Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

Walenkamp, Annemiek; Crespo, Guillermo; Maya, F Fierro; Fossmark, Reidar; Igaz, Péter; Rinke, Anja; Tamagno, Gianluca; Vitale, Giovanni; Öberg, Kjell; Meyer, Tim

doi:10.1530/erc-14-0106

Cited by 46 publications

(38 citation statements)

References 145 publications

(154 reference statements)

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“…The complexity of cancer has been reduced to a defined number of underlying principles (Hanahan & Weinberg 2000) which have been recently updated (Hanahan & Weinberg 2011). This approach has been transposed to NET disease (Walenkamp et al 2014). Using networking analysis, cancer hallmarks can be signified by molecular networks which have the advantage of allowing quantification and computational modeling .…”

Section: Discussionmentioning

confidence: 99%

Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status

Kidd¹,

Drozdov²,

Modlin³

2015

Endocrine-Related Cancer

128

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Section: Discussionmentioning

confidence: 99%

Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status

Kidd¹,

Drozdov²,

Modlin³

2015

Endocrine-Related Cancer

128

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“…However, the literature remains lacking in therapeutically useful knowledge [1,12,13,14,15]. As part of this study, we compared NLR and PLR with respect to the parameters with prognostic importance for NETs, and the subsequent survival analysis presented significant NLR and PLR findings for NETs.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of the Pretreatment Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio for Patients with Neuroendocrine Tumors: An Izmir Oncology Group Study

Salman

Kazaz²,

Varol

et al. 2016

Chemotherapy

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Background: Several studies evaluating the prognostic factors of gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs) have been published. The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have been accepted as prognostic factors for cancer patients. Materials and Methods: This study included 132 patients diagnosed with GEP-NETs. Peripheral blood samples were collected before the pretreatment period. Results: NLR and PLR were increased as the grade increased in NETs. The embryonic origin analysis revealed higher NLR and PLR rates in NETs of foregut origin. NLR and PLR were also higher in pancreatic NET patients compared to the gastroenteric NET patients. Analysis of NETs by TNM indicated that an advanced stage was accompanied by significantly higher NLR and PLR. We found a strong negative correlation between progression-free survival and NLR and PLR. Conclusion: The study verified that NLR and PLR are simple laboratory findings that can be used to identify NETs with a worse outcome.

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“…Recent sequencing studies have indicated that pathways regulating chromatin remodelling and epigenetic modifications are frequently altered in NETs [18,19]. As a result, targeting of deregulated epigenetic mechanisms has emerged as a possible novel treatment strategy in NETs [20,21]. Valproic acid (VPA), an inhibitor of class I and class IIa HDACs, has recently been tested in phase II studies on patients with metastatic NETs with promising results [22].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

et al. 2015

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Background/Aims: Histone deacetylases (HDACs) modulate lysine acetylation on histones and are frequently deregulated in cancer. HDAC inhibitors with potent anti-tumour effects have been developed and are now being tested in clinical trials. The aim of this study was to investigate the effects of valproic acid (VPA), an inhibitor of class I and class IIa HDACs, on neuroendocrine tumour (NET) cell growth. Methods: Three NET cell lines, GOT1 (small intestinal), KRJ-I (small intestinal), and BON (pancreatic), were treated with VPA and examined with respect to cell viability, cell cycle arrest, apoptosis, and global transcriptional response. Results: We found that VPA induced a dose-dependent growth inhibition of NET cells in vitro, which was mainly due to activation of extrinsic and intrinsic apoptotic pathways. VPA induced a major transcriptional response by altering the expression of 16-19% of the protein-coding genes in NET cell lines. Pathway analysis allowed the prediction of alterations in key regulatory pathways, e.g. activation of TGF-β1, FOXO3, p53 signalling, and inhibition of MYC signalling. Analysis of GOT1 xenografts showed reduced growth and reduced Ki-67 index, as well as an increase in apoptosis and necrosis after VPA treatment. Conclusions: We found that VPA treatment has a cytotoxic effect on NET cells of intestinal and pancreatic origin. There are several mechanisms by which VPA kills NET cells, which suggests the possibility of combination therapy. We propose that epigenetic therapy with HDAC inhibitors should be evaluated further in patients with NET disease.

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Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

Cited by 46 publications

References 145 publications

Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status

Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status

Prognostic Value of the Pretreatment Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio for Patients with Neuroendocrine Tumors: An Izmir Oncology Group Study

Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

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