Tumor Necrosis Factor: How to Make a Killer Molecule Tumor-Specific?

Abstract

The interest in TNF, discovered at the interface between inflammation and cancer, as an anti-cancer agent, has phased out in recent years. Indeed, despite its profound cytostatic and cytotoxic effects in primary tumors, the cytokine's systemic toxicity in general and its hepatotoxic and pro-metastatic nature in particular, prevent its routine use in cancer patients. An elegant approach to circumvent these problems consists in the local application of TNF in an isolated limb or organ setting, preferentially in the presence of cytostatic and alkylating agents, such as melphalan. However, this treatment, when locally applied during the perfusion of liver tumors, results in hepatotoxicity in a significant number of the patients, by means of a still unknown mechanism. The hemorrhagic necrosis of the tumors induced by TNF seems to be predominantly mediated by an induction of apoptosis as well as by an anti-angiogenic effect in the endothelial cells of the microvasculature supplying the tumor. These cells therefore represent a prime target for the action of anti-cancer drugs. In this review, we discuss preclinical studies which elucidated the mechanism of melphalan- and TNF-associated hepatotoxicity and, as a consequence, provided insights for preventing the adverse reactions of the drug. Moreover, we review recent findings aimed at improving the TNF molecule by means of specific mutations, or searching for alternative factors lacking the systemic toxicity of TNF.

The involvement of IL‐10, IL‐6, IFN‐γ, TNF‐α and TGF‐β gene polymorphisms among Turkish lung cancer patients

“…As TNF was reported to selectively target and destroy tumour-associated vessels, 16,17 the tendency to produce a lower amount of TNF-a might lead to a poor anti-tumour defence. 18 A high producing (G/A) genotype of TNF-a at position (À308) 19 was reported to be more common among Taiwanese lung cancer patients and associated with more advanced disease, 14 while in the present study the low-producing (G/G) genotype, was more frequent in Turkish population. However, no genotype difference was observed in a German population.…”

Single-Chain TNF, a TNF Derivative with Enhanced Stability and Antitumoral Activity

“…It is, therefore, tempting to speculate that reversible dissociation of TNF affects tissue distribution finally leading to enhanced toxic effects. Strong differences in the systemic toxicity in mice have also been described for human and mouse TNF, an effect which is not related to the fact that human TNF does not bind mouse TNFR2 (30). A possible explanation could be a differential interaction of scTNF and wild-type TNF with shedded extracellular TNF receptor domains in body fluids, potentially serving as inhibitors and/or storage pools.…”

Liver cancer: EphrinA2 promotes tumorigenicity through Rac1/Akt/NF-κB signaling pathway

“…Efforts have been made to improve its application, such as modification of TNF-␣ to ameliorate its specificity aiming at tumor tissues. 36 Another potential strategy is to increase the sensitivity of cancer cells to TNF-␣, which will decrease the effective dose of the cytokine and avoid unexpected systemic toxicity. According to the effects of EphrinA2 knockdown in our study, it is reasonable and hopeful to block EphrinA2 signaling with either its inhibitors or neutralizing antibodies to elevate the sensitivity of HCC cells to TNF-␣ in clinical use, suggesting that manipulation of EphrinA2 may facilitate the application of TNF-␣ in cancer therapy.…”