IL-6 signals through a cell-surface type I cytokine receptor complex consisting of the ligand-binding protein of IL-6Ra chain (also called CD126), and the signal-transducing component gp130 (also called CD130). The signal transduction of IL-6 involves the activation of janus kinase (JAK) tyrosine kinase family members, resulting in the activation of transcription factors of the signal transducers and activators of transcription 3 (Stat3). Stat3 has been identified as the prime transcriptional regulator mediating the IL-6 dependent cell growth, differentiation, and survival signals. IL-6 also ctivates Ras, MAPK, Cox-2, Wnt and PI3K/AKT pathways. These different pathways together contribute to the pro-tumorigenic and antiapoptotic activities of IL-6.
IL-6 is one of the most ubiquitously deregulated cytokines in cancer, with over-expression of IL-6 observed in virtually every tumor that has been studied. Several investigators have reported an aberrant IL-6 pathway activation in a variety of human cancer cell lines and solid tumors, including epithelial tumors of ovary, breast and prostate as well as multiple myelomas, leukemias and lymphomas.
1) IL-6 has been found to play an important role in various tumor behaviors including the development, cell migration, invasion, growth of malignancies, proliferation, apoptosis, progression, angiogenesis and differentiation of tumor cells. The role of IL-6 has been related to other factors. For example, IL-6 regulates tumor cell proliferation through activation epithelial growth factor, hepatocyte growth factor and other factors. It stimulates angiogenesis and tumor vascularisation through regulates vascular endothelial growth factor (VEGF) synthesis.
2) In cancer stem cell studies, IL-6 has been implicated as a potential regulator of normal and tumor stem cell self renewal. The potential roles of IL-6-Jak-Stat signaling pathway in tumorigeneis have been reported in different tumor models, including ovarian, lung, bladder, breast, colon, prostate cancer, and multiple myeloma.
3) IL-6 has also been correlated with cancer drug resistance where modulating the IL-6 pathway directly affects the cellular resistance to drug treatments. IL-6 is found to be a resistance factor for a number of cytotoxic agents including doxorubicin, VP-16 and cisplatin.
4) Preclinical and translational findings indicate that IL-6 plays an important role in diverse malignancies and provides a biologic rationale for targeted therapeutic investigations. Current targeted biological therapies mainly focus on IL-6-conjugated toxins and mAbs against IL-6 and IL-6R. For example, the CNTO 328 antibody has been shown to be capable of neutralizing IL-6's function in different types of human cancer including multiple myeloma89, ovarian cancer, and prostate cancer.
IL-6 concentrations have been found to depend upon tumor stage, which is correlated with patient survival. For example, serum IL-6 concentration in patients is associated with the progression, histological grade, bowel wall invasion, as well as tumor size and shorter survival periods of colorectal cancer. In patients with high IL-6 concentrations, the response to treatment with chemotherapy and hormone therapy was worse. Patients with higher IL-6 levels have a shorter survival while a reduction in the levels of IL-6 was visible in patients who responded better to therapy. There is also an increase in the intensity of IL-6 expression in the recurrent metastatic lesion as compared with the primary metastasis. These results suggest that IL-6 has the potential to be used as an independent prognostic factor for cancer.
Most of the clinical experience in direct inhibition of IL-6 for cancer therapy has been with the use of murine or humanized monoclonal antibodies (McAbs). Several IL-6 antibodies have been developed in recent years and evaluated in clinical trials, such as anti-IL-6 chimeric McAb, CNTO 328 (Siltuximab) developed by Centocor and BE-8, developed by Diaclone.
Earlier investigations used BE-8, a murine anti-IL-6 monoclonal antibody which is, however, associated with several problems. For example, BE-8 cannot efficiently block the daily production of IL-6 levels>8 mg. Moreover, it is difficult to suppress delayed IL-6 production without performing repeated dosing due to the short half-life of BE-8 (3–4 days). This is a challenge as murine antibodies generally are neutralized by human anti-mouse responses.
CNTO 328 is a human-mouse chimeric antibody, constructed from a murine anti IL-6 McAb, with anti-tumor and anti-inflammatory activities.31,108 It contains the antigenbinding region of the human immunoglobulin G j (IgG j) immunoglobulin and the variable antigen-binding region of the murine anti-IL6 antibody. CNTO 328 has a long half-life (approximately 2 weeks) without significant immunogenicity and hence may be more beneficial clinically relative to BE-8. It also has a high affinity for recombinant as well as native IL-6. This feature enables it to inhibit the binding of IL-6 to the IL-6R, resulting in the blockade of the IL-6/IL-6R/gp130 signal transduction pathway and, subsequently, antitumor and anti-inflammatory activities. CNTO 328 has been for a phase II multicenter trial in multiple myeloma.
Several fully human McAb or humanized McAb to IL-6 have also been developed, including CNTO 136 and ALD518.
The increasing knowledge regarding the molecular biology mechanisms of IL-6 and its interrelations to human cancer will lead to the development of novel antibody based therapies. New IL-6 target treatments not only target malignant tumor cells, but also target the interactions of cancer cells with their microenvironment. Extensive studies have identified IL-6 as a crucial part of tumor cell survival, proliferation, migration and drug resistance
Guo Y, et al. Interleukin-6 signaling pathway in targeted therapy for cancer[J]. Cancer treatment reviews, 2012, 38(7): 904-910.