer (32). These mutations in NOD2 have been suggested to provide a gain-of-func- tion that results in increased IL-1β production, which makes the environment more proinflammatory (33). Interestingly, polymor- phisms in the promoter region of the gene encoding IL-1β and the gene encoding the IL-1 receptor antagonist (IL-1RA) have also been linked to an increased risk of developing cancer, in particular gas- tric cancer (34, 35). IL-1 is abundant at tumor sites, where it can stimulate the growth and invasiveness of malignant cells (36). Inhi- bition of IL-1 function using the naturally occurring inhibitor of IL-1, IL-1RA, might be useful for the treatment of cancer (37).

Activation of TLR signaling can enhance tumor development through various mechanisms. In a mouse model of transplanted metastatic cancers, activation of TLR4 by intraperitoneal injec- tion of bacterial LPS stimulated the growth of lung metastases (21, 38, 39). TLR4 activation of host macrophages resulted in the production of several different inflammatory cytokines that influenced tumor growth. TNF-α was identified as the major host-produced factor that enhances the growth of lung metasta- ses in this mouse model, in part through activation of NF-kB in the tumor cells (39). However, TLR4 signaling also induced the production of IFNs, cytokines that have antitumor effects (39). In this particular case, IFNs were found to stimulate production of the TNF superfamily member TNF-related apoptosis-induc- ing ligand (TRAIL) (39). TRAIL is a potent inducer of tumor cell death (40), but in this mouse model of transplanted metastatic cancer, its tumoricidal activity was evident only upon inhibition of NF-kB activity in the tumor cells (39). These results illustrate that activation of innate immunity results in the production of different cytokines with opposing activities (Figure 2) — TNF-α stimulated tumor cell growth and survival, whereas TRAIL induced tumor cell death, leading to tumor regression. However, only by inhibiting NF-kB activation in the tumor cells was the balance shifted from stimulation of tumor growth by TNF-α to enhanced tumor cell killing by TRAIL (39).

TLR expression and function are not restricted to innate immune cells and can directly affect the tumor cell. For example, multiple myeloma (MM) cells frequently express multiple TLRs and can thereby sense the presence of microorganisms (41, 42). Indeed, ligands for both TLR7 and TLR9 have been shown to stimulate the growth of MM cells and to protect these cells from


The Journal of Clinical Investigation


Volume 117

Number 5

May 2007

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