Inflammation and Cancer

  • Inflammation is the body’s response to potentially harmful events.

  • It is a protective and necessary process that involves recruiting cells and molecules of the host’s immune system to the site of injury. The recruited cells and molecules, along with resident cells, remove damaged and dead (necrotic) cells and tissue. They work to eliminate the cause of the irritation, whether it is a chemical, foreign object, or an invasive organism. The immune cells begin the process of repairing the cells and tissues in the area. Inflammation is a complex immune response that involves a large number of different cells and signals. It is essential for our survival.

  • Our immune system works to attack and eliminate foreign invaders, but this defense mechanism, if not controlled, can also be harmful.  

  • In particular, inflammation can become harmful to an individual when the process is prolonged. 

  • In normal wound healing, inflammation and the cellular reproduction needed to repair damage subside after the injury is dealt with, but if the process is sustained for several years, epidemiologic studies have shown that it increases an individual’s risk for cancer. 

  • As with many aspects of cancer, inflammation’s role in cancer involves a normal biological process gone wrong. Something that should be over quickly occurs for a prolonged time, or at an inappropriate time. A primary way that chronic inflammation causes cancer involves the production of chemicals that can damage cells. It is similar to the accidental damage caused when weapons go astray. These chemicals, called reactive oxygen species (ROS) and nitric oxide species (NOS), are used by cells of the immune system (leukocytes and phagocytes) as a defense against infections. ROS and NOS cause DNA damage that can kill invading organisms.  If they attack our own cells, they can cause permanent DNA changes (mutations). Immune cells can also produce signaling molecules (cytokines), destructive enzymes (proteases), and other mediators of cell killing (including TNF-α and interleukins).

Emily Shacter and Sigmund A. Weitzman, Chronic Inflammation and Cancer, Colorectal Cancer, Oncology Journal, January 31, 2002

Lisa M. Coussens and Zena Werb, Inflammation and Cancer, Nature 420, 860-867, December 19, 2002

 Chronic inflammation

  • Usually involves recruitment of macrophages (derived from monocytes) and lymphocytes

  • Causes gradual to severe damage to host tissue

  • Subtle or non-existent physical signs

  • Chronic inflammation has been linked with increased cancer risk, and acute inflammation has not.

  • Chronic inflammation is a prolonged immune response that often leads to bystander tissue damage. These responses can last for many years. 

  • Chronic inflammation is different from acute inflammation, though acute inflammation can develop into chronic inflammation if the injury/infection is long-lasting or there is something preventing the normal healing process.

  • Chronic inflammation can be triggered by persistent infections, hypersensitivity diseases, and long-term exposure to toxic agents 

  • Chronic inflammation, in contrast to acute, is a highly specific response and involves different sets of immune cells, mostly lymphocytes and macrophages. Macrophages, which are derived from monocytes, are multi-functional cells. Their role in the inflammatory response includes elimination of microbes and necrotic tissue; initiation of repair; secretion of many cytokines (including chemokines, interleukins, tumor necrosis factor, and eicosanoids); and interactions with T lymphocytes. 

Kumar, Vinay, Abul K. Abbas, Jon C. Aster, and Stanley L. Robbins. "Chapter 2 Inflammation and Repair." <i>Robbins Basic Pathology</i>. 9th ed. Philadelphia, PA: Elsevier/Saunders, 2013. 29-74. Print

Chronic Inflammation and Cancer

  • There are a number of cancers which have been associated with chronic inflammatory conditions.

  • The most notable association is between inflammatorybowel disease (IBD) and the development of colorectal cancer (CRC). Patients with IBD are 5-7 times more likely to develop CRC.  Around 4 in 10 patients with ulcerative colitis—a type of IBD—develop CRC after 25-35 years.

  • Further evidence supporting the link between cancer and inflammation is that drugs that reduce inflammation also reduce the risk of some cancers. Studies investigating the effect of continuous use of non-steroidal anti-inflammatory drugs (NSAIDs) have shown decreased risks of developing certain cancers. NSAIDs are a common class of pain relieving drugs, which include ibuprofen, aspirin, and naproxen. Colon cancer risk is decreased by 50% with continued use (at least 6 months) of non-aspirin NSAIDs and by 40% with continuous long-term use of aspirin.

  • NSAIDs work by blocking proteins (called cyclooxygenases or COX) that are known to cause inflammation. 

  • Aspirin has also been shown to prevent cancer through a decrease in blood plasma levels of an oncometabolite, 2-Hydroxyglutarate (2HG) (a metabolite is a substance formed during metabolism and the prefix onco means the metabolite is associated with cancer).18The accumulation of 2HG has been linked with activating an oncogene, MYC.19This is another mechanism by which aspirin may prevent cancer.

  • Additionally, aspirin lowers risk of death from prostate cancer.

  • The United States Preventive Services Task Force recommends "initiating low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer (CRC) in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years.

García-Rodríguez LA, Huerta-Alvarez C; Epidemiology. 2001 Jan;12(1):88-93; Reduced risk of colorectal cancer among long-term users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs.

Lisa M. Coussens & Zena Werb. Inflammation and cancer. Nature (420). December 2002. [

Liesenfeld DB, Botma A, Habermann N, Toth R, Weigel C, Popanda O, Klika KD, Potter JD, Lampe JW, Ulrich CM; Aspirin Reduces Plasma Concentrations of the Oncometabolite 2-Hydroxyglutarate: Results of a Randomized, Double-Blind, Crossover Trial; Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):180-7.

Terunuma A, Putluri N, Mishra P, Mathé EA, Dorsey TH, Yi M, Wallace TA, Issaq HJ, Zhou M, Killian JK, Stevenson HS, Karoly ED, Chan K, Samanta S, Prieto D, Hsu TY, Kurley SJ, Putluri V, Sonavane R, Edelman DC, Wulff J, Starks AM, Yang Y, Kittles RA, Yfantis HG, Lee DH, Ioffe OB, Schiff R, Stephens RM, Meltzer PS, Veenstra TD, Westbrook TF, Sreekumar A, Ambs S; J Clin Invest. 2014 Jan;124(1):398-412; MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis.

Assayag J, Pollak MN, Azoulay L.J Urol; 2015 Apr;193(4):1220-5; The use of aspirin and the risk of mortality in patients with prostate cancer.

Bibbins-Domingo K, on behalf of the U.S. Preventive Services Task Force. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 12 April 2016

Inflammation and Cancer

Long-term inflammatory conditions increase the risk of cancer by:

  • Causing sustained cell proliferation

  • Increasing the presence of growth factors

  • Causing changes in surrounding cells and proteins creating activated stroma

  • Leading to the invasion and activation of inflammatory immune cells

  • Increasing the amounts of  DNA damaging agents in the area.

  • Because cancer is a disease caused by genetic changes, the presence of DNA-damaging chemicals, including reactive oxyen species (ROS) and nitric oxide species (NOS) produced by immune cells are critical in the development of cancer.  ROS and NOS are small chemicals (called free radicals) that can directly cause DNA damage. If the damage occurs in oncogenes or tumor suppressors, then the affected cell may begin to divide in an unregulated way, a key to the development of cancer.

  • Some of the other mechanisms are more elusive. The COX-2 enzyme, produced by immune cells, leads to the production of signaling molecules called prostaglandins, which then cause inflammation. The COX-2 protein has been shown to: lead to genomic instability and induce expression of BCL2-mediated (an oncogene that blocks apoptosis) resistance to the chemotherapy drug doxorubicin.

  • Another finding supporting this causal relationship is that a deficiency of the anti-inflammatory cytokine, IL-10, results in DNA mutations in a mouse model of IBD.

Singh B, Cook KR, Vincent L, Hall CS, Berry JA, Multani AS, Lucci A; J Surg Res. 2008 Jun 15;147(2):240-6; Cyclooxygenase-2 induces genomic instability, BCL2 expression, doxorubicin resistance, and altered cancer-initiating cell phenotype in MCF7 breast cancer cells. [PUBMED]

T SCHEININ, D M BUTLER, F SALWAY, B SCALLON, and M FELDMANN; Clin Exp Immunol. 2003 Jul; 133(1): 38¿43; Validation of the interleukin-10 knockout mouse model of colitis: antitumour necrosis factor-antibodies suppress the progression of colitis 

Inflammation Prevention

Inflammation is influenced by diet and lifestyle. As far as diet, many foods have been associated with either increased or decreased inflammation.  The following list includes some examples, with a brief description of the way that they are thought to work.  Note that this list does not mean that we are recommending any specific food or diet.

Anti inflammatory Foods

Turmeric and Curcumin 

  • Suppression of NF-kB and STAT3 pathways

  • Also exhibits similar activities to tumor necrosis factor blockers, vascular endothelial cell growth factor blockers, human epidermal growth factor receptor blockers, and a HER2 blocker 

Pomegranate

  • Juice and peel possess antioxidant properties 

  • Juice, peel and oil can interfere with tumor cell proliferation, cell cycle, invasion and angiogenesis

Extra Virgin Olive Oil (EVOO)

  • Phenolic compound in EVOO called oleocanthal acts as COX inhibitor

  • Oleocanthal also can induce apoptosis in cancer cells via lysosomal membrane permeability

Soy

  • A compound in soy called genistein can have anti-inflammatory properties by affecting monocytes, granulocytes, and lymphocytes

  • In mice, soy protein can inhibit NF-kB and AKT signaling pathways

Omega-3-fatty acids

  • Dietary omega-3-fatty acids have anti-inflammatory and immune system modulating factors

  • Higher ratios of omega-3-fatty acids to omega-6-fatty acids may decrease oxidative stress

Garlic

  • Garlic consumption leads to inhibition of NF-kB in in vitro studies

  • Allicin, a compound in garlic, alleviates inflammation in rats

Ginger

  • Has anti-inflammatory effects in mice

Phytochemicals (these are present in multiple different plants):

Flavenoids

  • Casticin and chrysosplenol D inhibit inflammation in vitro and in vivo in mice

Carotenoids

  • Studies have shown that carotenoids have anti-oxididant and anti-inflammatory properties

Kim JH, Gupta SC, Park B, Yadav VR, Aggarwal BB, Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-¿B and NF-¿B-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis, Mol Nutr Food Res. 2012 Mar;56(3):454-65

 Aggarwal BB, Sundaram C, Malani N, Ichikawa H.; Curcumin: the Indian solid gold.; Adv Exp Med Biol. 2007;595:1-75.

Lansky EP, Newman RA; Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer; J Ethnopharmacol. 2007 Jan 19;109(2):177-206.

Onica LeGendreab, Paul AS Breslincd & David A Fosterae; (-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization; Molecular & Cellular Oncology, Volume 2, Issue 4, 2015

Lucas L, Russell A, Keast R.; Molecular mechanisms of inflammation. Anti-inflammatory benefits of virgin olive oil and the phenolic compound oleocanthal.; Curr Pharm Des. 2011;17(8):754-68.

Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R, Malarkey WB, Hwang BS, Blackburn E.Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain Behav Immun. 2013 Feb;28:16-24

Mori TA, Beilin LJ. Curr Atheroscler Rep. 2004 Nov;6(6):461-7. Omega-3 fatty acids and inflammation.

Georgia Schäfer and Catherine H. Kaschula; The Immunomodulation and Anti-Inflammatory Effects of Garlic Organosulfur Compounds in Cancer Chemoprevention; Anticancer Agents Med Chem. 2014 Feb; 14(2): 233¿240.

Li C, Lun W, Zhao X, Lei S, Guo Y, Ma J, Zhi F. Allicin alleviates inflammation of trinitrobenzenesulfonic acid-induced rats and suppresses P38 and JNK pathways in Caco-2 cells. Mediators Inflamm. 2015;2015:434692.

Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, Hwang BS, Glaser R; Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial; Brain Behav Immun. 2012 Aug;26(6):988-95.

Hsiang CY, Cheng HM, Lo HY, Li CC, Chou PC, Lee YC, Ho TY; J Agric Food Chem. 2015 Jul 8;63(26):6051-8; Ginger and Zingerone Ameliorate Lipopolysaccharide-Induced Acute Systemic Inflammation in Mice, Assessed by Nuclear Factor-¿B Bioluminescent Imaging.

Li YJ, Guo Y, Yang Q, Weng XG, Yang Y, Wang YJ, Chen Y, Zhang D, Li Q, Liu XC, Kan XX, Chen X, Zhu XX, Kmoníèková E, Zídek Z; Toxicol Appl Pharmacol. 2015 Aug 1;286(3):151-8; Flavonoids casticin and chrysosplenol D from Artemisia annua L. inhibit inflammation in vitro and in vivo.

Kaulmann A, Bohn T; Nutr Res. 2014 Nov;34(11):907-29; Carotenoids, inflammation, and oxidative stress--implications of cellular signaling pathways and relation to chronic disease prevention.

Foods that have been linked with INCREASED inflammation include:

Trans fatty acids

  • Possible role in gut inflammation 

Red meat 

  • Contains a sugar molecule that may lead to inflammation.

Decreased inflammation has also been associated with mind-body therapies.

Activities linked to decreased inflammation include:

Tai chi

  • Breast cancer survivors* with insomnia who engaged in Tai Chi for three months showed a decrease in inflammatory markers IL-6 and TNF  

Yoga

  • Breast cancer survivors* who engaged in yoga showed decreases in IL-6 and TNF

Ann M. Bode and Zigang Dong; Chapter 7 The Amazing and Mighty Ginger Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. Benzie IFF, Wachtel-Galor S, editors. Boca Raton (FL): CRC Press/Taylor & Francis; 2011.

Samraj AN, Pearce OM, Läubli H, Crittenden AN, Bergfeld AK, Banda K1 Gregg CJ, Bingman AE, Secrest P, Diaz SL, Varki NM, Varki A. A red meat-derived glycan promotes inflammation and cancer progression. Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):542-7. Epub 2014 Dec 29. [PUBMED]

Michael R. Irwin,corresponding author Richard Olmstead, Elizabeth C. Breen, Tuff Witarama, Carmen Carrillo, Nina Sadeghi, Jesusa M. G. Arevalo, Jeffrey Ma, Perry Nicassio, Patricia A. Ganz, Julienne E. Bower, and Steve Cole. Tai Chi, Cellular Inflammation, and Transcriptome Dynamics in Breast Cancer Survivors With Insomnia: A Randomized Controlled Trial. J Natl Cancer Inst Monogr. 2014 Nov; 2014(50): 295-301.

Kiecolt-Glaser JK, Bennett JM, Andridge R, Peng J, Shapiro CL, Malarkey WB, Emery CF, Layman R, Mrozek EE, Glaser R. Yoga's impact on inflammation, mood, and fatigue in breast cancer survivors: a randomized controlled trial. J Clin Oncol. 2014 Apr 1;32(10):1040-9.

Summary

  • Inflammation is the body’s response to potentially harmful events. It is a protective and necessary process that involves recruiting cells and molecules of the host’s immune system to the site of injury. Inflammation itself can become harmful when the process is prolonged.

  • Acute inflammation has not been shown to increase cancer risk.

  • Chronic (long-term) inflammation does not show the symptoms of acute inflammation. It is a prolonged immune response that often leads to tissue damage. These responses can last for many years.  Chronic inflammation is different from acute inflammation, though acute inflammation can develop into chronic inflammation if the injury/infection is long-lasting or if something prevents the normal healing process. Things that can lead to chronic inflammation include persistent infections, hypersensitivity diseases, and long-term exposure to toxic agents.  Research also indicates that being overweight/obese can also trigger some aspects of chronic inflammation. 

Chronic Inflammation

Slower onset (days)

Involves recruitment of macrophages (derived from monocytes) and lymphocytes

Causes moderate to severe damage to host tissue

Chronic inflammatory conditions have been linked to increased risk of cancer. There are several ways that chronic inflammation can cause cancer, including:

1.     Causing sustained cell proliferation.
2.     Increasing the presence of growth factors.
3.     Causing changes in the proteins that surround cells (produces ‘activated’ stroma).
4.     Leading to the invasion and activation of inflammatory immune cells.
5.     Increasing the amounts of DNA damaging agents in the area.13

There are a number of ways to potentially prevent chronic inflammation and one of the most significant is avoiding being overweight or obese.

Source https://www.cancerquest.org/cancer-biology/immune-system