Materiały źródłowe

• #1 Pathophysiology and Treatment of Pancreatic Neuroendocrine Neoplasms (PNENS): New Developments – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279074/

  Pancreatic neuroendocrine neoplasms (PNENs) are a heterogenous group of relatively rare pancreatic malignancies with a unique biology and pathophysiology. […] Improvements in and a wider availability of high-quality imaging techniques and a well-established classification system are believed to be major factors in the increasing incidence of PNENs. […] PNENs can be divided into both functional (10-40%) and non-functional (60-90%) neoplasms. […] PNENs are also classified based on the tumor-node-metastasis (TNM) classification which estimates the prognosis of the tumors based on the anatomy of the tumor. […] PNENs are also often referred to as islet cell tumors since it is presumed that they arise from the islets of Langerhans. […] Others in turn suggest that PNENs develop from multipotent pancreatic progenitor (MPP) cells in the ductal and islet regions of the pancreas that would be able to generate new pancreatic islet cells.

• #1 Pathophysiology and Treatment of Pancreatic Neuroendocrine Neoplasms (PNENS): New Developments – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279074/

  Since genes such as MEN1, DAXX and ATRX are of importance in several epigenetic regulatory processes, it was extremely likely that also epigenetic alterations commonly occur in PNENs. […] In fact, both in hereditary and sporadic PNENs promotor hypermethylation is observed in tumor suppressor genes, which is associated with silencing of gene expression. […] The gold standard for diagnosing PNENs remains an immunohistochemical examination of the tumor tissue, but imaging and serum markers are also extremely important in the diagnostic process. […] The clinical presentation often determines the sequence of examinations. […] To correctly classify PNENs, tumor morphology and proliferation rates (Ki-67 and mitotic index) should be evaluated in tissue biopsies. […] Regardless of whether a PNEN is functional or non-functional, imaging is critical to assess the extent of the disease by localizing the primary tumor and identifying the size of metastatic disease.

• #2 Epidemiology, Pathogenesis, and Prognosis of Pancreatic Neuroendocrine Tumors | SpringerLink

  https://link.springer.com/10.1007/978-3-030-37482-2_36-1

  Pancreatic neuroendocrine tumors (NETs) account for 7% of pancreatic tumors. […] The three most common impaired signaling pathways in pancreatic NETs include the PI3K/AKT/mechanistic target of rapamycin (mTOR) pathway, T53/Rb pathway, and chromatin remodeling pathway. […] Considering mTOR pathway plays a crucial role in pathogenesis of NETs, mTOR inhibitor for management of pancreatic NETs has been shown beneficial.

• #2 Pathophysiology and Treatment of Pancreatic Neuroendocrine Neoplasms (PNENS): New Developments – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279074/

  However, it remains unclear whether these cells originate in the islets or whether they migrate from the pancreatic ducts to subsequently transform into endocrine cells. […] The actual origin and location of the MPP that can evolve into islet cells is not known to date and thus needs to be further investigated for a better understanding of the potential origin of PNENs. […] Although PNENs typically occur sporadically, approximately 10-20% of them develop in the context of hereditary syndromes. […] Through next-generation sequencing of PNENs, it became apparent that there are distinct genetic differences, strongly depending on differentiation and functionality of the tumor. […] In NF-PNENs, on the other hand, somatic mutations were most commonly identified in MEN1 (44.1%) followed by DAXX (25%) and ATRX (17.6%).

• #3 Pancreatic neuroendocrine tumors: A review of serum biomarkers, staging, and management

  https://www.wjgnet.com/1007-9327/full/v26/i19/2305.htm

  Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of tumors with complicated treatment options that depend on pathological grading, clinical staging, and presence of symptoms related to hormonal secretion. […] Reliable knowledge of the histologic characteristics, biological mechanism, and definition criteria of pNETs is a prerequisite for diagnosis, staging, treatment, and prognosis. […] Therefore, the aim of this review is to provide an overview of the serum biomarkers and controversial pathologic grading and clinical staging criteria and give an updated review of the comprehensive treatment of pNETs. […] Despite these advances, pNETs, as a distinct clinical entity, remain largely unexplored. […] The optimal timing of local control intervention, planning of sequential therapies, and implementation of multidisciplinary care remain pending. […] With a clearer understanding of the genetic and molecular pathogenesis of pNETs, the next decade of studies will provide new insight into early diagnosis, precise grading and staging systems, novel drug therapy, and optimal combination with local control therapies.

• #4 Pancreatic neuroendocrine tumors | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/pancreatic-neuroendocrine-tumours-2?lang=us

  Pancreatic neuroendocrine tumors (pNET), also known as endocrine tumors of the pancreas, arise from pancreatic ductal stem cells and include some distinct tumors that match the cell type of origin. […] It has since been shown that these tumors derive from ductal pluripotent stem cells, and „neuroendocrine tumor” is now preferred. […] Neuroendocrine tumors are classically defined by the expression of markers of neuroendocrine differentiation (including chromogranin A and synaptophysin) and hormone production. […] The term „syndromic” may be preferred over „functioning” since it is becoming increasingly clear that most tumors are functional (i.e. produce hormones), but either do not produce enough hormone or produce an ineffective form of the hormone, so that they may not produce a clinical syndrome. […] Biological behavior also depends on the cell of origin.

• #5 An Overview of Pancreatic Neuroendocrine Tumors | IntechOpen

  https://www.intechopen.com/chapters/75803

  Pancreatic neuroendocrine tumors are a group of endocrine tumors that constitute 7% of all pancreatic neoplasms. […] In the past, there was paucity of scientific data available about the diagnosis and treatment strategy of these neoplasms but in recent years, ongoing research has inferred much data regarding classification, prognostic stratification and therapy of pancreatic neuroendocrine tumors. […] As such pNETs were classically thought to arise from pancreatic islet cells or the islets of Langerhans, hence the term islet cell tumors was coined. […] However, current theory says that pNETs in fact arise from the APUD (amine precursor uptake and decarboxylation) cells. […] The most common genes involved in pancreatic neuroendocrine tumors are mentioned in Table 4. […] Other specific genes suggested to be implicated in the etiopathogenesis of NETs include BIN1, Serpine 10, BST2, IGFBP3, LCK, MET, fibronectin, PDGF, IGF- 1, fibroblast growth factor, TGF-alpha andbeta, EGFR, and stem cell factor receptor.

• #5 An Overview of Pancreatic Neuroendocrine Tumors | IntechOpen

  https://www.intechopen.com/chapters/75803

  Multiple studies have elucidated the underlying genetic mechanism regarding molecular development and progression of these tumors but still much remains unexplored in this area. […] Loss of chromosomes 3q, 6pq, and 10 pq, and gains of 5q, 12a, 18q, and 20q is associated with malignant behavior in these tumors. […] Most recent advancements in assessment of pancreatic NET is the development of microRNA profiling which corresponds to various proliferation indices and also propensity of tumor to cause local spread and distant metastasis. […] There is very limited data available regarding microRNA profiling of pNET. […] Circulating tumor cell count also plays an important role in delineating the prognostic value of pNETs, especially before and during the treatment. […] Further placental growth factor (PIGF) is also evaluated as a prospective biomarker in NET.

• #6 Molecular pathology of pancreatic neuroendocrine tumors – Chen – Journal of Gastrointestinal Oncology

  https://jgo.amegroups.org/article/view/416/html

  Most pancreatic neuroendocrine tumors occur sporadically (90%). However, they may be part of hereditary syndromes: multiple endocrine neoplasia type 1 (MEN1 syndrome), von Hippel-Lindau disease (VHL), von Recklinghausens disease or neurofibromatosis type 1 (NF-1), and tuberous sclerosis (TSC). […] In these cases, the underling genetic abnormalities play a significant role in the development of PETs which are often found to be multifocal. The pathological features of familial/hereditary PETs are generally similar to the sporadic form, although PETs arising in VHL syndrome patients may have clear cell features. […] Germline loss-of-function MEN-1 mutation leads to the formation of numerous microadenomas, mostly resulting in non-functional PETs and insulinomas. NF-1 or TSC1/2 mutations result in loss of function of their protein products neurofibromin and tuberin, respectively. Notably, the intact proteins suppress the function of a common target, namely mTOR (mammalian target of rapamycin).

• #6 Molecular pathology of pancreatic neuroendocrine tumors – Chen – Journal of Gastrointestinal Oncology

  https://jgo.amegroups.org/article/view/416/html

  Furthermore, hypoxia-induced factor (HIF)-dependent mTOR activation links disturbed mTOR signaling to VHL disease. mTOR is a key regulator of cell growth and integrates a wide variety of cellular inputs, such as growth factors, nutrients, energy status and hypoxia-induced stress, thus, it is a good therapeutic target for PETs. […] Somatic MEN1 gene mutations accompanied by a loss of the wild-type allele are demonstrated in 10-27% of insulinomas and 39-45% of gastrinomas. The rate of 11q13 loss of heterozygosity (LOH) in sporadic PETs is about 46%, and LOH is not always accompanied by somatic mutation, therefore, other mechanisms of MEN1 gene inactivation or other genes may play a role in sporadic tumor development. […] Studies indicate that additional onco/suppressor genes may reside at 11q distal to the MEN1 gene and may play a role in the pathogenesis of PETs.

• #6 Molecular pathology of pancreatic neuroendocrine tumors – Chen – Journal of Gastrointestinal Oncology

  https://jgo.amegroups.org/article/view/416/html

  Homozygous deletion or hypermethylation of p16/MTS1 or a deletion of the p16INK4a tumor suppressor gene on chromosome 9p21 was demonstrated in sporadic gastrinomas, but not in insulinomas. […] Both benign and malignant insulinomas demonstrated high LOH rates for markers on chromosome 22q (93%). […] Cyclin D1 overexpression was observed by both immunohistochemistry and northern blot analysis in 43% of PETs. […] High-grade PETs share a large fraction of gene abnormalities with conventional cancers, the most frequent abnormality being in the cell-cycle key regulatory gene TP53. […] In summary, the data suggest that multiple genetic defects may accumulate and result in PETs progression and malignancy. Molecular genetic tests are relevant to the pathogenesis, however, these tests are currently not useful in the diagnostic process. […] The epigenetic modifications and differential microRNA-expression mechanistically involved in the dysregulated signaling pathways of PETs are under further investigation.

• #6 Molecular pathology of pancreatic neuroendocrine tumors – Chen – Journal of Gastrointestinal Oncology

  https://jgo.amegroups.org/article/view/416/html

  Sporadic endocrine pancreatic tumors: molecular genetics and pathobiology genome-wide analyses by comparative genomic hybridization (CGH) indicate that the chromosomal losses occur slightly more frequently than gains, whereas amplifications are uncommon. Losses of chromosome 1 and 11q as well as gains of 9q appear to be early events in the development of pancreatic tumors. […] These findings point towards a tumor suppressor pathway and chromosomal instability as important mechanisms associated with malignancy in pancreatic endocrine tumors. […] Gains of chromosome 4 and losses of 6q were observed in about 50% of functioning tumors, the majority being insulinomas, with a size less than 2 cm. […] Recent studies using genome-wide single nucleotide polymorphism (SNP) analysis showed that about 30-40% of pancreatic endocrine tumors had high genetic imbalances defined by chromosomal aberrations.

• #7 The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours in: Endocrine-Related Cancer Volume 26 Issue 9 (2019)

  https://erc.bioscientifica.com/view/journals/erc/26/9/ERC-19-0175.xml

  Although various prognostic indicators and classification systems evolved over time have been clinically useful, they have their own inherent limitations and, most importantly, they do not reflect the biological and clinical heterogeneity of PanNETs. Such heterogeneity is more pronounced in G1 and G2 tumours that, unlike the predictable lethality of G3 NECs, have a variable clinical course ranging from indolent to aggressive. […] Somatic mutations in MEN1 are frequently detected in both functional and non-functional sporadic PanNETs and are commonly associated with LoH of the remaining WT allele, consistent with its role as a TSG. […] Approximately 43% of tumours were found to carry mutations in DAXX (25%) or ATRX (17.6%). […] The fact that mutations in DAXX/ATRX occur in a mutually exclusive fashion in the majority of cases indicates that both belong in the same pathway and is consistent with common functional roles in apoptosis, chromatin remodelling and telomere maintenance.

• #7 The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours in: Endocrine-Related Cancer Volume 26 Issue 9 (2019)

  https://erc.bioscientifica.com/view/journals/erc/26/9/ERC-19-0175.xml

  Dysregulation of the mTOR pathway is an intrinsic characteristic of PanNETs and has been successfully targeted by the drug everolimus. […] Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. […] Collectively, these findings highlight that dysregulation of the PI3K/Akt/mTOR pathway is an innate characteristic of a significant proportion of PanNETs. […] The most comprehensive genomic study of PanNETs to date identified five, whole-genome-derived mutational signatures from 98 G1/G2 PanNETs. […] The ALT phenotype has been described in other human cancers including neuroblastomas, paediatric glioblastomas, oligodendrogliomas and medulloblastomas.

• #7 The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours in: Endocrine-Related Cancer Volume 26 Issue 9 (2019)

  https://erc.bioscientifica.com/view/journals/erc/26/9/ERC-19-0175.xml

  Recent higher detection frequencies have reignited the interest in NET research leading to concentrated efforts to decipher their molecular landscape with recent findings holding the promise of shaping the future of NET research. Recurrent schemes have emerged from various studies all pointing towards key driving roles of the MEN1/DAXX/ATRX/ALT axis and genes in the mTOR and DNA damage pathways in disease pathogenesis alongside a plethora of chromosomal and telomere alterations and a highly dysregulated epigenetic machinery.

• #8 Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

  https://www.mdpi.com/2072-6694/13/20/5117

  Whole exome sequencing of non-familial pNETs revealed inactivating-to-missense mutations in either ATRX or DAXX in up to 65% of tumors, predicting tumor suppressive roles in pNET pathogenesis. […] The TP53 gene, which encodes the p53 tumor suppressor, is rarely mutated in pNETs. However, evidence suggests loss of p53 activity via alterations in its regulators is critical for pNET genesis. […] The importance of reduced p53 tumor suppressive activity in driving pNET pathogenesis is supported by several genetically engineered pNET animal models. […] Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene located on chromosome 3p25.5 cause an autosomal dominant tumor syndrome called VHL disease. […] The common VHL-associated pancreatic lesions are cysts and cystadenomas, which are benign in nature and found in 35–75% individuals. About 12–17% of VHL patients also develop pNETs, which are almost invariably non-functional and have metastatic potential correlating to the primary tumor size.

• #8 Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

  https://www.mdpi.com/2072-6694/13/20/5117

  The molecular pathogenesis of pNETs is only partially understood. By comparison, much more is known about pancreatic ductal adenocarcinomas (PDACs), the most common type of pancreatic cancer, which arise from exocrine cells and are primarily driven by KRAS activation. Several groups have conducted whole genome and exome sequencing of patient-derived pNETs to gain more insight into genetic alterations driving their development. One of the major conclusions has been that pNETs, unlike PDACs, have a low mutational burden. These and other molecular profiling studies, along with functional investigations performed in pNET cells and mouse models, have identified the most frequently altered, biologically relevant genes and pathways underlying the pathogenesis of familial and sporadic pNETs. […] The MEN1 gene encodes a 610-amino acid nuclear scaffold protein called menin, which plays an important role in chromosomal remodeling and gene transcription. Inheritance of germline mutations in one MEN1 allele from either parent leads to a familial autosomal dominant tumor syndrome called multiple endocrine neoplasia type 1 (MEN 1). Of all the different familial causes of pNETs, MEN1 syndrome remains the most frequent.

• #8 Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

  https://www.mdpi.com/2072-6694/13/20/5117

  Over 90% of MEN1 patients exhibit one or more different types of endocrine tumors by the age of 50. This mainly includes parathyroid (with a frequency of 95–100%), pancreatic (80–100%), and pituitary (54–64%) tumors. Nearly all MEN1 patients (80–100%) develop NF-pNETs, which remain small and asymptomatic in most individuals. […] In addition to its prominent role in familial pNETs, somatic MEN1 mutations are arguably the most frequent genetic event found in sporadic pNETs. Whole exome sequencing revealed MEN1 somatic mutations are present in 40–56% of sporadic pNETs, far exceeding the incidence of alterations in any other single gene within these tumors. […] Aberrant activation of oncogenic PI3K-Akt-mTOR pathway is implicated in both familial and sporadic pNETs. Inherited mutations in TSC2 (Tuberous Sclerosis Complex 2) and PTEN tumor suppressors, key negative regulators of this oncogenic pathway, lead to autosomal dominant, multisystem disorders in which a small percentage of individuals develop pNETs.

• #8 Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

  https://www.mdpi.com/2072-6694/13/20/5117

  The importance of PI3K-Akt-mTOR pathway activation in sporadic pNETs is well established and clinically relevant. Whole genome sequencing studies have revealed mutations in mTOR pathway genes including PTEN, TSC2, PIK3CA, and DEPDC5 in 12–25% sporadic pNETs. […] Mounting evidence implicates the role of the INK4A/ARF (originally called CDKN2A) gene locus and retinoblastoma 1 (RB1) tumor suppressor pathway in pNET pathogenesis. […] Inactivating p16INK4a gene alterations are common in pNETs. Several studies reveal homozygous deletions of the INK4A gene or hypermethylation of its promoter 5′ CpG island in the vast majority (up to 92%) of pNETs comprising gastrinomas and non-functional PNETs. […] Mutations in ATRX and DAXX have been frequently observed in pNETs. The ATRX protein is a component of heterochromatin bearing an ATPase/helicase-like domain characteristic of the SNF2 family of chromatin remodeling proteins.

• #8 Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

  https://www.mdpi.com/2072-6694/13/20/5117

  The prognostic significance of VEGF expression levels and angiogenic status of pNETs seems to be context dependent. […] The importance of targeting multiple pathways in pNET therapy is underscored by the need for combination therapies that can overcome resistance mechanisms. […] In summary, a deeper understanding of the molecular mechanisms driving pNET pathogenesis is essential for the development of new therapeutic strategies.

• #9 Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8533967/

  The TP53 gene, which encodes the p53 tumor suppressor, is rarely mutated in pNETs. […] However, evidence suggests loss of p53 activity via alterations in its regulators is critical for pNET genesis. […] The common VHL-associated pancreatic lesions are cysts and cystadenomas, which are benign in nature and found in 35-75% individuals. […] About 12-17% of VHL patients also develop pNETs, which are almost invariably non-functional and have metastatic potential correlating to the primary tumor size.

• #10

  https://journals.lww.com/md-journal/fulltext/2023/11170/a_review_of_functional_pancreatic_neuroendocrine.124.aspx

  The high rate of MEN1 mutations observed in both sporadic and syndromic PanNETs provides strong evidence that mutation of MEN1 plays a crucial role in pathogenesis. […] The most common genetic event seen in sporadic PanNETs are MEN1 somatic mutations, which are present in 40 to 56% of cases. […] DAXX and ATRX are implicated in chromatin stabilization, specifically in relation to telomeric chromatin. […] Loss of DAXX/ATRX is associated with alternative lengthening of telomeres (ALT), leading to unlimited cell cycling in neoplastic PanNET cells. […] The development of panNETs in the context of TSC is less frequent than in the other familial syndromes, ranging from 1.8% to 9%, with the majority being NF-PanNETs. […] The genetic mechanisms involved in the malignant progression of glucagonomas are still largely unknown. […] Somatostatinomas are associated with MEN1 syndrome in 40 to 50% of familial cases and also with NF1 and VHL syndromes.

• #10

  https://journals.lww.com/md-journal/fulltext/2023/11170/a_review_of_functional_pancreatic_neuroendocrine.124.aspx

  Pancreatic neuroendocrine tumors (PanNETs) are a rare subtype of pancreatic cancer and can be divided into functional (30-40%) and nonfunctional subtypes. […] The PI3K-Akt-mTOR and ATRX/DAXX signaling pathways have been recognized as key genetic pathways implicated in the pathogenesis. […] Researchers should also focus their efforts on identifying novel pathways implicated in the pathogenesis of F-PanNETs in order to develop new targeted therapies that may reduce the need for surgical intervention and on the establishment of novel biomarkers that may reduce the need for invasive testing and allow for earlier detection of F-PanNETs. […] Our understanding of the etiology and pathogenesis of this rare group of tumors has been greatly enhanced in recent times, and thus more modern treatment options such as targeted therapies have become available.

• #11 Update on pancreatic neuroendocrine tumors – McKenna – Gland Surgery

  https://gs.amegroups.org/article/view/4839/html

  Recent pNET exome sequencing demonstrated that gene mutations typical for adenocarcinoma, such as KRAS, are absent in pNETs. Furthermore, pNETs appear to commonly involve distinct mutations from adenocarcinoma, particularly MEN1 in 44% of tumors, DAXX in 25% of tumors, ATRX in 18% of tumors, and mTOR pathway genes in 16% of tumors. […] MEN1 codes for menin, which has an essential function in chromatin remodeling regulation, and its role in NET development has long been known due to its involvement in the MEN1 syndrome. […] Interestingly DAXX and ATRX mutations have not been previously associated with cancer. DAXX and ATRX participate in chromatin remodeling at telomeres and other genomic sites, and appear to be associated with pNETs through development of a telomerase-independent telomere maintenance process termed alternative lengthening of telomeres (ALT).

• #11 Update on pancreatic neuroendocrine tumors – McKenna – Gland Surgery

  https://gs.amegroups.org/article/view/4839/html

  The ALT phenotype is found in immortalized cell lines and has been implicated in some human cancers. […] Loss of DAXX/ATRX and development of ALT appear to occur late in pNET development, being found in larger tumors (2-3 cm) and metastatic lymph nodes. […] DAXX/ATRX mutations are also a poor prognostic sign and are associated with earlier recurrence and decreased disease specific survival. […] Furthermore, the DAXX/ATRX pathway appears to be unique to pNETs among other gastrointestinal NETs. […] These recent discoveries, particularly the mutations in the mTOR pathway genes, suggest exciting possibilities for targeted molecular therapy.

• #12 Pancreatic neuroendocrine tumor – Wikipedia

  https://en.wikipedia.org/wiki/Pancreatic_neuroendocrine_tumor

  Pancreatic neuroendocrine tumours (PanNETs, PETs, or PNETs), often referred to as „islet cell tumours” or „pancreatic endocrine tumours” are neuroendocrine neoplasms that arise from cells of the endocrine (hormonal) and nervous system within the pancreas. […] Analysis of somatic DNA mutations in well-differentiated pancreatic neuroendocrine tumors identified four important findings: as expected, the genes mutated in NETs, MEN1, ATRX, DAXX, TSC2, PTEN and PIK3CA, are different from the mutated genes previously found in pancreatic adenocarcinoma. […] Mutations affecting a new cancer pathway involving ATRX and DAXX genes were found in about 40% of pancreatic NETs. The proteins encoded by ATRX and DAXX participate in chromatin remodeling of telomeres; these mutations are associated with a telomerase-independent maintenance mechanism termed ALT (alternative lengthening of telomeres) that results in abnormally long telomeric ends of chromosomes. […] ATRX/DAXX and MEN1 mutations were associated with a better prognosis.

• #13 Pancreatic endocrine tumors | Modern Pathology

  https://www.nature.com/articles/modpathol2010127

  Chromosomal instability has been implicated in tumor progression. Comparative genomic hybridization studies have shown losses of genetic material more often than gains, and amplifications are uncommon, and the number of genomic changes per tumor is associated with tumor size and disease stage, indicating that genetic alterations accumulate during tumor progression. […] Losses of chromosome 1 and 11q and gains on 9q appear to be early events that are already identified in small tumors. […] Metastases show prevalent gains of chromosomes 4 and 7 and loss of 21q, implying that these alterations may contribute to tumor dissemination. […] The common oncogenes and tumor suppressor genes, including K-ras, TP53, Rb, PTEN, DPC4, CDKN2A/p16, von HippelLindau (VHL), RET, BRAF, SMAD3 and the DNA mismatch repair genes, are not implicated in the molecular pathogenesis of these tumors, as mutations and/or loss of heterozygosity are either not found or are extremely rare in sporadic tumors.

• #14 Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations

  https://www.wjgnet.com/1007-9327/full/v26/i28/4036.htm

  Recently, cross-species analysis of mice and human panNET tissues illustrate the existence of three molecular subtypes of PNETs including Islet/Insulinoma tumors, metastasis-like/primary, and intermediate. […] However, hyperactivation of PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways have been well documented to be the main regulators of proliferation in NETs. […] Frequent mutations in multiple endocrine neoplasia 1 (MEN1; 44%), death domain-associated protein (DAXX)/chromatin remodeler (ATRX; 43%), mTOR (15%) pathway genes, and Von Hippel Lindau (VHL) alongside several other hereditary disorders are observed in PNETs. […] Loss of function of the tumor suppressor gene PTEN is frequently found in PanNETs and is responsible for the over-activation of the PI3K-Akt-mTOR cascade. […] Compared to other gastroenteropancreatic neuroendocrine tumors (GEP-NETs), PNETs are a very heterogeneous subtype of cancers with unique pathophysiological features that constitutes a major challenge in the management of this neoplasia.

• #14 Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations

  https://www.wjgnet.com/1007-9327/full/v26/i28/4036.htm

  Systemic treatments for PNETs only stabilize the disease most likely because of inherent and acquired drug resistance. […] The small population of relevant candidates with PNETs is a major challenge for conducting larger clinical trials. […] Despite significant increase in the incidence of PNETs in the United States, this disease remains an understudied and underfunded area of research. […] The majority of FDA approved drugs for the management of PNETs lack objective response characterized by meager progression free survival (PFS) and inability to shrink tumors in the clinic. […] The management of NETs and PNETs, in particular, is greatly personalized and requires expert multidisciplinary strategies including surgery, medical oncology, endocrinology, radiation oncology, cardiology, gastroenterology, pathology, interventional radiology, diagnostic radiology, and nuclear medicine.

• #14 Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations

  https://www.wjgnet.com/1007-9327/full/v26/i28/4036.htm

  PNETs heterogeneity is considered the major challenge in the management of this specific type of neoplasia in the clinic. […] Lack of reliable PNETs cell lines holds back meaningful research and has significantly disadvantaged the management of PNETs for decades. […] The development of novel anticancer drugs necessitates the development and use of appropriate and relevant representative in vitro and in vivo models. […] The absence of preclinical models, mainly cellular models, limits effective anticancer examination and a better understanding of the biology of PNETs in the laboratory. […] Several factors contribute to the management failure of PNETs in the clinic.

• #15 Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation

  https://www.mdpi.com/1422-0067/25/2/1331

  Pancreatic neuroendocrine tumors (PNETs) are characterized by dysregulated signaling pathways that are crucial for tumor formation and progression. […] The pathogenesis of PNETs is intricate and characterized by complex interactions among numerous signaling pathways. Each pathway plays a role in different facets of tumor development, encompassing cell proliferation, survival, migration, and angiogenesis. Together, these pathways constitute a complex network that, when disrupted, can result in uncontrolled tumor growth and metastasis. […] While somatic and germline mutations remain of great significance for diagnosis and therapeutic treatment, emerging evidence highlights the pivotal role of epigenetic modifications in shaping the intricate landscape of PNET-related signaling. […] Epigenetic alterations can lead to aberrant gene expression patterns, contributing to uncontrolled cell growth, evasion of cell death, and increased metastatic potential—the hallmark characteristics of cancer.

• #15 Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation

  https://www.mdpi.com/1422-0067/25/2/1331

  The contributions of these epigenetic modifications to PNET pathology have yet to be fully explored. […] The unique slowing growth characteristic of PNETs also presents a practical challenge for research work in laboratories. […] Despite the inherent challenges, some encouraging advancements have been achieved. Notably, recognizing the limited effectiveness of epigenetic cancer drugs has prompted investigations into combining these therapies with existing or emerging targeted treatments for a synergistic and combinatorial approach. […] The ongoing exploration of the specific mechanisms governing epigenetic changes in PNETs, alongside innovative strategies for drug development, holds considerable promise for enhancing the prognosis and quality of life for individuals grappling with this challenging malignancy.

• #16 Research advances in the mechanism of tumor microenvironment and targeted therapy for pancreatic neuroendocrine tumor

  https://www.lcgdbzz.org/en/article/doi/10.3969/j.issn.1001-5256.2023.08.036

  The tumor microenvironment of pancreatic neuroendocrine tumor is a tumor-promoting microenvironment composed of tumor cells, immune/immunosuppressive cells, and extracellular matrix and has the marked feature of immunosuppression. […] It can lead to the immune escape, invasion, and metastasis of tumor cells by inhibiting antitumor immune response and promoting angiogenesis and is also the main cause of drug resistance to antitumor treatment. […] Therefore, it is of great significance to design new therapeutic strategies from the perspective of the tumor microenvironment of pancreatic neuroendocrine tumor to reverse suppressive tumor microenvironment and improve the treatment outcome of pancreatic neuroendocrine tumor.

• #17 Unraveling the impact of cancer-associated fibroblasts on hypovascular pancreatic neuroendocrine tumors | British Journal of Cancer

  https://www.nature.com/articles/s41416-023-02565-8

  Pancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. […] In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes. […] A higher abundance of -SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. […] Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis.

• #18 Antiangiogenic Therapy in Pancreatic Neuroendocrine Tumors | Anticancer Research

  https://ar.iiarjournals.org/content/36/10/5025

  Angiogenesis is a crucial process during tumor progression and plays a key role in development of metastasis. […] The role of angiogenesis in the malignant spread of pNET cells is finally supported by in vivo studies conducted on the RIP1-Tag2 mouse model. […] In the future, research is needed to improve the identification of the key regulators of angiogenesis in different phases of pNETs and develop a progressively personalized antiangiogenic therapy. […] This characteristic is associated to the overexpression of both ligand and related receptor of vascular endothelial factor (VEGF), particularly in hepatic metastases. […] VEGF is a key driver in the metastatic process of pNETs and, therefore, a pharmaceutical treatment against this pathway should be an interesting therapeutic option for patients with advanced disease.

• #18 Antiangiogenic Therapy in Pancreatic Neuroendocrine Tumors | Anticancer Research

  https://ar.iiarjournals.org/content/36/10/5025

  The recent advances in the comprehension of pNETs’ biology have prompted oncologists to investigate targeted therapies, particularly the pathways of somatostatin, VEGF and mammalian target of rapamycin. […] Basic research, aimed to clarify mechanisms of resistance and find markers of response, is necessary in the near future for designing more appropriate and personalized clinical trials.

• #19

  https://insight.jci.org/articles/view/160130

  Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. […] We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. […] RNA-Seq analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. […] We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared with localized tumors. […] A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs. […] Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, and this augmentation was substantiated in a mouse model of PNET.

• #19

  https://insight.jci.org/articles/view/160130

  Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs. […] We identify significantly activated immune cell signaling pathways in metastatic compared with localized PNETs by RNA-Seq analysis. […] More metastatic PNETs are associated with moderate levels of T cell infiltration than localized PNETs. […] This enhanced chemokine expression results in increased T cell migration toward patient-derived PNET tissue and was supported by findings in a PNET mouse model, suggesting that modulation of the TME among PNETs may serve a clinical benefit in future treatment algorithms.

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