oa Editorial: [Cytokines as Anti-Cancer Agents Rational, Results and Perspectives (Guest Editor: S. Mocellin)]

Cytokines are a large and growing family of hormone-like proteins that play a variety of roles in different physiological and pathological circumstances such as inflammation and immunity. Given their ability of influencing a number of biological phenomena such as cell growth, apoptosis, migration, angiogenesis and immune surveillance, cytokines play a key role also in cancer development and progression. Cytokine-based anticancer biotherapy represented one of the first types of anticancer approaches by exploiting either the direct antitumor effects of these proteins, or their immunostimulating properties, or their synergistic effects with conventional chemotherapeutics and other anticancer agents. Cytokine-based biotherapy is currently utilized for the routine treatment of different tumors in the clinical setting. However, due to their pleiotropic biological activities, administration of cytokines is often accompanied by significant side effects, which tempers the enthusiasm for the promising tumor response rates that can be observed in patients who are given this type of treatment. Advances in our understanding of the role of cytokines in modulating the tumor-host interactions as well as the improvement in patient selection are paving the way for a significant improvement of the therapeutic index (the ratio between efficacy and toxicity) of cytokines used as anticancer agents. This issue is an authoritative, comprehensive and critical overview on the biological rational, the preclinical and clinical findings as well as the potential developments of the use of cytokines (alone or in combination with other therapeutic agents) to fight cancer. In particular, Sandro Pasquali et al. provide an in depth coverage of the molecular and cellular mechanisms underlying the anticancer effects of interferon (IFN) alpha, one of the most studied cytokines in the oncology field; the Authors also report on the results of the utilization of this molecule in the clinical setting, with a focus on cutaneous melanoma. Tumor necrosis factor (TNF) is the focus of the essay by Loris Bertazza et al.: these Authors outline the controversies regarding the role of this cytokine in tumor biology; they also overview the clinical findings so far reported regarding the use of TNF as an anticancer agent and conclude with an original hypothesis to explain the apparently conflicting data surrounding the relationship between TNF and cancer. Arkadiusz Dudek et al. report on the anticancer properties of interleukin-2 (IL-2), one of the cytokines most prescribed in the oncology field. With introduction of novel kinase inhibitors, immunomodulatory molecules, cytokines, and vaccines for treatment of cancer there is an increased interest in combining these therapeutic strategies with IL-2: accordingly, the Authors discuss toxicity and established activity of IL-2 in the management of advanced malignancies, and speculate on future use of this cytokine for treatment of cancer. The emerging role of TNF-related apoptosis inducing ligand (TRAIL) in the development of effective anticancer strategies is highlighted by Shulin Wang: besides reviewing the molecular biology of this cytokine, the Author summarizes the results so far obtained and the hurdles encountered by using TRAIL in the fight against malignancies. More recently, two other cytokines have drawn the attention of researchers involved in the fight against cancer: interleukin- 18 (IL-18) and interleukin-24 (IL-24). The preclinical data so far available in favor but also against the use of these molecules in the treatment of cancer are the focus of the essays by Michael Robertson and Stephanie Kreis, respectively.