Inflammation and Cancer

 

The Connection Between Inflammations and Cancer

Debeshi Kundu & Dr Lopamudra Das Roy

Published 2020

@BreastCancerHub, All Rights Reserved

Inflammatory diseases have been linked to increased risk of cancer. Chronic inflammations are tied to approximately 20 percent of cancer cases in the world. These inflammations trigger changes in cell bodies that allow cancer growth which leads to a patient having a higher risk of cancer [1]. Chronic inflammatory diseases include hyperactive molecules containing oxygen and nitrogen are produced by immune cells. These immune cells have the ability to damage DNA but also stimulate the growth of cell division.

When chronic inflammation damages DNA, it branches off other conditions such as heart problems, type 2 diabetes, and cancer because the DNA is replicating at a much faster rate in order to cope with the damage.  For example, inflammatory diseases such as colitis and hepatitis link to colon cancer and liver cancer respectively. Although inflammation impacts the growth of cancer cells by damaging DNA, it can produce cytokines which vitalizes the growth of blood vessels. This growth gives the tumor access to oxygen and nutrients allowing the tumor itself to aggrandize. The cytokine protein molecules send signals to the cells, misguiding their communication and behavior within each other. Because cytokines are pro-inflammatory, they stimulate a contraption that allows breast cancer cells to metastasize starting from its blood vessels [2]. For example, tumor necrosis is a highly inflammatory cytokine that is associated with breast carcinomas. It activates a protein called TNF-α/NF-κB which inhibits the behavior of breast cells, causing it to react in a malignant way [3]. 

While fighting infections, the body is creating cancerous DNA through its immune system. The immune system creates white blood cells in its bone marrow, allowing it to fight infections. This is often seen in conditions such as lymphoma or leukemia. When cancerous DNA hits the white blood cells in the bone marrow, it is preventing the production of white blood cells thus weakening the immune system [4]. When the immune system is weak, it becomes more prone to inflammations and infections in the body which increases the risk of cancer. 

Inflammation in certain areas of the body causes the activation of a protein called Mucin gene 1 (MUC1). This activation of the gene causes a tumor progression which then triggers the production of microR-155. MicroR-155 is a protein that repairs DNA but since it stimulates multiple gene mutations, it raises the risk for cancer.2  Along with MicroR-155, proteins such as  C-reactive protein (CRP) and interleukin 6 (IL-6) have been found as a risk for inflammation. These proteins are biomarkers that indicate the presence of breast cancer cells. These inflammations profoundly get affected by conditions such as obesity. There is a direct relationship between the production of fat cells and insulin resistance. The more fat cells there are present, the less insulin resistance occurs in the body- causing the body to overproduce insulin in the blood. When obesity increases, fat cells encourage the production of estrogen and insulin production which raises the risk for breast cancer.2 Other inflammatory conditions such as diabetes and Crohn’s disease also increase the risk of cancer as they produce higher levels of insulin developing extra-intestinal malignancies [5].  

The connection between Arthritis and Breast Cancer

Since Arthritis is a form of inflammation, there is a significant connection between this disease and metastasis. Stem cells are known to activate mast cells (MCs) which produce proinflammatory factors seen in Arthritis. The stem cells remodel the tumor environment which then turns to MCs suggesting that they are not only participating in worsening the tumor but are also regulating the environment [6].

Arthritis is also mostly regulated by two pro-inflammatory cytokines which are  IL-1 and TNFα. These are key cytokines that mainly create joint inflammation in the cartilage and the bone. Although TNFα alone is seemingly unharmful, it enhances the destructive behavior of IL-1.7

Breast Infections

Non Cancerous Breast Infections

  • Mastitis [8]: Mastitis is a breast infection that occurs from breastfeeding. It occurs when the breast milk is clogged in the milk duct causing it the release of white blood cells. This can lead to an effect of increased blood flow in the breast and swelling. Although this infection occurs in the breast, it does not have an effect of causing cancer. 

  • Granulomatous lobular mastitis: This condition occurs when a noncancerous mass develops in the breast causing a lot of pain. The recommended method of diagnosis is a core needle biopsy that identifies the specific type of infection that created the mass. For example, the different types of granulomatous mastitis can be formed through a bacterial, fungal, or mycobacterial infection. Due to this reason, it is reasoned that this infection may be autoimmune [9]. Often mistaken as mammary tuberculosis, the GLM is caused by infections such as gram-negative bacteria, zinc deficiency, and sarcoidosis [10].   Along with tuberculosis, the presence of Histoplasma capsulatum, a fungi bacteria caused by reproductive cells, may cause this disease. Combined with Paracoccidioides, another thermally developed fungal infection, the appearance of this mastitis occurred in a case study. [11].

  • Central or Subareolar Infection: Subareolar infection is caused by an infected milk duct from an abscess. An abscess forms when there are imperil cells and tissues in the body. In other words, there could be a growth of neoplastic cells or a demolition of tissues that is harming the immune system. A buildup of fluid secretions in the breast duct due to these neoplastic cells become prone to infection. Although this process may cause change in breast tissue and lymph glands, it is too benign to be converted into breast cancer.  Underlying conditions such as rheumatoid arthritis, diabetes, and inflammatory carcinoma serve as symptoms [12]. 

  • Peripheral non-lactating infections: This infection is commonly seen in those who have previously been diagnosed with Rheumatoid arthritis or diabetes. As the infection progresses throughout the breast, it tends to leave an inflammation or abscess on the breast [19].  Connected with peripheral non-lactating infection, Idiopathic granulomatous mastitis and non-lactating mastitis are uncommon inflammatory diseases that are associated with non-lactating infections. 

  • Cellulitis or skin infections: This infection is possibly caused by sebaceous cysts. These cysts are produced on oil secreted glands. Those who have undergone radiation therapy or any breast surgery have a risk of obtaining this infection [13]  Those with weak immune systems are prone to this infection.


Created by Debeshi Kundu  © 2020 Breast Cancer Hub  

[14, 15] (Data Source) 

Cancerous Breast Infections: 

  • Paget’s disease [16]:  Paget’s disease is a rare skin disorder that is often linked to breast cancer where cancer cells formulate around the nipple. Although it is uncertain how the condition develops, signs first appear around the milk ducts of the nipple which then gradually spreads across to the areola or the darker circular part of the nipple. Physicians have also concluded that another possibility of this condition can be through the cells of the nipple becoming cancerous. The cells can become cancerous in two ways: previous cancerous nipple cells already residing in the breast or having another type of breast cancer aside from Paget’s disease [17].  Because Paget’s is so rare, it has a one percent chance of affecting the breast compared to the other breast cancer diseases. From Paget’s disease, the occurrence of other forms of breast cancer can occur such as Lobular carcinoma in situ, Phyllodes tumor, and Angiosarcoma. 

Picture: [16]

  • Inflammatory Breast Cancer (IBC)[18]: Inflammatory Breast Cancer is a rare type of breast cancer in which the lymph channels in the lymphatic system are blocked by cancer cells.  The lymph channels purpose in the body are to drain the excess fluid that is stored in tissues and organs. Without the lymph channels, the skin surrounding the area becomes red and inflamed. IBC [19] is different from any other breast cancer in the sense that symptoms do not appear like a typical breast cancer. As typical signs of breast cancer include the indication of a lump, IBC does not have this symptom which makes it harder to diagnose. Along with that, this condition is more aggressive than most common types of cancer which also makes it difficult to treat. When diagnosed, cancer cell growth has reached stage III because that is when cancer has grown into the breast skin and is visible [20]. Diagnosis includes breast screening such as a mammogram, breast MRI and biopsies. The biopsy detects this cancer when the growth contains too much of a protein called Human Epidermal Growth Factor receptor 2 (HER2). 

Conclusion: 

It is crucial to understand how inflammation affects breast cancer cells. Oftentimes, the inflammation of the cancer is forgotten so cancer cells begin to feed off of each other. Thus, expediting the spread of cancer and worsening one’s condition. 


Sources:

  1. Fox Chase Cancer Center: Temple Health. Chronic Inflammation and Cancer: What's the Connection?, 14 Nov. 2019, www.foxchase.org/blog/chronic-inflammation-and-cancer-what%E2%80%99s-connection. 

  2. Tiberian, Janet. “The Connection Between Inflammation and Breast Cancer.” MDVIP, 5 July 2017, www.mdvip.com/about-mdvip/blog/connection-between-inflammation-and-breast-cancer.

  3. Esquivel-Velázquez, Marcela, et al. “The Role of Cytokines in Breast Cancer Development and Progression.” Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research, Mary Ann Liebert, Inc., Jan. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4291218/. 

  4. Cancer Research UK. “Inflammatory Breast Cancer.” Inflammatory Breast Cancer | Breast Cancer | Cancer Research UK, 18 Feb. 2020, www.cancerresearchuk.org/about-cancer/breast-cancer/stages-types-grades/types/inflammatory-breast-cancer.   

  5. Pellino, Gianluca, et al. “Relatives of Crohn's Disease Patients and Breast Cancer: An Overlooked Condition.” International Journal of Surgery, Elsevier, 24 May 2014, www.sciencedirect.com/science/article/pii/S1743919114001216.    

  6. Das Roy et.al., Breast Cancer Research, 15:R32 doi: 10.1186/6cr3412 Press Release: American Association of Cancer Research, Chicago, 2012

  7. Lubberts, Erik. “Cytokines in the Pathogenesis of Rheumatoid Arthritis and Collagen-Induced Arthritis.” Madame Curie Bioscience Database [Internet]., U.S. National Library of Medicine, 1 Jan. 1970, www.ncbi.nlm.nih.gov/books/NBK6288/#:~:text=Two%20key%20pro%2Dinflammatory%20cytokines,importance%20in%20the%20RA%20disease.&text=IL%2D4%20and%20IL%2D10,systemic%20disorder%20of%20unknown%20etiology.

  8. Cancer Treatment Centers of America. “Inflammation Tied To Cancer, Lifestyle Changes May Help.” Cancer Treatment Centers of America, 14 July 2020, www.cancercenter.com/community/blog/2018/08/inflammation-linked-to-cancer-but-lifestyle-changes-may-help.  

  9. Genetic and Rare Diseases Information Center. “Granulomatous Lobular Mastitis.” Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, 14 Oct. 2016, rarediseases.info.nih.gov/diseases/13119/granulomatous-lobular-mastitis.

  10. De Sousa, R, and R Patil. “Breast Tuberculosis or Granulomatous Mastitis ... - Atmph.org.” Http://Www.atmph.org/Article.asp?Issn=1755-6783;Year=2011;Volume=4;Issue=2;Spage=122;Epage=125;Aulast=De#:~:Text=Although%20TB%20was%20considered%2C%20the,of%20diagnosis%20to%20tuberculous%20mastitis., 2011, www.atmph.org/article.asp?issn=1755-6783;year=2011;volume=4;issue=2;spage=122;epage=125;aulast=De;type=0.

  11. Merino-Alado , Rommie, et al. “Granulomatous Mastitis Due to Coinfection with Histoplasma Sp. and Paracoccidioides Sp.: A Case Report.” Medical Mycology Case Reports, U.S. National Library of Medicine, 16 Jan. 2020, pubmed.ncbi.nlm.nih.gov/31993319/.

  12. Dr. Halls. “Subareolar Breast Abscess: Everything You Need to Know - Moose and Doc.” Breast Cancer - Moose and Doc, 20 Sept. 2019, breast-cancer.ca/abscess/.

  13. Nall, Rachel. “Breast Infection: Symptoms, Causes, Types, and Treatment.” Medical News Today, MediLexicon International, 17 Dec. 2018, www.medicalnewstoday.com/articles/324016.

  14. Toomy, Ariel, and Jacqueline K. “Breast Abscess.” National Center for Biotechnology Information, 1 July 2020, www.ncbi.nlm.nih.gov/books/NBK459122/.

  15. Yaghan, Rami, et al. “A Proposal of a Clinically Based Classification for Idiopathic Granulomatous Mastitis.” Asian Pacific Journal of Cancer Prevention : APJCP, West Asia Organization for Cancer Prevention, 26 Mar. 2019, www.ncbi.nlm.nih.gov/pmc/articles/PMC6825786/.

  16. Breastcancer.org. “Paget's Disease of the Nipple: Symptoms, Diagnosis, and More.” Breastcancer.org, 22 June 2019, www.breastcancer.org/symptoms/types/pagets.

  17. Larinka Health Tutor. “Facts about Breast Cancer.” Jtown Connect, 23 Sept. 2016, larinkahealthtutor.blogspot.com/2016/09/facts-about-breast-cancer.html.

  18. Martin, Laura J. “Is Your Rash a Breast Infection or Inflammatory Breast Cancer?” WebMD, WebMD, 17 Mar. 2019, www.webmd.com/breast-cancer/breast-infection-breast-cancer.

  19. The American Cancer Society Medical Team. “Inflammatory Breast Cancer: Details, Diagnosis, and Signs.” American Cancer Society, 20 Sept. 2019, www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/types-of-breast-cancer/inflammatory-breast-cancer.html.

  20. Mayo Clinic. “Inflammatory Breast Cancer.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 14 July 2020, www.mayoclinic.org/diseases-conditions/inflammatory-breast-cancer/symptoms-causes/syc-20355413.

 
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