New Insights into the Role of Chronic Inflammation and Cytokines in the Etiopathogenesis of Gastroenteropancreatic Neuroendocrine Tumors

Berković, Maja Cigrovski; Čačev, Tamara; Ivković, Tina Catela; Zjačić-Rotkvić, Vanja; Kapitanović, Sanja

doi:10.1159/000362339

Cited by 27 publications

(15 citation statements)

References 97 publications

(108 reference statements)

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“…Several studies hypothesized that a family history of MEN-127 and the presence of a glucagon-producing tumor originating from the alpha cells of the pancreas28 may result in elevated blood glucose levels. Furthermore, it is possible that diabetes may act as a mediator for chronic inflammation and oxidative stress inside the cell, which may lead to DNA mutation and the development of PNETs2930.…”

Section: Discussionmentioning

confidence: 99%

Risk Factors for Sporadic Pancreatic Neuroendocrine Tumors: A Case-Control Study

Ben

Zhong

Fei

et al. 2016

Sci Rep

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The current study examined risk factors for sporadic pancreatic neuroendocrine tumors (PNETs), including smoking, alcohol use, first-degree family history of any cancer (FHC), and diabetes in the Han Chinese ethnic group. In this clinic-based case-control analysis on 385 patients with sporadic PNETs and 614 age- and sex-matched controls, we interviewed subjects using a specific questionnaire on demographics and potential risk factors. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs). No significant differences were found between patients and controls in terms of demographic variables. Most of the patients with PNETs had well-differentiated PNETs (G1, 62.9%) and non-advanced European Neuroendocrine Tumor Society (ENETS) stage (stage I or II, 83.9%). Ever/heavy smoking, a history of diabetes and a first-degree FHC were independent risk factors for non-functional PNETs. Only heavy drinking was found to be an independent risk factor for functional PNETs (AOR = 1.87; 95% confidence interval [CI], 1.01–3.51). Ever/heavy smoking was also associated with advanced ENETS staging (stage III or IV) at the time of diagnosis. This study identified first-degree FHC, ever/heavy smoking, and diabetes as risk factors for non-functional PNETs, while heavy drinking as a risk factor for functional PNETs.

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Section: Discussionmentioning

confidence: 99%

Risk Factors for Sporadic Pancreatic Neuroendocrine Tumors: A Case-Control Study

Ben

Zhong

Fei

et al. 2016

Sci Rep

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“…Nowadays, it is generally accepted that proinflammatory microenvironments are important drivers of all tumors; thus, substantial efforts have been devoted to the biochemical and immunological cytokine network interactions that promote the progression of tumors. Several multicenter studies have demonstrated that the presence of various polymorphisms in genes coding for ILs, such as IL-1, IL-6, and/or IL-8, is strongly associated with increased risks of cancer development [11,12]. There is extensive evidence that the neuroendocrine system (network of neuroendocrine cells) influences the function of the immune system; however, little is known about the potential diagnostic and clinical values derived from measuring systemic cytokine levels in patients with different types of neuroendocrine tumors, as well as their potential diagnostic abilities during the pathohistological evaluation of tumors [12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemical staining was evaluated for the whole tumor surface for each slide and tumor percentage was at least 50% of slide material. A slide was recorded negative (0) if there was no staining or staining was <5% tumor cells stained with medium to strong intensity; weak (1) for staining up to 25% tumor cells; moderate (2) 25-50% tumor cells; and strong (3) >50% tumor cells [12]. TNF-α was analyzed as a membranous reaction and IL-1β, IL-2, and IL-6 as cytoplasmic reaction.…”

Section: Methodsmentioning

confidence: 99%

“…Currently, little is known about the potential diagnostic or clinical value of measuring systemic cytokine levels in patients with different types of neuroendocrine tumors or their value as diagnostic or prognostic indicators for pathohistological evaluations. Abnormal interactions between cytokines may be an overlooked mechanism for linking the development of different types of neuroendocrine tumors [11,12]. In this study, immunohistochemical expression of TNF-α, IL-6, IL-1β, and IL-2 in GEP-NENs was evaluated and correlated with the proliferation, tumor grade, tumor, node, metastasis (TNM), and outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Inflammation-related cytokines and their roles in gastroenteropancreatic neuroendocrine neoplasms

Mahečić¹,

Berković

Zjačić-Rotkvić³

et al. 2020

Bosn J of Basic Med Sci

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Proinflammatory counterworks are important at different stages of tumor development, particularly during invasion and metastasis. Immune cells and their signal molecules can influence all stages of tumor progression, as well as therapeutic intervention. Proinflammatory cytokines are known triggers of growth in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we explored the immunohistochemical expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), IL-2, and IL-6 in tissues from 43 GEP-NEN patients with tumors of gastric, duodenal, ileal, appendical, and colonic origin. The immunohistochemical expression of TNF-α was increased in tumor groups with high proliferation rates (Ki67; p = 0.034), as well as in those with higher tumor grades (p = 0.05). Moreover, the immunohistochemical expression of TNF-α positively correlated with death outcomes (p = 0.016). Expression of IL-6, IL-1β, and IL-2 displayed similar immunohistochemical expression patterns regardless of Ki67, although the expression between the ILs differed. Most GEP-NENs had high levels of IL-6 and lower levels of IL-1β and IL-2. Although further comprehensive studies are required for a complete understanding of activated mechanisms in proinflammatory protumoral microenvironment of GEP-NENs, TNF-α is a potential marker in the prognosis of those tumors.

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“…For example, in a study by Berkovic et al, not only was interleukin-2 (IL-2) associated with increased susceptibility to NENs, but also, when serum levels were compared to established neuroendocrine markers such as CgA and 5-hydroxyindoleacetic acid (5-HIAA), IL-2 was more sensitive than 5-HIAA and CgA in NEN diagnostics [20]. In this context, pro-inflammatory cytokines may be linked with the basis of NEN etiology and, along with other biochemical markers, such as CgA, may be utilized as prognostic indexes in patients with NENs [21].…”

Section: Introductionmentioning

confidence: 99%

The Diagnostic Value of Chromogranin A in Neuroendocrine Neoplasms is Potentiated by Clinical Factors and Inflammatory Markers

et al. 2020

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Objective: Neuroendocrine neoplasms (NENs) are a heterogenous group of indolent tumors, with variable clinical behavior and steadily rising incidence. The aim of this study is to investigate the clinical and laboratory factors that contribute in predicting the aggressiveness and invasiveness of NENs. Special focus is given to clinical parameters that would enhance the diagnostic value of chromogranin A (CgA), via formalizing an integrated probability model, which would contribute to the timely and accurate identification of patients at high risk for metastatic disease at initial diagnosis. Designs and Methods: We identified a total of 93 patients with NENs, recruited at a specialized academic center in Athens, Greece. Anthropometric, clinical, laboratory, and pathological data were obtained from every patient before any therapeutic intervention. Results: Age over 50 years and male gender were accompanied by increased risk for metastases at the time of initial diagnosis. Additionally, when these parameters were combined with CgA levels, they were shown to enhance the predictive capacity of CgA. Different patient scenarios combining age, gender, and CgA levels are associated with different probabilities for metastatic disease, demonstrated schematically in a gradually escalating model, as age and CgA levels increase in both males and females. The lowest risk is observed in women aged <50 years old with CgA levels <200 ng/dl (6.5%), while the highest one is in males over 50 years old with CgA > 200 ng/dl (62.9%). Finally, it was shown that c-reactive protein (CRP) can predict disease extent at the time of diagnosis. Conclusions: CgA levels can not only be used as a direct predictor of tumor load in patients with NENs, but also, when interpolated with the effects of age and gender, cumulatively predict whether a NEN would be metastatic or not at the time of initial diagnosis, via a risk-escalating probability model.

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New Insights into the Role of Chronic Inflammation and Cytokines in the Etiopathogenesis of Gastroenteropancreatic Neuroendocrine Tumors

Cited by 27 publications

References 97 publications

Risk Factors for Sporadic Pancreatic Neuroendocrine Tumors: A Case-Control Study

Risk Factors for Sporadic Pancreatic Neuroendocrine Tumors: A Case-Control Study

Inflammation-related cytokines and their roles in gastroenteropancreatic neuroendocrine neoplasms

The Diagnostic Value of Chromogranin A in Neuroendocrine Neoplasms is Potentiated by Clinical Factors and Inflammatory Markers

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