SurveyTumor necrosis factor, cancer and anticancer therapy
Introduction
Several cytokines have been tested as antineoplastic agents, both alone and in combination with conventional chemotherapeutic agents or antitumor vaccines [1], [2]. From the historical viewpoint, tumor necrosis factor (TNF, formerly referred to as TNF-α) was the first cytokine to be employed for cancer biotherapy. TNF is a pleiotropic protein [3] that was first isolated from the serum of mice treated with bacterial endotoxin, and was shown to replicate the ability of endotoxin to induce haemorrhagic necrosis of methylcholanthrene-induced sarcomas [4]. This discovery ended a long search for the active component of “Coley's toxin”, which consisted of a crude bacterial filtrate developed by Willam Coley, a New York surgeon and pioneer of cancer biotherapy at the turn of the 20th century [5]. Coley's toxin-induced high fever and tumor necrosis in some patients affected with sarcoma, carcinoma and lymphoma. The phenomenon is now attributed, at least in part, to the effect of macrophage-derived TNF released upon activation of these leukocytes by the endotoxin contained within Coley's mixture.
In the 1980s, TNF was also characterized as cachectin [6] for its role in the wasting syndrome, and as T-lymphocyte differentiation factor [7]. Cloning of TNF gene in 1984 [8] led to the era of clinical experimentation. As systemic TNF administration was associated with lack of objective tumor response and serious side-effects, researchers investigated the delivery of TNF through the locoregional route, which culminated in a license from the European Medicine Evaluation Agency (EMEA) for the TNF-based treatment of limb-threatening soft tissue sarcomas [9].
Section snippets
TNF and its receptors
The TNF gene is located on chromosome 6p21.3 and is mainly expressed by activated macrophages, NK-cells and T-lymphocytes, even though other cell types (e.g. fibroblasts, astrocytes, Kupffer cells, smooth-muscle cells, keratinocytes, and tumor cells) have been shown to express it [10].
In its soluble form, TNF acts as a homotrimer with a subunit molecular mass of 17 kDa (157 amino acids). TNF is first synthesized as a 26 kDa (233 amino acids) membrane-bound pro-peptide (pro-TNF) and is released
Direct cytotoxic effects
The in vitro antiproliferative/cytotoxic property of TNF was among the first activities attributed to the cytokine [2]. TNF-R1 is expressed on virtually any cell type and has been demonstrated to exert cytostatic/cytotoxic effects on some animal and human tumor cell lines. Intriguingly, the genomic derangement proper of cancer development can itself sensitize malignant cells to TNF-driven cell death by leading to the overexpression of cathepsin-B [30], which might partly explain the selective
TNF tumor promoting effects
While physiologically TNF plays a major role in growth regulation, cell differentiation, response to viral, bacterial, fungal, and parasitic infections, its inappropriate overexpression has been implicated in the pathogenesis of a wide spectrum of human disorders, such as autoimmunity (e.g. multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease), allergy, septic shock, allograft rejection and insulin resistance [10]. Despite the above-discussed evidence of its antitumor activity,
TNF circulating levels and gene polymorphism
Cancer anorexia-cachexia syndrome (CACS) is a combination of anorexia, tissue wasting, weight loss and poor performance status. Although CACS signs/symptoms also depend upon macrophage-derived IL-1 and tumor-derived IL-6, TNF is considered a major mediator of this syndrome [107]. A consistent correlation has been reported between TNF plasma levels and occurrence of cachexia in patients with different tumor types. Following the promising results obtained in animals [108], the use of TNF
TNF-based anticancer therapy
The dose-limiting side effect of TNF systemic administration is represented by dose-dependent hypotension that can progress to a shock-like syndrome due to a depression of the cardiac function combined with a capillary leak syndrome resembling that of septic shock. Unfortunately, at the maximum tolerated dose (150–300 μg/m2), TNF systemic administration is not associated with significant antitumor activity, as demonstrated by phases I–II trials [2]. This is the reason why in the clinical setting
TNF muteins
Splitting the molecular domains of TNF responsible for the cytokine antitumor properties from those causing systemic toxicity has been the objective of studies on TNF analogues [142]. Moreover, muteins selectively binding to a specific TNF-R might show reduced tumor promoting effects, as supported by the observation that TNF-induced cytotoxicity towards some malignant cells lines is mediated by interaction with TNF-R1, whereas TNF-induced proliferation of these cells is mediated by the
Conclusions
The interest in TNF as an antineoplastic agent is witnessed by the continuous flow of scientific production on this subject [203], [204], [205]. The role played by TNF in cancer development/progression, even if less understood than that in the pathogenesis of autoimmune/inflammatory disorders, might appear to shadow the anticancer potential of this cytokine. Although further elucidation of TNF biology and the conduction of novel clinical trials are warranted to explain some apparent
Acknowledgements
We apologize to those authors whose work was not cited due to space limitations.
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