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Tnf α: Contradictory Roles In Cancer Progression And As A Chemotherapeutic Agent

2480 words - 10 pages

The Tumor Necrosis Factor (TNF) family of proteins constitute a large, potent class of cytokines capable of inducing apoptosis, including 19 different ligands and 29 receptors (Aggarwal et al, 2012). Importantly, TNF-induced apoptosis is known to be involved in several preventive pathological states, including the inflammatory response and cytotoxicity in tumorigenesis. TNF-α, the most well-known member of the TNF family, is the cytotoxic agent produced primarily by macrophages. It was first alluded to in a 1962 sarcoma study which found that viral-induced sarcomas could be damaged when exposed to “activated” (bacterial exposed) sera (Omalley, 1962). It wasn’t until 1975, however, that TNF-α was officially identified, characterized, and linked to tumor inhibition (Carswell et al, 1975). Interestingly, several studies since then have found that tumors constitutively produce TNF-α to retain tumorigenic potential, indicating that this molecule has complex and contradictory roles. Current research studies have aimed to determine the therapeutic potential of TNF-α cytotoxic activity as an anti-cancer treatment; however, because of its ability to induce anaphylactic shock when administered in large amounts, it has not served as an appropriate systemic treatment in cancer patients (Balkwill, 2006). Nonetheless, several studies have demonstrated an important (albeit limited) clinical application: it has been used to diminish soft tissue tumors in the extremities using the “isolated limb perfusion technique”. This brief review will discuss the current understanding of TNF-α signaling in both normal and tumorigenic physiology. Furthermore, it will examine the recently tapped, “rational” therapeutic potential of TNF-α in cancer pathology.

TNF-α regulation and signaling TNF-α exists as both a soluble cytokine and a homotrimeric transmembrane protein. The membrane-bound version of TNF-α releases the soluble cytokine upon proteolytic cleavage by a metalloprotease. While the exact evolutionary driving force for having both membrane and soluble factions remains unclear, research suggests that the vast diversity observed in the TNF family protein types may have been a result of increases in gene number/ whole genome duplication; from there, the soluble cytokine probably evolved from membrane-bound TNF as a means of regulation, given that soluble TNF-α is highly cytotoxic (Wiens et al, 2011).

TNF-α levels are generally expressed in the circulatory system at low, basal levels in non-disease state, and are usually stimulated in the pro-inflammatory response to a foreign stimulus, i.e. LPS (McNaul et al, 1992; Liu et al 2000). Transcription regulation of TNF-α levels is mediated by multiple transcription factors present in macrophages, primarily NF-κB and c-Jun (Yao et al, 1997; Udalova et al, 1998). Both of these factors have been found to possess binding sites in the proximal promoter of the TNF-α gene; mutational analyses have confirmed that these sites...

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