Role of the tumor microenvironment in digestive neuroendocrine tumors

Cuny, Thomas; Herder, Wouter W. de; Barlier, Anne; Hofland, Leo J.

doi:10.1530/erc-18-0025

Cited by 15 publications

(15 citation statements)

References 194 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation is in accordance with the accumulating literature that attempts to unravel the immune landscape of PNENs and which reports a presence of TILs within the tumor microenvironment of PNENs, but mostly in very small numbers [41][42][43]. In addition, the loss of expression of MHC I class molecules and altered expression of immunomodulatory factors has been reported in PNENs and might allow them to evade control of the immune system [41,42]. Several of the master regulator proteins, differentially expressed proteins with an important role in tumorigenesis, that were identified by Alvarez et al in gastroenteropancreatic NENs (GEP-NENs) were immunomodulatory factors [44].…”

Section: Discussionsupporting

confidence: 91%

“…In general, a low percentage of TILs (≤5%) was observed with only three samples that had a percentage of TILs between 5% and 30%. This observation is in accordance with the accumulating literature that attempts to unravel the immune landscape of PNENs and which reports a presence of TILs within the tumor microenvironment of PNENs, but mostly in very small numbers [41][42][43]. In addition, the loss of expression of MHC I class molecules and altered expression of immunomodulatory factors has been reported in PNENs and might allow them to evade control of the immune system [41,42].…”

Section: Discussionsupporting

confidence: 91%

See 1 more Smart Citation

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

Boons

Vandamme

Ibrahim

et al. 2020

Cancers

View full text Add to dashboard Cite

DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation. However, the exact changes in DNA methylation between PNENs and the endocrine cells of the pancreas, their likely cell-of-origin, remain largely unknown. Recently, two subtypes of PNENs have been described which were linked to cell-of-origin and have a different prognosis. A difference in the expression of the transcription factor PDX1 was one of the key molecular differences. In this study, we performed an exploratory genome-wide DNA methylation analysis using Infinium Methylation EPIC arrays (Illumina) on 26 PNENs and pancreatic islets of five healthy donors. In addition, the methylation profile of the PDX1 region was used to perform subtyping in a global cohort of 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples. In our exploratory analysis, we identified 26,759 differentially methylated CpGs and 79 differentially methylated regions. The gene set enrichment analysis highlighted several interesting pathways targeted by altered DNA methylation, including MAPK, platelet-related and immune system-related pathways. Using the PDX1 methylation in 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples, two subtypes were identified, subtypes A and B, which were similar to alpha and beta cells, respectively. These subtypes had different clinicopathological characteristics, a different pattern of chromosomal alterations and a different prognosis, with subtype A having a significantly worse prognosis compared with subtype B (HR 0.22 [95% CI: 0.051–0.95], p = 0.043). Hence, this study demonstrates that several cancer-related pathways are differently methylated between PNENs and normal islet cells. In addition, we validated the use of the PDX1 methylation status for the subtyping of PNENs and its prognostic importance.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

Boons

Vandamme

Ibrahim

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…Such factors are increasingly appreciated to be implicated in pharmacological treatment efficacy/resistance, tumour aggressiveness, proclivity to metastasis and tumour growth. These have been extensively reviewed elsewhere [78,79].…”

Section: The Tumour Microenvironmentmentioning

confidence: 99%

“…By virtue of their expression of pro-angiogenic factors, including but not limited to VEGF, platelet-derived growth factor, fibroblast growth factor and angiopoietin-2 (more so in PanNEN) [78], NETs are highly vascularised, with a microvasculature network up to an order of magnitude denser than that observed in epithelial neoplasms. The "neoangiogenic switch" may be related to tumour-infiltrating immune cells, but this requires further investigation.…”

Section: The Tumour Microenvironmentmentioning

confidence: 99%

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

et al. 2019

View full text Add to dashboard Cite

The traditionally promulgated perspectives of neuroendocrine neoplasms (NEN) as rare, indolent tumours are blunt and have been outdated for the last 2 decades. Clear increments in their incidence over the past decades render them increasingly clinically relevant, and at initial diagnosis many present with nodal and/or distant metastases (notably hepatic). The molecular pathogenesis of these tumours is increasingly yet incompletely understood. Those arising from the small bowel (SB) or pancreas typically occur sporadically; the latter may occur within the context of hereditary tumour predisposition syndromes. NENs can also be associated with endocrinopathy of hormonal hypersecretion. Tangible advances in the development of novel biomarkers, functional imaging modalities and therapy are especially applicable to this sub-set of tumours. The management of SB and pancreatic neuroendocrine tumours (NET) may be challenging, and often comprises a multidisciplinary approach wherein surgical, medical, interventional radiological and radiotherapeu-tic modalities are implemented. This review provides a comprehensive overview of the epidemiology, pathophysiology, diagnosis and treatment of SB and pancreatic NETs. Moreover, we provide an outlook of the future in these tumour types which will include the development of precision oncology frameworks for individualised therapy, multi-analyte predictive biomarkers, artificial intelligence-derived clinical decision support tools and elucidation of the role of the microbiome in NEN development and clinical behaviour.According to SEER version 18, SBNEN and PanNEN incidences are currently estimated at 1.2 and 0.7 per 100,000, respectively [5]. The overall 20-year duration prevalence of all NEN is estimated at 171,321; SBNEN constituting 32,122 patients with 3-fold fewer PanNEN (10,707) [5]. Possible attributable factors for this increase evolving epidemiology include increased use of endoscopy and also improvements in the sensitivity of widely used imaging modalities, leading to increased detection of early-stage, asymptomatic disease [5].The median overall survival (OS) for NEN (irrespective of site and grade) is 9.3 years [5]. For SB (median OS: 14 years), this ranges from 70 months (advanced disease with distant metastases) to 170 months (localised disease) and from 30 months (Grade 3) to 160 months (Grade 1). For pancreas (median OS: 3.6 years): 21 months (advanced) to 235 months (localised disease) and from 15 months (Grade 3) to 140 months (Grade 1) [5].Multivariable analyses have identified that ethnicity, age, differentiation, stage and site all have statistically significant correlations with survival. In general, Caucasian ethnicity, age (< 50 years) and localised, well-differentiated NEN exhibit the best survival. SB tumour patients are approximately 1.5 times more likely to survive longer than those with PanNEN [19]. Many of these correlations are self-evident since they pertain to degree of malignancy, disease duration and patient performance status.OS (median 5-year) app...

show abstract

“…The tumor cell microenvironment includes tumor cells and other cells, such as fibroblasts, lymphocytes, macrophages, adipocytes, and other secreted factors, to form a unique tumor microenvironment system. An abnormal imbalance of the cell microenvironment often leads to tumorigenesis (16). It is suggested that molecules related to metabolic syndrome can accelerate the progression of endometrial cancer not only by acting directly on tumor cells but also by further remodeling the immune microenvironment of tumors.…”

Section: Introductionmentioning

confidence: 99%

The Role of Metabolic Syndrome in Endometrial Cancer: A Review

Yang

Wang

2019

Front. Oncol.

View full text Add to dashboard Cite

Endometrial cancer is one of the most common cancers of the female reproductive system. Although surgery, radiotherapy, chemotherapy, and hormone therapy can significantly improve the survival of patients, the treatment of patients with very early lesions and a strong desire to retain reproductive function or late recurrence is still in the early stages. Metabolic syndrome (MS) is a clustering of at least three of the five following medical conditions: central obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Obesity, diabetes and hypertension often coexist in patients with endometrial cancer, which increases the risk of endometrial cancer, also known as the “triple syndrome of endometrial cancer.” In recent years, epidemiological and clinical studies have found that MS associated with metabolic diseases is closely related to the incidence of endometrial cancer. However, the key molecular mechanisms underlying the induction of endometrial cancer by MS have not been elucidated to date. Characterizing the tumor metabolism microenvironment will be advantageous for achieving a comprehensive view of the molecular mechanism of metabolic syndrome associated with endometrial cancer and for providing a new target for the treatment of endometrial cancer. This review focuses on recent advances in determining the role of metabolic syndrome-related factors and mechanisms in the pathogenesis of endometrial cancer. We suggest that interfering with the tumor metabolic microenvironment-related molecular signals may inhibit the occurrence of endometrial cancer.

show abstract

Role of the tumor microenvironment in digestive neuroendocrine tumors

Cited by 15 publications

References 194 publications

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

The Role of Metabolic Syndrome in Endometrial Cancer: A Review

Contact Info

Product

Resources

About