Inflammation in Cancer: a Therapeutic Target?

A role for inflammation in cancer initiation and progression has been inferred for a long time, but it has only been in the last 10 to 15 years that the molecular mechanisms have been dissected such that targeting inflammatory pathways for cancer prevention and therapy has become a practical possibility. The Greek physician Claudius Galenus reported almost 2,000 years ago on the similarity between inflamed tissues and cancerous tissues. Galenus explained that Hippocrates originally used the word “cancer” to describe inflammatory breast tumors in which superficial veins appeared markedly swollen and radiated in a manner that resembled the claws of a crab. In 1863, Virchow[1] described leukocyte infiltration in neoplastic tissues and suggested that this “lymphoreticular infiltrate” reflected the origin of cancer at sites of chronic inflammation. Dvorak,[2] over two decades ago, observed that cancer shares with inflammation developmental mechanisms (angiogenesis) and types of infiltrating cells (lymphocytes, macrophages, and mast cells), and he noted that tumors appear like “wounds that do not heal.”

In a fifth or more of cancers, the inflammation caused by infectious pathogens may be linked to cancer origin.[3] Some pathogens, such as human papillomaviruses, can directly induce cell transformation; however, it is the chronic inflammation associated with the infection caused by most or all pathogens (eg, hepatitis B and C viruses and Helicobacter pylori) that favors initiation and progression of tumors. In addition to infections, mechanical, radiation, and chemical insults, as well as genetic factors, may be responsible for induction of the inflammation associated with human malignancy. Much attention has been devoted in recent years to the interaction of the organism with commensal microbiota, and the way in which this interaction affects tissue homeostasis and might contribute to inflammatory conditions that favor carcinogenesis either at the level of epithelia directly exposed to the bacteria or systemically.[4]

In the article by Kamp et al, the mechanisms involved in the cross-talk between cancer and inflammation are described in detail and with clarity, providing the reader with a comprehensive review of the state of the art in this field of research. In their review, the authors focus primarily on two types of cancer, colorectal carcinoma and lung cancer; the former is a typical example of a cancer that, in a certain percentage of patients, can arise from tissues inflamed because of colitis, while the latter is more rarely discussed in terms of having an inflammatory etiopathogenesis-although the authors provide a review of quite compelling evidence suggesting that possibility. Indeed, chronic inflammation can affect all phases of carcinogenesis, from inducing DNA instability and mutation in the tumor-initiating cells, to acting as tumor promoter by creating a microenvironment in which the tumor is able to progress and metastasize-for example, through activation of immunosuppressive mechanisms that prevent an effective immune response against the tumors. In the tissue in which cancer arises, not only are infiltrating pro-inflammatory hematopoietic cells responsible for the inflammation, but all cell types, including epithelial cells, endothelial cells, fibroblasts, and other stromal cells, may play a role-for example, by secreting and responding to pro-inflammatory factors such as cytokines, chemokines, growth factors, and proteases.

The strongest evidence in humans of the important role of inflammation in cancer has been provided by studies showing that long-term therapy with anti-inflammatory drugs resulted in decreased numbers of relapses or fewer appearances of new tumors. Recently, Rothwell et al[5] re-analyzed patient data from eight randomized trials of daily aspirin taken for prevention of cardiovascular disease. Aspirin users were found to have a significantly lower risk of death from cancer than those who didn’t take the drug.[5] Earlier studies reported that daily use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) over extended periods reduced the risk of colorectal cancer or polyp recurrence, but little evidence was available that aspirin might also reduce risk of other cancers.[6] In trials in which the patients took aspirin for at least 7.5 years, the 20-year risk of cancer death, starting from the time the trials began, was reduced by 60% for gastrointestinal cancers and by 30% on average for other solid cancers, such as esophageal, pancreatic, stomach, lung, brain, and prostate cancers.[5] These data indicate that anti-inflammatory drugs prevent both gastrointestinal and other solid-organ cancers, and they suggest that inflammation may be an underlying cause of cancer even in tumor types that have not traditionally been thought to originate in chronically inflamed tissues.

What distinguishes the review by Kamp et al is its focus on the role that mitochondrial damage and the production of reactive oxygen species (ROS) in response to tissue damage from infection or other insults play in induction of inflammation, DNA damage, lack of DNA repair, activation of oncogenes, and carcinogenesis. Indeed, there is much emerging evidence that tissue damage such as occurs with hypoxia and nutritional stress causes an elevation in mitochondrial ROS production that is implicated in malignant transformation, when a few cells overcome and escape oxidative damage–induced senescence and cell death.[7] Thus, mitochondria could be a possible target for cancer therapy.[7]

Indeed, mitochondrial ROS production has been shown to be part of the mechanism of malignant transformation mediated by c-Myc, K-Ras, and the Wnt signaling pathways.[8-10] In addition, mitochondrial products released by damaged cells can activate inflammation through at least two innate receptor systems: N-formylated peptides can activate inflammation through the N-formyl peptide receptor (FPR) or its homologue FPRL1, while mitochondrial DNA can activate Toll-like receptor 9 (TLR9).[11,12] In addition, adenosine triphosphate (ATP) produced by mytochondria and realeased from damaged cells can activate the inflammasome-inducing Caspase 1 and the processing of pro-interleukin (IL) -1β and pro-IL-18.[13] Three recent publications have directly shown that mitochondrial ROS act as signaling molecules that trigger production of pro-inflammatory cytokines. Interestingly, these studies have shown, somewhat counter-intuitively, that ROS originating from mitochondria play a more important role in inducing inflammation than those generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which are important for oxygen burst responses in inflammatory cells.[14] In two of these papers, mitochondrial ROS are shown to be induced by inflammasome activators, and these mitochrondrial ROS are in turn required for the activation of the inflammasome.[15,16] The generation of ROS and activation of the inflammasome are increased by blockage of autophagy, which results in the accumulation of ROS-producing damaged mitochondria.[16] Conversely, Balua et al,[17] using cells from patients with tumor necrosis factor receptor 1 (TNFR1)-associated periodic syndrome (TRAPS) and a mouse model of this autoinflammatory disorder, showed an inflammasome-independent role for mitochondrial ROS in the induction of pro-inflammatory cytokines such as IL-6, TNF, and IL-8. Overall, important new molecular pathways involving mitochondrial damage and ROS production are being elucidated that profoundly affect not only DNA damage and activation of oncogenes, but also different aspects of inflammation; these pathways may thus affect tumor cell malignant transformation, intrinsic inflammation, and carcinogenesis. Knowledge of these mechanisms should not only enhance our understanding of the process of carcinogenesis and of the multifaceted role inflammation plays in it, but it should also help in the identification of new therapeutic targets for cancer prevention and therapy.

Financial Disclosure:The authors have no significant interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES:

1. Virchov R. Cellular pathology as based upon physiological and pathological histology. Philadelphia: J. B. Lippincott; 1863.

2. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315:1650-9.

3. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539-45.

4. Pamer EG. Immune responses to commensal and environmental microbes. Nat Immunol. 2007;8:1173-8.

5. Rothwell PM, Fowkes FG, Belch JF, et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377:31-41.

6. Menter DG, Schilsky RL, DuBois RN. Cyclooxygenase-2 and cancer treatment: understanding the risk should be worth the reward. Clin Cancer Res. 2010;16:1384-90.

7. Ralph SJ, Rodriguez-Enriquez S, Neuzil J, et al. The causes of cancer revisited: “mitochondrial malignancy” and ROS-induced oncogenic transformation - why mitochondria are targets for cancer therapy. Mol Aspects Med. 2010;31:145-70.

8. KC S, Carcamo JM, Golde DW. Antioxidants prevent oxidative DNA damage and cellular transformation elicited by the over-expression of c-MYC. Mutat Res. 2006;593:64-79.

9. Weinberg F, Hamanaka R, Wheaton WW, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A. 2010;107:8788-93.

10. Yoon JC, Ng A, Kim BH, et al. Wnt signaling regulates mitochondrial physiology and insulin sensitivity. Genes Dev. 2010;24:1507-18.

11. Rabiet MJ, Huet E, Boulay F. Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR. Eur J Immunol. 2005;35:2486-95.

12. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104-7.

13. Iyer SS, Pulskens WP, Sadler JJ, et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A. 2009;106:20388-93.

14. Naik E, Dixit VM. Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med. 2011;208:417-20.

15. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221-5.

16. Nakahira K, Haspel JA, Rathinam VA, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12:222-30.

17. Bulua AC, Simon A, Maddipati R, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208:519-33.