interleukin-8 and Neuroendocrine-Tumors

After years of limited progress in the treatment of patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs), strategies using targeted agents have been developed on the basis of increased knowledge of the biology of these tumors. Some of these agents, targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway, have shown efficacy in randomized clinical trials. The tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus have received international approval for the treatment of advanced well differentiated pancreatic NETs after showing survival benefit in randomized phase III trials. There is now an imperative need to identify biomarkers of the biologic activity of such targeted therapies in specific disease contexts, as well as new markers of response and prognosis. This approach may allow rational development of drugs and early identification of patients who may obtain benefit from treatments. In this article, we review recent developments in circulating biomarkers of the clinical benefit of targeted therapies for GEP-NET, including soluble proteins and circulating cells, with an emphasis on sunitinib. No validated molecular biomarkers are yet integrated into clinical practice for sunitinib in NET, although some markers have shown correlation with clinical outcomes and may be implicated in resistance. The VEGF-pathway proteins and interleukin-8 (IL-8) are possibly prognostic in GEP-NET; other possible soluble markers of the activity of sunitinib and everolimus include stromal cell-derived factor 1α, chromogranin A, and neuron-specific enolase. We additionally discuss treatment-induced modulation of circulating endothelial cells and progenitors and subpopulations of cells of the myeloid lineage. These candidate markers should be considered in the development of future combination or sequential therapies.

Topics: Antineoplastic Agents; Biomarkers, Pharmacological; Biomarkers, Tumor; Everolimus; Gastrointestinal Neoplasms; Humans; Indoles; Interleukin-8; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyrroles; Sirolimus; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

The factors triggering pancreatic neuroendocrine tumor (PanNET) progression are largely unknown. Here we investigated the role and mechanisms of the sumoylation enhancing protein RSUME in PanNET tumorigenesis. Immunohistochemical studies showed that RSUME is strongly expressed in normal human pancreas, in particular in β-cells. RSUME expression is reduced in insulinomas and is nearly absent in other types of PanNETs suggesting a role in PanNET tumorigenesis. In human pancreatic neuroendocrine BON1 cells, RSUME stimulates hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A), which are key components of tumor neovascularisation. In contrast, RSUME suppresses nuclear factor-κB (NF-κB) and its target interleukin-8 (IL-8). Correspondingly, PanNET cells with RSUME knockdown showed decreased HIF-1α activity and increased NF-κB and IL-8 production leading to a moderate reduction of VEGF-A release as reduced HIF-1α/VEGF-A production is partly compensated by NF-κB/IL-8-induced VEGF-A. Notably, RSUME stabilizes the tumor suppressor PTEN, which is frequently lost in PanNETs and whose absence is associated with metastasis formation. In vivo orthotopic transplantation of PanNET cells with or without RSUME expression into nude mice showed that PanNETs without RSUME have reduced PTEN expression, grow faster and form multiple liver metastases. In sum, RSUME differentially regulates key components of PanNET formation suggesting that the observed loss of RSUME in advanced PanNETs is critically involved in PanNET tumorigenesis, particularly in metastasis formation.

Topics: Animals; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Female; HEK293 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Interleukin-8; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; Neuroendocrine Tumors; NF-kappa B; Pancreatic Neoplasms; Sumoylation; Transcription Factors; Vascular Endothelial Growth Factor A

Inflammatory mediators influence tumour progression. IL-8 has been shown to have pro-angiogenic, mitogenic and motogenic effects and several studies have demonstrated the expression of IL-8 by various human pancreatic cancer cell lines.. The expression of IL-8 and IL-8 receptors was studied in 52 pancreatic adenocarcinomas and 52 pancreatic neuroendocrine tumours using immunohistochemistry. The expression of IL-8 and IL-8 receptors was also assessed in eight pancreatic adenocarcinomas and seven neuroendocrine tumours in comparison to normal pancreatic tissue using real time quantitative PCR (qRT-PCR).. Immunohistochemical analysis of the expression of IL-8, IL-8RA and IL-8RB in 52 pancreatic adenocarcinomas demonstrated expression in 25%, 75% and 79% of pancreatic adenocarcinomas, respectively. There was no statistically significant correlation between expression and tumour grade and stage for any of the three antigens. IL-8, IL-8RA and IL-8RB expression was detected in 21%, 63% and 92% of 52 pancreatic neuroendocrine tumours. There was no statistically significant correlation between expression and tumour grade for any of the three antigens. Using qRT-PCR, the expression of each of IL-8, IL-8RA and IL-8RB mRNA was increased in 75% of pancreatic adenocarcinomas. IL-8, IL-8RA and IL-8RB mRNA expression was also increased in 57%, 43% and 29% of pancreatic neuroendocrine tumours. Quantitatively, there was a significant increase in expression level of IL-8 in tumours of both types in comparison to normal pancreatic tissue (38.5-fold in adenocarcinomas and 43.9-fold in neuroendocrine tumours). There was also increased expression of IL-8RA in both tumour types, with higher levels in adenocarcinomas, 2.7-fold and neuroendocrine tumours, 1.7-fold. IL-8RB was slightly increased in adenocarcinomas in comparison to normal pancreas (1.4-fold), but the expression was decreased in neuroendocrine tumours compared with normal pancreas (0.9-fold).. This is the first study to show that IL-8 and IL-8 receptors are upregulated in both pancreatic adenocarcinomas and neuroendocrine tumours, and indicate this signalling pathway may modulate tumour behaviour through autocrine and/or paracrine loops.

Topics: Adenocarcinoma; Adult; Aged; Female; Humans; Interleukin-8; Male; Middle Aged; Neuroendocrine Tumors; Pancreas; Pancreatic Neoplasms; Receptors, Interleukin-8; Signal Transduction; Young Adult

The growth behaviour of well-differentiated neuroendocrine carcinomas of the gastro-entero-pancreatic system varies greatly and parameters predicting their prognosis are lacking. The aim of our study was to investigate whether tumour growth could be correlated with the release of proangiogenic factors into the circulation.. Circulating vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), basic fibroblast growth factor (bFGF) and angiogenin were measured in 38 patients with advanced neuroendocrine carcinomas and compared to healthy age-matched controls. In 20 patients, angiogenic cytokine levels were measured at consecutive time points and correlated to tumour progression as assessed by abdominal CT scan, MRI and chromogranin A levels.. VEGF levels were elevated in patients compared to controls (P < 0.002) and clearly associated with tumour progression (P < 0.005). Angiogenin levels were significantly higher in patients than in controls (P < 0.003), while high IL-8 levels were predictive of shorter survival. Angiogenin and bFGF levels were correlated neither with tumour growth nor with patient survival.. VEGF and IL-8 are associated with tumour progression and might qualify as markers of prognosis and therapy control in patients with neuroendocrine carcinomas. Our results support the notion that specific anti-angiogenic therapies should be evaluated in neuroendocrine carcinoma patients.

Topics: Adult; Aged; Angiogenic Proteins; Biomarkers, Tumor; Case-Control Studies; Chi-Square Distribution; Female; Fibroblast Growth Factor 2; Humans; Interleukin-8; Intestinal Neoplasms; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Predictive Value of Tests; Ribonuclease, Pancreatic; Stomach Neoplasms; Survival Rate; Vascular Endothelial Growth Factor A

Chemokines effect their proinflammatory and growth regulatory roles through interaction with serpentine receptors. One such receptor, CXCR2, binds multiple CXC chemokines, including interleukin 8, GRO-alpha, GRO-beta, GRO-gamma, and NAP-2. We have previously identified CXCR2 expression on myeloid cells, notably mature granulocytes, and projection neurons.. To determine the expression of CXCR2 by cells of the neuroendocrine system.. Archival specimens from normal neuroendocrine tissues and their malignant counterparts were analyzed by immunohistochemistry with monoclonal antibodies specific for CXCR1 and CXCR2.. Immunohistochemical analysis revealed high-level expression of CXCR2 by cells in the pituitary, adrenal medulla, pancreatic islets, thyroid C cells, scattered Kulchitsky cells in the bronchi, and counterpart neuroendocrine cells in the stomach, small bowel, colon, and appendix. Neuroendocrine neoplasms that demonstrated high-level CXCR2 expression included (1) primary carcinoids localized to the stomach, small bowel, colon, appendix, fallopian tube, ovary, and lung; (2) atypical carcinoids of the lung; (3) metastatic carcinoids; (4) pituitary adenomas; (5) pheochromocytomas; and (6) medullary carcinomas of the thyroid. Small cell lung carcinomas, large cell neuroendocrine carcinomas of the lung, small cell carcinoma of the cervix, Merkel cell carcinomas, neuroblastomas, and malignant melanomas lacked evidence of CXCR2 expression.. The expression of CXCR2 by normal neuroendocrine cells and neoplastic counterparts that have retained phenotypic features of this differentiation program suggests that chemokines may play an important role in functions that are characteristic of this cell type. In addition, this raises the possibility that chemokines may modulate secretion of biologically active products of these cells and their neoplastic counterparts.

Topics: Antibodies, Monoclonal; Antigens, CD; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Humans; Immunohistochemistry; Interleukin-8; Neoplasms; Neuroendocrine Tumors; Neurosecretory Systems; Organ Specificity; Receptors, Chemokine; Receptors, Interleukin; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Reference Values