Chronic Inflammation and Cancer: Correlation or Causation?

By: Nicole Askar

While normal acute inflammation is typically a response to regulate homeostasis within the body, chronic inflammation often results in damage to other pathological systems (Monteiro et. al 2010). This damage can manifest itself in increased tumor growth, resulting in the presentation of cancer. Is this presentation of cancer just correlated or caused by inflammation?

How is this relationship possible?

1. Inflammatory cells and cytokines found in tumors may contribute to tumor growth, progression, and immunosuppression rather than mount an antitumor response.
2. Functional polymorphisms of inflammatory cytokine genes may result in increased cancer susceptibility (Balkwill et. al 2001).

How does this happen?

In some cancers, the inflammatory response is a cofactor in carcinogenesis. Tumor-infiltrating lymphocytes may contribute to cancer growth and spread, and suppression of the immune system (Balkwill et. al 2001). The cytokine network tends to lack cytokines associated with long-term immune responses. However, tumor cells and/or tumor-associated leucocytes and platelets can produce cytokines and chemokines that may contribute to the malignant progression of tumors. In tumor tissues, hypoxia, which is the deficiency of oxygen reaching the cells, can induce cytokines and chemokines (Balkwill et. al 2001).

Additionally, malfunctioning TNF-a can lead to the proliferation of cancer. TNF-a is a mediator of inflammation (Monteiro et. al 2010). While inducing the death of diseases cells, TNF, through stimulation of fibroblast growth, can kill blood vessels while stimulating angiogenesis, the physiological process through which new blood vessels form from pre-existing vessels. In malignant disease, TNF-a is supposed to destroy tumor blood vessels. However, when chronically produced, TNF-a may act as a tumor promoter (Balkwill et. al 2001).

Why does the presence of TNF matter?

TNF has been detected in human ovarian, breast, prostate, bladder, and colorectal cancer, lymphomas, and leukemias (Balkwill et. al 2001).

How do we know this?

Animal models have also depicted evidence of TNF’s pro-cancer actions. In a study on mice, mice lacking the gene for TNF were resistant to skin carcinogenesis (Scott et. al). Because the mice that had TNF-a experienced more tumors, one can conclude that TNF-a is at least correlated with the proliferation of cancer cells. Additionally, mice who had the gene for TNF were given cV1q, an antibody thought to neutralize the effects of TNF-a. These mice experienced less skin carcinogenesis than the mice with the TNF gene that did not receive the treatment (Radley et. al 2008). Since the mice that had TNF-a neutralized experienced fewer tumors than mice that did not have TNF-a neutralized, one can conclude that TNF-a may cause the presentation of cancer.

Figure 1: The squares are mice with TNF-a, the control group, and the circles are mice with TNF-a who were injected cV1q to neutralize the TNF-a. The mice whose TNF-a were neutralized experienced less tumours over time (Scott et. al).

Although the causal relationship between inflammation, immunity, and cancer is more widely accepted than previously, the molecular and cellular mechanisms for this relationship are still unconfirmed (Coussens et. al 2002). Continued research on the role of TNF inhibitors is needed to determine the role of inflammation in the presentation of cancer.

TLDR

If the inflammatory response malfunctions, tumor cells can produce cytokines, like TNF-a, that increase the size of the tumor and result in cancer. The presence of TNF-a in cancer cells supports the hypothesis that the inflammatory response has a role in the manifestation of cancer.

Works Cited

Balkwill, F., & Mantovani, A. (2001). Inflammation and cancer: back to Virchow?. The Lancet, 357(9255), 539–545.

Coussens, L. M., & Werb, Z. (2002). Inflammation and cancer. Nature, 420(6917), 860.

Monteiro, R., & Azevedo, I. (2010). Chronic inflammation in obesity and the metabolic syndrome. Mediators of inflammation, 2010.

Radley, H. G., Davies, M. J., & Grounds, M. D. (2008). Reduced muscle necrosis and long-term benefits in dystrophic mdx mice after cV1q (blockade of TNF) treatment. Neuromuscular Disorders, 18(3), 227–238.

Scott, K. A., Moore, R. J., Arnott, C. H., East, N., Thompson, R. G., Scallon, B. J., … & Balkwill, F. R. (2003). An anti-tumor necrosis factor-α antibody inhibits the development of experimental skin tumors. Molecular cancer therapeutics, 2(5), 445–451.