The Cytokinome Profile in Patients with Hepatocellular Carcinoma and Type 2 Diabetes

Abstract

Understanding the dynamics of the complex interaction network of cytokines, defined as ‘‘cytokinome’’, can be useful to follow progression and evolution of hepatocellular carcinoma (HCC) from its early stages as well as to define therapeutic strategies. Recently we have evaluated the cytokinome profile in patients with type 2 diabetes (T2D) and/or chronic hepatitis C (CHC) infection and/or cirrhosis suggesting specific markers for the different stages of the diseases. Since T2D has been identified as one of the contributory cause of HCC, in this paper we examined the serum levels of cytokines, growth factors, chemokines, as well as of other cancer and diabetes biomarkers in a discovery cohort of patients with T2D, chronic hepatitis C (CHC) and/or CHC-related HCC comparing them with a healthy control group to define a profile of proteins able to characterize these patients, and to recognize the association between diabetes and HCC. The results have evidenced that the serum levels of some proteins are significantly and differently up-regulated in all the patients but they increased still more when HCC develops on the background of T2D. Our results were verified also using a separate validation cohort. Furthermore, significant correlations between clinical and laboratory data characterizing the various stages of this complex disease, have been found. In overall, our results highlighted that a large and simple omics approach, such as that of the cytokinome analysis, supplemented by common biochemical and clinical data, can give a complete picture able to improve the prognosis of the various stages of the disease progression. We have also demonstrated by means of interactomic analysis that our experimental results correlate positively with the general metabolic picture that is emerging in the literature for this complex multifactorial disease.

Serum Cytokinome Profile Evaluation: A Tool to Define New Diagnostic and Prognostic Markers of Cancer Using Multiplexed Bead-Based Immunoassays

“…However, often the patients develop firstly liver fibrosis and cirrhosis and, then, HCC [61]. Our group has recently evaluated a large panel of cytokines in patients subdivided in four groups, T2D, HCV, HCV-related HCC alone, and HCV-related HCC with T2D, compared to healthy controls, to identify new markers specific for diabetes and/or HCC [39]. The obtained data evidenced that the levels of HGF, leptin, sVEGFR-1, sVEGFR-2, IL-2R, s-IL-6Ra, and IL-18, were higher in patients with T2D, HCV, and HCC.…”

“…The obtained data evidenced that the levels of HGF, leptin, sVEGFR-1, sVEGFR-2, IL-2R, s-IL-6Ra, and IL-18, were higher in patients with T2D, HCV, and HCC. On the other hand, the levels of β -NGF, CXCL1, CXCL9, CXCL12, IL-16, and PECAM-1 increased in patients with HCV and HCC and those of IFN- α and Prolactin only in HCC patients [39]. …”

“…Moreover the comparison between the cytokine levels in T2D and T2D-HCC patients showed that CXCL9, PECAM-1, Prolactin, and glucagon levels were higher in T2D-HCC patients compared to T2D patients, and VEGFR-1 and sVEGFR-2 were lower in T2D-HCC patients [39]. Hence, also in the case of multifactorial HCC, the cytokinome analysis can be used to identify new markers useful for improving the prognosis of its progression [39]. …”

“…This means that many prevalent chronic diseases, believed to be pathophysiologically similar and, therefore, treatable inhibiting the same target cytokine, have shown surprising failures when similarly treated [75]. From this point of view, in our opinion, one of the best available methodological approaches for this purpose is the cytokinome determination [18, 19, 39, 48], that is, the detection of the whole set of cytokines present in a biological fluid in a certain moment. Indeed, classical single cytokine assays fail to capture the physiological dynamics of the whole set of cytokines, due to their limited sensibility of response for the numerous less represented cytokines of which often we still do not have a specific assay [18, 19, 39, 48].…”

“…From this point of view, in our opinion, one of the best available methodological approaches for this purpose is the cytokinome determination [18, 19, 39, 48], that is, the detection of the whole set of cytokines present in a biological fluid in a certain moment. Indeed, classical single cytokine assays fail to capture the physiological dynamics of the whole set of cytokines, due to their limited sensibility of response for the numerous less represented cytokines of which often we still do not have a specific assay [18, 19, 39, 48]. A valid approach to this aim is based on multiplexing measurements where the presence of less abundant cytokines can be expressed as internal ratio [18, 19, 39, 48].…”