Abstract
Colorectal cancer (CRC) is the third most frequent cancer worldwide and the second greatest cause of cancer deaths. About 75% of all CRCs are sporadic cancers and arise following somatic mutations, while about 10% are hereditary cancers caused by germline mutations in specific genes. Several factors, such as growth factors, cytokines, and genetic or epigenetic alterations in specific oncogenes or tumor-suppressor genes, play a role during the adenoma–carcinoma sequence. Recent studies have reported an increase in interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) levels in the sera of patients affected by colon cancer that correlate with the tumor size, suggesting a potential role for IL-6 in colon cancer progression. IL-6 is a pleiotropic cytokine showing both pro- and anti-inflammatory roles. Two different types of IL-6 signaling are known. Classic IL-6 signaling involves the binding of IL-6 to its membrane receptor on the surfaces of target cells; alternatively, IL-6 binds to sIL-6R in a process called IL-6 trans-signaling. The activation of IL-6 trans-signaling by metalloproteinases has been described during colon cancer progression and metastasis, involving a shift from membrane-bound interleukin-6 receptor (IL-6R) expression on the tumor cell surface toward the release of soluble IL-6R. In this review, we aim to shed light on the role of IL-6 signaling pathway alterations in sporadic colorectal cancer and the development of familial polyposis syndrome. Furthermore, we evaluate the possible roles of IL-6 and IL-6R as biomarkers useful in disease follow-up and as potential targets for therapy, such as monoclonal antibodies against IL-6 or IL-6R, or a food-based approach against IL-6.
Highlights
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Polyposis syndromes are a heterogeneous group of hereditary syndromes predisposing to colorectal cancers, characterized by the onset of several polyposes of the colon and rectum, which are classified as adenomatous polyposis and hamartomatous polyposis syndromes
Adenomatous polyposis syndromes include familial adenomatous polyposis (FAP), attenuated FAP (AFAP), and MUTYH-associated polyposis (MAP); hamartomatous polyposis syndromes consist of PTEN hamartoma tumor syndrome (PHTS), juvenile polyposis syndrome (JPS), and Peutz–Jeghers syndrome (PJS)
Summary
IL-6 is a pleiotropic cytokine taking on pro- or anti-inflammatory roles, produced by many cell types, such as stromal, hematopoietic, epithelial, and muscle cells. Soluble IL-6R can be produced by a transcriptional mechanism that generates an alternatively spliced mRNA isoform of the receptor without the region encoding the transmembrane domain, yielding a protein that differs at its COOH terminus by 14 amino acid residues [35,36,37] This mechanism allows the activation of IL-6 signaling even without IL-6R, when the level of sIL-6R circulating is very high, as observed in several pathological conditions. This mechanism allows the activation of IL-6 signaling even without ILMembranes 2021, 116, 3R1,2when the level of sIL-6R circulating is very high, as observed in several pathological conditions. Role of the IL-6 Signaling in CRC Since IL-6 is able to activate pro- and anti-inflammatory cell responses, it shows pro- or anti-neoplastic activity, in a cell-specific manner, that is associated with the pres-
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