Tumor-infiltrating platelets predict postoperative recurrence and survival in resectable pancreatic neuroendocrine tumor

Xu, Shuai; Xu, Hua; Wang, Wen Quan; Li, Shuo; Li, Hao; Li, Tian Jiao; Zhang, Wu Hu; Liu, Liang

doi:10.3748/wjg.v25.i41.6248

Cited by 23 publications

(19 citation statements)

References 28 publications

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“…Platelet-related pathways were also enriched, which has been observed previously by Tirosh et al in familial PNENs [12]. It has been shown that PNEN patients with tumor-associated platelets have a worse prognosis, possibly through modulation of the platelet behavior [38]. Another enriched gene set was olfactory receptors.…”

Section: Discussionsupporting

confidence: 71%

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

Boons

Vandamme

Ibrahim

et al. 2020

Cancers

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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.

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Section: Discussionsupporting

confidence: 71%

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

Boons

Vandamme

Ibrahim

et al. 2020

Cancers

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“…While it is well known that different components of the tumor microenvironment play a crucial role in enhancing cancer invasiveness and metastatic spreading, little is understood in this regard in NETs. Preliminary evidence from our group indicates that cancer-associated fibroblasts stimulate both EMT and in vitro migration of NET cells, while tumor-infiltrating platelets, a key regulator of EMT, have been recently demonstrated to predict poor outcomes and early relapse in patients with resected panNETs [32].…”

Section: Bone Metastases In Nets: Molecular Pathogenesismentioning

confidence: 99%

Bone Metastases in Neuroendocrine Tumors: Molecular Pathogenesis and Implications in Clinical Practice

et al. 2020

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Skeletal colonization is often regarded as a rare event in patients with neuroendocrine tumors (NETs) although both national registries and retrospective series report an incidence of bone metastases as high as 20% in subjects with advanced disease. While the biological mechanisms leading to bone metastatic colonization in NETs have been poorly investigated so far, key steps of osteotropic mechanisms, including the epithelial-to-mesenchymal transition, preparation of the premetastatic niche, migration of circulating tumor cells towards the bone marrow as well as the resulting alterations of the skeletal metabolism, are likely to operate also during the development of NET bone metastases. The skeleton involvement by NETs has a detrimental impact on both quality of life and patients’ prognosis, leading to pain in the majority of symptomatic subjects. While it is currently unclear whether or not the earlier recognition of bone involvement by PET/CT imaging techniques employing ⁶⁸Ga-DOTA-conjugated peptides might improve outcomes through the exploitation of timely treatments, the management of bone-colonizing NETs is today based only on clinical experience from other osteotropic tumors. Here, we summarize the fundamental molecular mechanisms driving bone colonization and revisit both established and novel treatments for patients with bone metastatic NETs.

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“…Current clinical drugs that are used to treat nonfunctional pNETs mainly target tumor cells ( 7 , 8 ). However, the tumor microenvironment in pNETs, including immune cells, stromal cells, and extracellular substances, has an important role in tumor progression ( 9 , 10 ). The roles of immune cells in tumor progression have been reported in many tumors, and corresponding immunotherapies have been recommended in clinical treatment guidelines or are being evaluated in clinical trials for certain tumors ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Neutrophil Extracellular Traps and Macrophage Extracellular Traps Predict Postoperative Recurrence in Resectable Nonfunctional Pancreatic Neuroendocrine Tumors

et al. 2021

Front. Immunol.

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BackgroundExtracellular traps (ETs) and tumor-infiltrating immune cells can contribute to disease progression. The clinical significance of tumor-infiltrating neutrophils and macrophages and related extracellular traps in pancreatic neuroendocrine tumors (pNETs) has not been fully elucidated. This study aimed to explore the prognostic value of tumor infiltration and ET formation by neutrophils and macrophages in pNETs.MethodsA total of 135 patients with radical resection of nonfunctional pNETs were analyzed retrospectively. Immunohistochemistry and immunofluorescence were utilized to stain tumor tissue sections. The recurrence-free survival (RFS) of subgroups determined by Kaplan-Meier analysis was compared with the log-rank test. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. A nomogram was established to predict 3-year RFS.ResultsPatients with high tumor-infiltrating neutrophils or macrophages or positive expression of neutrophils ETs or macrophage ETs displayed worse RFS (all p<0.05). Moreover, univariate and multivariate Cox regression analyses showed that neutrophil and macrophage infiltration and ETs were independent prognostic factors for RFS (all p<0.05). A combined parameter including WHO grade, TNM stage, tumor-infiltrating neutrophils and macrophages, and neutrophil and macrophage ETs had the highest C-index (0.866) and lowest Akaike information criteria (326.557). The calibration plot of nomogram composed of the combined parameter exhibited excellent prognostic values for 3-year RFS.ConclusionsInfiltration and ETs by neutrophils and macrophages can be used as biological indicators of patient prognosis, suggesting the treatment potential for targeting those in nonfunctional pNETs.

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Tumor-infiltrating platelets predict postoperative recurrence and survival in resectable pancreatic neuroendocrine tumor

Cited by 23 publications

References 28 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

Bone Metastases in Neuroendocrine Tumors: Molecular Pathogenesis and Implications in Clinical Practice

Neutrophil Extracellular Traps and Macrophage Extracellular Traps Predict Postoperative Recurrence in Resectable Nonfunctional Pancreatic Neuroendocrine Tumors

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