Tumor-related interleukins: old validated targets for new anti-cancer drug development

Molecular Cancer, Sep 2017

In-depth knowledge of cancer molecular and cellular mechanisms have revealed a strong regulation of cancer development and progression by the inflammation which orchestrates the tumor microenvironment. Immune cells, residents or recruited, in the inflammation milieu can have rather contrasting effects during cancer development. Accumulated clinical and experimental data support the notion that acute inflammation could exert an immunoprotective effect leading to tumor eradication. However, chronic immune response promotes tumor growth and invasion. These reactions are mediated by soluble mediators or cytokines produced by either host immune cells or tumor cells themselves. Herein, we provide an overview of the current understanding of the role of the best-validated cytokines involved in tumor progression, IL-1, IL-4 and IL-6; in addition to IL-2 cytokines family, which is known to promote tumor eradication by immune cells. Furthermore, we summarize the clinical attempts to block or bolster the effect of these tumor-related interleukins in anti-cancer therapy development.

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Tumor-related interleukins: old validated targets for new anti-cancer drug development

Setrerrahmane and Xu Molecular Cancer Tumor-related interleukins: old validated targets for new anti-cancer drug development Sarra Setrerrahmane 1 Hanmei Xu 0 1 0 State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University , Nanjing, Jiangsu 210009 , People's Republic of China 1 The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University , Nanjing, Jiangsu 210009 , People's Republic of China In-depth knowledge of cancer molecular and cellular mechanisms have revealed a strong regulation of cancer development and progression by the inflammation which orchestrates the tumor microenvironment. Immune cells, residents or recruited, in the inflammation milieu can have rather contrasting effects during cancer development. Accumulated clinical and experimental data support the notion that acute inflammation could exert an immunoprotective effect leading to tumor eradication. However, chronic immune response promotes tumor growth and invasion. These reactions are mediated by soluble mediators or cytokines produced by either host immune cells or tumor cells themselves. Herein, we provide an overview of the current understanding of the role of the best-validated cytokines involved in tumor progression, IL-1, IL-4 and IL-6; in addition to IL-2 cytokines family, which is known to promote tumor eradication by immune cells. Furthermore, we summarize the clinical attempts to block or bolster the effect of these tumor-related interleukins in anti-cancer therapy development. Cancer; Tumor microenvironment; Immune cells; Cytokines; Anti-cancer Background Early in 1863, Virchow postulated cancer proliferation at sites of chronic inflammation and infection. His conclusion was based, in part, on the hypothesis that some classes of mediators causing the inflammation can enhance tumor cells proliferation, in another part on the evidences revealing the presence of leukocytes in neoplastic tissue [ 1 ]. Several experimental and epidemiological data came to support this contention. Examples include increased incidence of virus-associated cancers, liver and pancreas cancer caused by alcohol induced inflammation and smoking- related lung inflammation and carcinoma [ 2–5 ]. Other data suggested that sporadic or inherited genetic mutations in some critical genes regulating cell cycle, programmed cell death or differentiation and adhesion might be the actual cause of tumorigenesis. Chronic inflammation and cytokines production favor selection of additional features in initiated cells, which may be the promotor of malignant transition [ 6, 7 ]. The tumor microenvironment is rich in a variety of immune cells, composed of both myeloid (innate immunity) and lymphoid (adaptive immunity) lineages [ 8– 10 ]. The former involves macrophages, granulocytes, mast cells, dendritic cells (DCs), and natural killer (NK) cells. Contrary to what was thought, not all these leukocytes represent an attempt by the host to eradicate transformed neoplastic cells. Only some are [ 11 ], and all other classes may support tumor growth, invasion, metastasis, and escape from the host immune response and conventional anti-cancer therapy [ 12, 13 ]. On the other hand, adaptive immunity is generally represented by B and T lymphocytes. Acute activation of B cells may play a role in eradicating early neoplastic cells, or inducing tumor regression via the secretion of antigen-specific immunoglobulins [14]; meanwhile, the chronic activation of B cells may paradoxically play a role in potentiating cancer development. Moreover, cytotoxic T lymphocytes (CTLs) recruited in acute tumor-directed immune responses, appear to protect against tumor development [ 15, 16 ], whereas the immune responses involving chronic activation of humoral immunity and infiltration of Th2 cells, result in the promotion of tumor development and disease progression [16]. As shown in Fig. 1, the regulation of such immune responses is mediated by the cytokines secreted to initiate or to weaken the host antitumor immunity, [ 17, 18 ] . In chronic inflammation, tissue homeostasis is dramatically perturbed. Tissue-resident macrophages and mast cells locally secrete soluble factors such as cytokines, chemokines, bioactive mediators, and matrix-remodeling proteins that recruit additional leukocytes from the circulation into damaged area [ 19 ], this contributes to the development of most human solid tumors. Recently, a growing body of literature claimed that cytokines are not only produced by the immune cells present in the tumor microenvironment, the autocrine origin of some inflammatory cytokines, especially IL-1, IL-4 and IL-6, was observed in large range of solid tumors [ 20–22 ]. Cancer cells not only express the cytokine, but also over expresses the related receptor to use it and escape from the immune response [ 23, 24 ]. The secreted molecules could also serve as messengers in the cross ta (...truncated)


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Sarra Setrerrahmane, Hanmei Xu. Tumor-related interleukins: old validated targets for new anti-cancer drug development, Molecular Cancer, 2017, pp. 153, DOI: 10.1186/s12943-017-0721-9