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Tumor Necrosis Factor (TNF) is a multifaceted protein that plays a crucial role in the body's immune response. As a cytokine, a type of signaling molecule, TNF is primarily produced by macrophages—white blood cells that are key players in immune defense. Its name derives from its ability to induce the death (necrosis) of tumor cells, discovered in the 1970s. However, TNF's functions extend far beyond cancer cell death; it's involved in systemic inflammation and is a mediator of acute phase reactions. TNF can trigger fever, inflammation, and apoptosis (cell death), and it's implicated in a variety of diseases, including autoimmune disorders, such as rheumatoid arthritis, and inflammatory bowel disease.
Given its significant role in inflammation and the immune system, TNF has become a prime target for therapeutic intervention. Anti-TNF drugs, known as TNF inhibitors, have been developed to treat chronic inflammatory diseases. For instance, the global market for TNF inhibitors was valued at approximately $40 billion in 2020, highlighting their importance in modern medicine (Statista, 2021). These drugs work by neutralizing TNF's activity, thereby reducing inflammation and alleviating symptoms in patients. While these treatments have revolutionized the management of chronic inflammatory conditions, they also require careful administration and monitoring due to potential side effects, such as increased risk of infections.
Tumor necrosis factors (TNFs) are a family of small proteins that are used to signal cells throughout the body. The family consists of two proteins, designated TNF-α and TNF-β. TNF-α is the most studied of the two proteins and is commonly referred to as simply "tumor necrosis factor." The proteins are involved in controlling cell death, as well as inflammation in the body. Dysregulation of TNF can lead to a number of diseases, including cancer.
The proteins of tumor necrosis factor are classified as cytokines — a large class of proteins responsible for signaling to cells. TNF works by binding to and activating tumor necrosis factor receptor (TNF-R) that is found on the surface of cells. Activation of TNF-R then induces a biological signal within the cell to produce a range of cellular responses. Specifically, when TNF binds to TNF-R, it signals an increase in inflammation in the surrounding area, and can also instruct the cell to undergo programmed cell death. The amount of TNF within the body is closely regulated in order to monitor the amount of cell death and inflammation occurring at any given time.
Binding of tumor necrosis factors to their receptors can become deregulated in the body, leading to a range of diseases. Specifically, TNF has been linked to Crohn’s disease — a disorder where the colon is constantly inflamed. Crohn’s patients have more active TNF signaling to cells in their colon, which triggers sustained inflammation within the colon and causes the Crohn’s disease. Many Crohn’s disease sufferers are prescribed drugs, called tumor necrosis factor inhibitors, which decrease the levels of active TNF in the colon and therefore decrease inflammation to reduce symptoms of the disease.
Tumor necrosis factor has also been implicated in several forms of cancer, such as breast and stomach cancers, which occur when cells that are supposed to undergo cell death fail to do so. In this sense, TNF fights cancer because it triggers cell death of potentially cancerous cells. On the other hand, inflammation is known to play a role in the progression of cancer, where sustained inflammation promotes the growth of tumors. Therefore, although some features of TNF fight cancer by inducing cell death, other features of TNF signaling contribute to cancer by promoting inflammation.
Due to this dual role of TNF in cancer, the overall effects of tumor necrosis factor as a cancer treatment have been a subject of debate in cancer research. This has lead to the development of a number of therapeutics designed to retain the cancer-fighting role of TNF, which diminish its inflammatory effect. To this end, scientists have developed forms of TNF that induce cancer cell death with little inflammation. Additionally, scientists have discovered that treatment of tumors with cocktails of TNF in combination with other therapeutics leads to recession of cancer without inflammation. Ultimately, this research will allow doctors to provide customized treatment with tumor necrosis factors to cancer patients to induce remission of tumors.