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1
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Butz H, Patócs A, Igaz P. Circulating non-coding RNA biomarkers of endocrine tumours. Nat Rev Endocrinol 2024; 20:600-614. [PMID: 38886617 DOI: 10.1038/s41574-024-01005-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/23/2024] [Indexed: 06/20/2024]
Abstract
Circulating non-coding RNA (ncRNA) molecules are being investigated as biomarkers of malignancy, prognosis and follow-up in several neoplasms, including endocrine tumours of the pituitary, parathyroid, pancreas and adrenal glands. Most of these tumours are classified as neuroendocrine neoplasms (comprised of neuroendocrine tumours and neuroendocrine carcinomas) and include tumours of variable aggressivity. We consider them together here in this Review owing to similarities in their clinical presentation, pathomechanism and genetic background. No preoperative biomarkers of malignancy are available for several forms of these endocrine tumours. Moreover, biomarkers are also needed for the follow-up of tumour progression (especially in hormonally inactive tumours), prognosis and treatment efficacy monitoring. Circulating blood-borne ncRNAs show promising utility as biomarkers. These ncRNAs, including microRNAs, long non-coding RNAs and circular RNAs, are involved in several aspects of gene expression regulation, and their stability and tissue-specific expression could make them ideal biomarkers. However, no circulating ncRNA biomarkers have yet been introduced into routine clinical practice, which is mostly owing to methodological and standardization problems. In this Review, following a brief synopsis of these endocrine tumours and the biology of ncRNAs, the major research findings, pathomechanisms and methodological questions are discussed along with an outlook for future studies.
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Affiliation(s)
- Henriett Butz
- HUN-REN-SU Hereditary Tumours Research Group, Budapest, Hungary
- Department of Molecular Genetics and the National Tumour Biology Laboratory, National Institute of Oncology, Budapest, Hungary
- Department of Laboratory Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Attila Patócs
- HUN-REN-SU Hereditary Tumours Research Group, Budapest, Hungary
- Department of Molecular Genetics and the National Tumour Biology Laboratory, National Institute of Oncology, Budapest, Hungary
- Department of Laboratory Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Peter Igaz
- Department of Endocrinology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
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2
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Tan B, Zhang B, Chen H. Gastroenteropancreatic neuroendocrine neoplasms: epidemiology, genetics, and treatment. Front Endocrinol (Lausanne) 2024; 15:1424839. [PMID: 39411312 PMCID: PMC11474919 DOI: 10.3389/fendo.2024.1424839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 09/10/2024] [Indexed: 10/19/2024] Open
Abstract
The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) is increasing at a rapid pace and is becoming an increasingly important consideration in clinical care. Epidemiological data from multiple countries indicate that the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) exhibits regional, site-specific, and gender-based variations. While the genetics and pathogenesis of some GEP NEN, particularly pancreatic NENs, have been investigated, there are still many mechanisms that require further investigation. The management of GEP NEN is diverse, but surgery remains the primary option for most cases. Peptide receptor radionuclide therapy (PRRT) is an effective treatment, and several clinical trials are exploring the potential of immunotherapy and targeted therapy, as well as combination therapy.
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Affiliation(s)
- Baizhou Tan
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Beiyu Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Hongping Chen
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Experimental Animals, Nanchang University, Nanchang, China
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3
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Majer AD, Hua X, Katona BW. Menin in Cancer. Genes (Basel) 2024; 15:1231. [PMID: 39336822 PMCID: PMC11431421 DOI: 10.3390/genes15091231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 09/13/2024] [Accepted: 09/14/2024] [Indexed: 09/30/2024] Open
Abstract
The protein menin is encoded by the MEN1 gene and primarily serves as a nuclear scaffold protein, regulating gene expression through its interaction with and regulation of chromatin modifiers and transcription factors. While the scope of menin's functions continues to expand, one area of growing investigation is the role of menin in cancer. Menin is increasingly recognized for its dual function as either a tumor suppressor or a tumor promoter in a highly tumor-dependent and context-specific manner. While menin serves as a suppressor of neuroendocrine tumor growth, as seen in the cancer risk syndrome multiple endocrine neoplasia type 1 (MEN1) syndrome caused by pathogenic germline variants in MEN1, recent data demonstrate that menin also suppresses cholangiocarcinoma, pancreatic ductal adenocarcinoma, gastric adenocarcinoma, lung adenocarcinoma, and melanoma. On the other hand, menin can also serve as a tumor promoter in leukemia, colorectal cancer, ovarian and endometrial cancers, Ewing sarcoma, and gliomas. Moreover, menin can either suppress or promote tumorigenesis in the breast and prostate depending on hormone receptor status and may also have mixed roles in hepatocellular carcinoma. Here, we review the rapidly expanding literature on the role and function of menin across a broad array of different cancer types, outlining tumor-specific differences in menin's function and mechanism of action, as well as identifying its therapeutic potential and highlighting areas for future investigation.
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Affiliation(s)
- Ariana D Majer
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Xianxin Hua
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Bryson W Katona
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Xu J, Lou X, Wang F, Zhang W, Xu X, Ye Z, Zhuo Q, Wang Y, Jing D, Fan G, Chen X, Zhang Y, Zhou C, Chen J, Qin Y, Yu X, Ji S. MEN1 Deficiency-Driven Activation of the β-Catenin-MGMT Axis Promotes Pancreatic Neuroendocrine Tumor Growth and Confers Temozolomide Resistance. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308417. [PMID: 39041891 PMCID: PMC11425246 DOI: 10.1002/advs.202308417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 07/12/2024] [Indexed: 07/24/2024]
Abstract
O6-methylguanine DNA methyltransferase (MGMT) removes alkyl adducts from the guanine O6 position (O6-MG) and repairs DNA damage. High MGMT expression results in poor response to temozolomide (TMZ). However, the biological importance of MGMT and the mechanism underlying its high expression in pancreatic neuroendocrine tumors (PanNETs) remain elusive. Here, it is found that MGMT expression is highly elevated in PanNET tissues compared with paired normal tissues and negatively associated with progression-free survival (PFS) time in patients with PanNETs. Knocking out MGMT inhibits cancer cell growth in vitro and in vivo. Ectopic MEN1 expression suppresses MGMT transcription in a manner that depends on β-Catenin nuclear export and degradation. The Leucine 267 residue of MEN1 is crucial for regulating β-Catenin-MGMT axis activation and chemosensitivity to TMZ. Interference with β-Catenin re-sensitizes tumor cells to TMZ and significantly reduces the cytotoxic effects of high-dose TMZ treatment, and MGMT overexpression counteracts the effects of β-Catenin deficiency. This study reveals the biological importance of MGMT and a new mechanism by which MEN1 deficiency regulates its expression, thus providing a potential combinational strategy for treating patients with TMZ-resistant PanNETs.
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Fuentes ME, Lu X, Flores NM, Hausmann S, Mazur PK. Combined deletion of MEN1, ATRX and PTEN triggers development of high-grade pancreatic neuroendocrine tumors in mice. Sci Rep 2024; 14:8510. [PMID: 38609433 PMCID: PMC11014914 DOI: 10.1038/s41598-024-58874-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of tumors that exhibit an unpredictable and broad spectrum of clinical presentations and biological aggressiveness. Surgical resection is still the only curative therapeutic option for localized PanNET, but the majority of patients are diagnosed at an advanced and metastatic stage with limited therapeutic options. Key factors limiting the development of new therapeutics are the extensive heterogeneity of PanNETs and the lack of appropriate clinically relevant models. In that context, genomic sequencing of human PanNETs revealed recurrent mutations and structural alterations in several tumor suppressors. Here, we demonstrated that combined loss of MEN1, ATRX, and PTEN, tumor suppressors commonly mutated in human PanNETs, triggers the development of high-grade pancreatic neuroendocrine tumors in mice. Histopathological evaluation and gene expression analyses of the developed tumors confirm the presence of PanNET hallmarks and significant overlap in gene expression patterns found in human disease. Thus, we postulate that the presented novel genetically defined mouse model is the first clinically relevant immunocompetent high-grade PanNET mouse model.
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Affiliation(s)
- Mary Esmeralda Fuentes
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Xiaoyin Lu
- The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Natasha M Flores
- The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Simone Hausmann
- The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Pawel K Mazur
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
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Xue J, Lyu Q. Challenges and opportunities in rare cancer research in China. SCIENCE CHINA. LIFE SCIENCES 2024; 67:274-285. [PMID: 38036799 DOI: 10.1007/s11427-023-2422-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 06/15/2023] [Indexed: 12/02/2023]
Abstract
Cancer is one of the major public health challenges in China. Rare cancers collectively account for a considerable proportion of all malignancies. The lack of awareness of rare cancers among healthcare professionals and the general public, the typically complex and delayed diagnosis, and limited access to clinical trials are key challenges. Recent years have witnessed an increase in funding for research related to rare cancers in China. In this review, we provide a comprehensive overview of rare cancers and summarize the status of research on rare cancers in China and overseas, including the trends of funding and publications. We also highlight the challenges and perspectives regarding rare cancers in China.
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Affiliation(s)
- Jianxin Xue
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Natural Science Foundation of China, Beijing, 100085, China
| | - Qunyan Lyu
- National Natural Science Foundation of China, Beijing, 100085, China.
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7
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Forsythe SD, Pu T, Andrews SG, Madigan JP, Sadowski SM. Models in Pancreatic Neuroendocrine Neoplasms: Current Perspectives and Future Directions. Cancers (Basel) 2023; 15:3756. [PMID: 37568572 PMCID: PMC10416968 DOI: 10.3390/cancers15153756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/21/2023] [Accepted: 07/23/2023] [Indexed: 08/13/2023] Open
Abstract
Pancreatic neuroendocrine neoplasms (pNENs) are a heterogeneous group of tumors derived from multiple neuroendocrine origin cell subtypes. Incidence rates for pNENs have steadily risen over the last decade, and outcomes continue to vary widely due to inability to properly screen. These tumors encompass a wide range of functional and non-functional subtypes, with their rarity and slow growth making therapeutic development difficult as most clinically used therapeutics are derived from retrospective analyses. Improved molecular understanding of these cancers has increased our knowledge of the tumor biology for pNENs. Despite these advances in our understanding of pNENs, there remains a dearth of models for further investigation. In this review, we will cover the current field of pNEN models, which include established cell lines, animal models such as mice and zebrafish, and three-dimensional (3D) cell models, and compare their uses in modeling various disease aspects. While no study model is a complete representation of pNEN biology, each has advantages which allow for new scientific understanding of these rare tumors. Future efforts and advancements in technology will continue to create new options in modeling these cancers.
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Affiliation(s)
- Steven D. Forsythe
- Neuroendocrine Cancer Therapy Section, Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (S.D.F.); (S.G.A.); (J.P.M.)
| | - Tracey Pu
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Stephen G. Andrews
- Neuroendocrine Cancer Therapy Section, Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (S.D.F.); (S.G.A.); (J.P.M.)
| | - James P. Madigan
- Neuroendocrine Cancer Therapy Section, Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (S.D.F.); (S.G.A.); (J.P.M.)
| | - Samira M. Sadowski
- Neuroendocrine Cancer Therapy Section, Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (S.D.F.); (S.G.A.); (J.P.M.)
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8
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Xu J, Ye Z, Zhuo Q, Gao H, Qin Y, Lou X, Zhang W, Wang F, Wang Y, Jing D, Fan G, Zhang Y, Chen X, Chen J, Xu X, Yu X, Ji S. MEN1 Degradation Induced by Neddylation and the CUL4B-DCAF7 Axis Promotes Pancreatic Neuroendocrine Tumor Progression. Cancer Res 2023; 83:2226-2247. [PMID: 36939378 DOI: 10.1158/0008-5472.can-22-3599] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/04/2023] [Accepted: 03/16/2023] [Indexed: 03/21/2023]
Abstract
UNLABELLED Pancreatic neuroendocrine tumors (PanNET) are a group of rare sporadic malignant tumors in the pancreas. MEN1 is the most frequently mutated gene in PanNETs. The MEN1-encoded protein is a typical tumor suppressor that forms a complex with epigenetic and transcription factors and is an attractive target for therapeutic interventions for patients with PanNET. A better understanding of the regulation of MEN1 protein expression in PanNETs could identify strategies for targeting MEN1. Here, we found that the neddylation pathway and DCAF7-mediated ubiquitination regulated MEN1 protein expression. Increased expression of members of the neddylation pathway and DCAF7 was found in PanNET tissues compared with paired-adjacent tissues and was associated with poor prognosis in patients with PanNET. Suppression of neddylation using the neddylation inhibitor MLN4924 or RNA interference significantly induced MEN1 accumulation and repressed cancer-related malignant phenotypes. CUL4B and DCAF7 promoted MEN1 degradation by binding and catalyzing its ubiquitination. In PanNET cells resistant to everolimus, a pharmacologic mTOR inhibitor widely used for advanced PanNET patient treatment, the downregulation of DCAF7 expression overcame resistance and synergized with everolimus to suppress mTOR activation and to inhibit cancer cell growth. The effects of DCAF7 loss could be counteracted by the simultaneous knockdown of MEN1 both in vitro and in vivo. The inverse correlation between DCAF7 and MEN1 was further validated in clinical specimens. This study revealed that the posttranslational control of MEN1 expression in PanNET is mediated by neddylation and the CUL4B-DCAF7 axis and identifies potential therapeutic targets in patients with MEN1-associated PanNET. SIGNIFICANCE Identification of neddylation and ubiquitination pathways that regulate MEN1 protein stability provides an opportunity for therapeutic interventions for treating patients with pancreatic neuroendocrine tumors.
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Affiliation(s)
- Junfeng Xu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Zeng Ye
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Qifeng Zhuo
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Heli Gao
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yi Qin
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xin Lou
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wuhu Zhang
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Fei Wang
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yan Wang
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Desheng Jing
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Guixiong Fan
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yue Zhang
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xuemin Chen
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jie Chen
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xiaowu Xu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shunrong Ji
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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9
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Wang Y, Wang F, Qin Y, Lou X, Ye Z, Zhang W, Gao H, Chen J, Xu X, Yu X, Ji S. Recent progress of experimental model in pancreatic neuroendocrine tumors: drawbacks and challenges. Endocrine 2023; 80:266-282. [PMID: 36648608 DOI: 10.1007/s12020-023-03299-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/31/2022] [Indexed: 01/18/2023]
Abstract
The neuroendocrine neoplasm, in general, refers to a heterogeneous group of all tumors originating from peptidergic neurons and neuroendocrine cells. Neuroendocrine neoplasms are divided into two histopathological subtypes: well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Pancreatic neuroendocrine tumors account for more than 80% of pancreatic neuroendocrine neoplasms. Due to the greater proportion of pancreatic neuroendocrine tumors compared to pancreatic neuroendocrine carcinoma, this review will only focus on them. The worldwide incidence of pancreatic neuroendocrine tumors is rising year by year due to sensitive detection with an emphasis on medical examinations and the improvement of testing technology. Although the biological behavior of pancreatic neuroendocrine tumors tends to be inert, distant metastasis is common, often occurring very early. Because of the paucity of basic research on pancreatic neuroendocrine tumors, the mechanism of tumor development, metastasis, and recurrence are still unclear. In this context, the representative preclinical models simulating the tumor development process are becoming ever more widely appreciated to address the clinical problems of pancreatic neuroendocrine tumors. So far, there is no comprehensive report on the experimental model of pancreatic neuroendocrine tumors. This article systematically summarizes the characteristics of preclinical models, such as patient-derived cell lines, patient-derived xenografts, genetically engineered mouse models, and patient-derived organoids, and their advantages and disadvantages, to provide a reference for further studies of neuroendocrine tumors. We also highlight the method of establishment of liver metastasis mouse models.
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Affiliation(s)
- Yan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Fei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Xin Lou
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Zeng Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Wuhu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Heli Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jie Chen
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
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Yu Y, Sun Y, Li Z, Li J, Tian D. Systematic analysis identifies XRCC4 as a potential immunological and prognostic biomarker associated with pan-cancer. BMC Bioinformatics 2023; 24:44. [PMID: 36765282 PMCID: PMC9921312 DOI: 10.1186/s12859-023-05165-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 01/30/2023] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND XRCC4 is a NHEJ factor identified recently that plays a vital role in repairing DNA double-stranded breaks. Studies have reported the associations between abnormal expression of XRCC4 and tumor susceptibility and radiosensitivity, but the potential biological mechanisms by which XRCC4 exerts effects on tumorigenesis are not fully understood. This study aimed to systematically investigate the role of XRCC4 across cancer types. METHODS The TIMER, GTEX and Xiantao Academic database were used to interpret the expression of XRCC4. Genomic alterations and protein expression in human organic and tumor tissues were applied in cBioPortal and the Human Protein Atlas databases. Correlations between XRCC4 expression and immune and molecular subtypes were analyzed by using the TISIDB database. Protein-protein interactions, GO and KEGG enrichment were also applied for XRCC4-related genes. The TIMER and the Tumor Immune Single Cell Hub (TISCH) online databases were used to explore the relationship between XRCC4 and tumor immune microenvironment. Drug sensitivity information was acquired from the CellMiner database to analyze the effect of XRCC4 on sensitivity analysis. RESULTS The XRCC4 expression was significantly upregulated in 15 tumor types and downregulated in two tumor types compared with the normal tissues, most of which were validated by the results of Xiantao academic platform. XRCC4 was expressed at intermediate level in malignant cells. The XRCC4 expression was related to the molecular and immune subtypes of human cancers, and the survival outcome of 11 types of cancers, including KIRC, STAD and LIHC. The main type of frequent genetic alteration is amplification. Strong correlations were also found between XRCC4 and immune checkpoint genes in 33 human cancers. Furthermore, the abnormal expression of XRCC4 was related to immune cell infiltration and drug sensitivity. Enrichment analysis showed that XRCC4 was significantly correlated with DNA damage response. CONCLUSIONS This comprehensive pan-cancer analysis suggested that XRCC4 may play a vital role in the prognosis and immunotherapy response in cancer patients, and it is a promising therapy target in the future.
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Affiliation(s)
- Yang Yu
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, 300190 China
| | - Yanyan Sun
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, 300190 China
| | - Zhaoxian Li
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, 300190 China ,grid.216938.70000 0000 9878 7032School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071 China
| | - Jiang Li
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, 300190 China
| | - Dazhi Tian
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, 300190, China.
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11
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Bevere M, Gkountakos A, Martelli FM, Scarpa A, Luchini C, Simbolo M. An Insight on Functioning Pancreatic Neuroendocrine Neoplasms. Biomedicines 2023; 11:303. [PMID: 36830839 PMCID: PMC9953748 DOI: 10.3390/biomedicines11020303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms arising from islets of the Langerhans in the pancreas. They can be divided into two groups, based on peptide hormone secretion, functioning and nonfunctioning PanNENs. The first group is characterized by different secreted peptides causing specific syndromes and is further classified into subgroups: insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma and tumors producing serotonin and adrenocorticotrophic hormone. Conversely, the second group does not release peptides and is usually associated with a worse prognosis. Today, although the efforts to improve the therapeutic approaches, surgery remains the only curative treatment for patients with PanNENs. The development of high-throughput techniques has increased the molecular knowledge of PanNENs, thereby allowing us to understand better the molecular biology and potential therapeutic vulnerabilities of PanNENs. Although enormous advancements in therapeutic and molecular aspects of PanNENs have been achieved, there is poor knowledge about each subgroup of functioning PanNENs.Therefore, we believe that combining high-throughput platforms with new diagnostic tools will allow for the efficient characterization of the main differences among the subgroups of functioning PanNENs. In this narrative review, we summarize the current landscape regarding diagnosis, molecular profiling and treatment, and we discuss the future perspectives of functioning PanNENs.
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Affiliation(s)
- Michele Bevere
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
- ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Anastasios Gkountakos
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
- ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Filippo Maria Martelli
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
- ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Michele Simbolo
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
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12
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Gaspar TB, Lopes JM, Soares P, Vinagre J. An update on genetically engineered mouse models of pancreatic neuroendocrine neoplasms. Endocr Relat Cancer 2022; 29:R191-R208. [PMID: 36197786 DOI: 10.1530/erc-22-0166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/29/2022] [Indexed: 11/09/2022]
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) are rare and clinically challenging entities. At the molecular level, PanNENs' genetic profile is well characterized, but there is limited knowledge regarding the contribution of the newly identified genes to tumor initiation and progression. Genetically engineered mouse models (GEMMs) are the most versatile tool for studying the plethora of genetic variations influencing PanNENs' etiopathogenesis and behavior over time. In this review, we present the state of the art of the most relevant PanNEN GEMMs available and correlate their findings with the human neoplasms' counterparts. We discuss the historic GEMMs as the most used and with higher translational utility models. GEMMs with Men1 and glucagon receptor gene germline alterations stand out as the most faithful models in recapitulating human disease; RIP-Tag models are unique models of early-onset, highly vascularized, invasive carcinomas. We also include a section of the most recent GEMMs that evaluate pathways related to cell cycle and apoptosis, Pi3k/Akt/mTOR, and Atrx/Daxx. For the latter, their tumorigenic effect is heterogeneous. In particular, for Atrx/Daxx, we will require more in-depth studies to evaluate their contribution; even though they are prevalent genetic events in PanNENs, they have low/inexistent tumorigenic capacity per se in GEMMs. Researchers planning to use GEMMs can find a road map of the main clinical features in this review, presented as a guide that summarizes the chief milestones achieved. We identify pitfalls to overcome, concerning the novel designs and standardization of results, so that future models can replicate human disease more closely.
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Affiliation(s)
- Tiago Bordeira Gaspar
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal
- Ipatimup - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto, Porto, Portugal
- FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - José Manuel Lopes
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal
- Ipatimup - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Department of Pathology, Centro Hospitalar e Universitário de São João, Porto, Portugal
| | - Paula Soares
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal
- Ipatimup - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - João Vinagre
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal
- Ipatimup - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal
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Preclinical Models of Neuroendocrine Neoplasia. Cancers (Basel) 2022; 14:cancers14225646. [PMID: 36428741 PMCID: PMC9688518 DOI: 10.3390/cancers14225646] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/15/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022] Open
Abstract
Neuroendocrine neoplasia (NENs) are a complex and heterogeneous group of cancers that can arise from neuroendocrine tissues throughout the body and differentiate them from other tumors. Their low incidence and high diversity make many of them orphan conditions characterized by a low incidence and few dedicated clinical trials. Study of the molecular and genetic nature of these diseases is limited in comparison to more common cancers and more dependent on preclinical models, including both in vitro models (such as cell lines and 3D models) and in vivo models (such as patient derived xenografts (PDXs) and genetically-engineered mouse models (GEMMs)). While preclinical models do not fully recapitulate the nature of these cancers in patients, they are useful tools in investigation of the basic biology and early-stage investigation for evaluation of treatments for these cancers. We review available preclinical models for each type of NEN and discuss their history as well as their current use and translation.
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14
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Smolkova B, Kataki A, Earl J, Ruz-Caracuel I, Cihova M, Urbanova M, Buocikova V, Tamargo S, Rovite V, Niedra H, Schrader J, Kohl Y. Liquid biopsy and preclinical tools for advancing diagnosis and treatment of patients with pancreatic neuroendocrine neoplasms. Crit Rev Oncol Hematol 2022; 180:103865. [PMID: 36334880 DOI: 10.1016/j.critrevonc.2022.103865] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
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15
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Parekh VI, Sun H, Chen M, Weinstein LS, Agarwal SK. Mice With RIP-Cre-mediated Deletion of the Long Noncoding RNA Meg3 Show Normal Pancreatic Islets and Enlarged Pituitary. J Endocr Soc 2022; 6:bvac141. [PMID: 37283960 PMCID: PMC9581224 DOI: 10.1210/jendso/bvac141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Indexed: 11/19/2022] Open
Abstract
Context Maternally expressed gene 3 (MEG3) is a long noncoding RNA (lncRNA) that has been implicated as a tumor suppressor. Objective The expression of MEG3 RNA is downregulated in various human tumors, including pituitary adenoma and pancreatic islet tumors due to MEG3 gene deletion or DNA hypermethylation. Mouse models with conventional germline deletion of Meg3 have shown that Meg3 is essential for perinatal or postnatal development and survival. However, a direct role of Meg3 loss in tumorigenesis has not been shown. Methods To observe a causal relationship between Meg3 loss and tumorigenesis, we have generated a mouse model with conditional deletion of Meg3 mediated by the RIP-Cre transgene that initiated Meg3 deletion in pancreatic islet β cells and anterior pituitary. Results Meg3 loss did not lead to the development of islet tumors. Interestingly, RIP-Cre-mediated Meg3 loss led to the development of an enlarged pituitary. The genes in the Meg3 region are transcribed together as a 210 kb RNA that is processed into Meg3 and other transcripts. Whether these tandem transcripts play a functional role in the growth of pancreatic endocrine cells and pituitary cells remains to be determined. Conclusion Our mouse model shows that Meg3 loss leads to hyperplasia in the pituitary and not in pancreatic islets, thus serving as a valuable model to study pathways associated with pituitary cell proliferation and function. Future mouse models with specific inactivation of Meg3 alone or other transcripts in the Meg3 polycistron are warranted to study tissue-specific effects on initiating neoplasia and tumor development.
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Affiliation(s)
- Vaishali I Parekh
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802, USA
| | - Hui Sun
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802, USA
| | - Min Chen
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802, USA
| | - Lee S Weinstein
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802, USA
| | - Sunita K Agarwal
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802, USA
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16
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Insights into Epigenetic Changes Related to Genetic Variants and Cells-of-Origin of Pancreatic Neuroendocrine Tumors: An Algorithm for Practical Workup. Cancers (Basel) 2022; 14:cancers14184444. [PMID: 36139607 PMCID: PMC9496769 DOI: 10.3390/cancers14184444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/04/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Pancreatic neuroendocrine tumors are composite entities due to their heterogeneity illustrated in clinical behavior, mutational pattern, and site of origin. Pancreatic neuroendocrine tumors display a low mutation burden with frequently epigenetic alterations, such as histone modifications, chromatin remodeling, or DNA methylation status. Using the epigenomic data of the pancreatic neuroendocrine tumors converged to the identification of molecularly distinct subgroups. Furthermore, epigenetic signatures could be used as biomarkers due to their link to cell lineages and genetic driver mutations. We integrated the current knowledge on genetic and epigenetic alterations involved in endocrine lineage associated with these neoplasms to present a pathway-based overview. In this review, we suggest a simplified algorithm on how to manage pancreatic neuroendocrine tumors from a practical perspective based on pathologist ’analysis. Abstract Current knowledge on the molecular landscape of pancreatic neuroendocrine tumors (PanNETs) has advanced significantly. Still, the cellular origin of PanNETs is uncertain and the associated mechanisms remain largely unknown. DAXX/ATRX and MEN1 are the three most frequently altered genes that drive PanNETs. They are recognized as a link between genetics and epigenetics. Moreover, the acknowledged impact on DNA methylation by somatic mutations in MEN1 is a valid hallmark of epigenetic mechanism. DAXX/ATRX and MEN1 can be studied at the immunohistochemical level as a reliable surrogate for sequencing. DAXX/ATRX mutations promote alternative lengthening of telomeres (ALT) activation, determined by specific fluorescence in situ hybridization (FISH) analysis. ALT phenotype is considered a significant predictor of worse prognosis and a marker of pancreatic origin. Additionally, ARX/PDX1 expression is linked to important epigenomic alterations and can be used as lineage associated immunohistochemical marker. Herein, ARX/PDX1 association with DAXX/ATRX/MEN1 and ALT can be studied through pathological assessment, as these biomarkers may provide important clues to the mechanism underlying disease pathogenesis. In this review, we present an overview of a new approach to tumor stratification based on genetic and epigenetic characteristics as well as cellular origin, with prognostic consequences.
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17
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Sun C, Estrella JS, Whitley EM, Chau GP, Lozano G, Wasylishen AR. Mouse modeling provides insights into Daxx and Atrx tumor suppressive mechanisms in the endocrine pancreas. Dis Model Mech 2022; 15:276356. [PMID: 35976056 PMCID: PMC9438929 DOI: 10.1242/dmm.049552] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/19/2022] [Indexed: 11/20/2022] Open
Abstract
Genome sequencing has revealed the importance of epigenetic regulators in tumorigenesis. The genes encoding the chromatin remodeling complex DAXX:ATRX are frequently mutated in pancreatic neuroendocrine tumors (PanNETs); however, the underlying mechanisms of how mutations contribute to tumorigenesis are only partially understood, in part because of the lack of relevant pre-clinical models. Here we used genetically engineered mouse models combined with environmental stress to evaluate the tumor suppressor functions of Daxx and Atrx in the mouse pancreas. Daxx or Atrx loss, alone or in combination with Men1 loss, do not drive nor accelerate pancreatic neuroendocrine tumorigenesis. Moreover, Daxx loss does not cooperate with environmental stresses (ionizing radiation or pancreatitis) or with the loss of other tumor suppressors (Pten or p53) to promote pancreatic neuroendocrine tumorigenesis. However, due to promiscuity of the Cre promoter used, hepatocellular carcinomas (HCC) and osteosarcomas were observed in some instances. Overall, our findings suggest that Daxx and Atrx are not robust tumor suppressors in the endocrine pancreas of mice and indicate the context of a human genome is essential for tumorigenesis.
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Affiliation(s)
- Chang Sun
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.,Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Jeannelyn S Estrella
- Department of Anatomic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Elizabeth M Whitley
- Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Gilda P Chau
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Guillermina Lozano
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.,Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Amanda R Wasylishen
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
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18
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Duan S, Sawyer TW, Sontz RA, Wieland BA, Diaz AF, Merchant JL. GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming. Cell Mol Gastroenterol Hepatol 2022; 14:1025-1051. [PMID: 35835391 PMCID: PMC9490044 DOI: 10.1016/j.jcmgh.2022.06.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 06/16/2022] [Accepted: 06/28/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine cell specification, resulting in an induction of gastrin in enteric glia. Here, we investigated the hypothesis that cell autonomous Men1 inactivation in glial fibrillary acidic protein (GFAP)-expressing cells induced neuroendocrine differentiation and tumorigenesis. METHODS Transgenic GFAPΔMen1 mice were generated by conditional GFAP-directed Men1 deletion in GFAP-expressing cells. Cre specificity was confirmed using a tdTomato reporter. GFAPΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. Small interfering RNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel. RESULTS GFAPΔMen1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAPΔMen1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Men1 deletion induced loss of glial-restricted progenitor lineage markers and an increase in neuroendocrine genes, suggesting a reprogramming of GFAP+ cells. Deleting Kif3a, a mediator of Hedgehog signaling, in GFAP-expressing cells attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate. Similar results in the pancreas were observed when Sox10 was used to delete Men1. CONCLUSIONS GFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.
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Affiliation(s)
- Suzann Duan
- University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona
| | - Travis W. Sawyer
- Wyant College of Optical Sciences, University of Arizona, Tucson, Arizona
| | - Ricky A. Sontz
- University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona
| | - Bradley A. Wieland
- University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona
| | - Andres F. Diaz
- University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona
| | - Juanita L. Merchant
- University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Tucson, Arizona,Correspondence Address correspondence to: Dr Juanita L. Merchant, University of Arizona, 1515 N. Campbell Ave, Tucson, AZ 85724; tel: (520) 626-7897; fax: (520) 626-1291.
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Duan S, Rico K, Merchant JL. Gastrin: From Physiology to Gastrointestinal Malignancies. FUNCTION (OXFORD, ENGLAND) 2021; 3:zqab062. [PMID: 35330921 PMCID: PMC8788842 DOI: 10.1093/function/zqab062] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/14/2021] [Accepted: 11/16/2021] [Indexed: 01/07/2023]
Abstract
Abetted by widespread usage of acid-suppressing proton pump inhibitors (PPIs), the mitogenic actions of the peptide hormone gastrin are being revisited as a recurring theme in various gastrointestinal (GI) malignancies. While pathological gastrin levels are intricately linked to hyperplasia of enterochromaffin-like cells leading to carcinoid development, the signaling effects exerted by gastrin on distinct cell types of the gastric mucosa are more nuanced. Indeed, mounting evidence suggests dichotomous roles for gastrin in both promoting and suppressing tumorigenesis. Here, we review the major upstream mediators of gastrin gene regulation, including inflammation secondary to Helicobacter pylori infection and the use of PPIs. We further explore the molecular biology of gastrin in GI malignancies, with particular emphasis on the regulation of gastrin in neuroendocrine neoplasms. Finally, we highlight tissue-specific transcriptional targets as an avenue for targetable therapeutics.
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Affiliation(s)
- Suzann Duan
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA
| | - Karen Rico
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA
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Maharjan CK, Ear PH, Tran CG, Howe JR, Chandrasekharan C, Quelle DE. Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets. Cancers (Basel) 2021; 13:5117. [PMID: 34680266 PMCID: PMC8533967 DOI: 10.3390/cancers13205117] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/16/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive 'omic' analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.
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Affiliation(s)
- Chandra K. Maharjan
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
| | - Po Hien Ear
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (P.H.E.); (C.G.T.); (J.R.H.)
| | - Catherine G. Tran
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (P.H.E.); (C.G.T.); (J.R.H.)
| | - James R. Howe
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (P.H.E.); (C.G.T.); (J.R.H.)
| | - Chandrikha Chandrasekharan
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
| | - Dawn E. Quelle
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
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21
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Carpizo DR, Harris CR. Genetic Drivers of Ileal Neuroendocrine Tumors. Cancers (Basel) 2021; 13:cancers13205070. [PMID: 34680217 PMCID: PMC8533727 DOI: 10.3390/cancers13205070] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Although ileal neuroendocrine tumors are the most common tumors of the small intestine, they are not well-defined at the genetic level. Unlike most cancers, they have an unusually low number of mutations, and also lack recurrently mutated genes. Moreover ileal NETs have been difficult to study in the laboratory because there were no animal models and because cell lines were generally unavailable. But recent advances, including the first ileal NET mouse model as well as methods for culturing patient tumor samples, have been described and have already helped to identify IGF2 and CDK4 as two of the genetic drivers for this tumor type. These advances may help in the development of new treatments for patients. Abstract The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing of ileal NETs demonstrated a distinct lack of recurrently mutated genes, suggesting that the mechanisms that drive the formation of I-NETs may be quite different than the cell-intrinsic mutations that drive the formation of other tumor types. However, recent mouse studies have identified the IGF2 and RB1 pathways in the formation of ileal NETs, which is supported by the subsequent analysis of patient samples. Thus, ileal NETs no longer appear to be a cancer without genetic causes.
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Pastorino L, Grillo F, Albertelli M, Ghiorzo P, Bruno W. Insights into Mechanisms of Tumorigenesis in Neuroendocrine Neoplasms. Int J Mol Sci 2021; 22:10328. [PMID: 34638668 PMCID: PMC8508699 DOI: 10.3390/ijms221910328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/16/2021] [Accepted: 09/22/2021] [Indexed: 11/16/2022] Open
Abstract
Genomic studies have identified some of the most relevant genetic players in Neuroendocrine Neoplasm (NEN) tumorigenesis. However, we are still far from being able to draw a model that encompasses their heterogeneity, elucidates the different biological effects consequent to the identified molecular events, or incorporates extensive knowledge of molecular biomarkers and therapeutic targets. Here, we reviewed recent insights in NEN tumorigenesis from selected basic research studies on animal models, highlighting novel players in the intergenic cooperation and peculiar mechanisms including splicing dysregulation, chromatin stability, or cell dedifferentiation. Furthermore, models of tumorigenesis based on composite interactions other than a linear progression of events are proposed, exemplified by the involvement in NEN tumorigenesis of genes regulating complex functions, such as MEN1 or DAXX. Although limited by interspecies differences, animal models have proved helpful for the more in-depth study of every facet of tumorigenesis, showing that the identification of driver mutations is only one of the many necessary steps and that other mechanisms are worth investigating.
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Affiliation(s)
- Lorenza Pastorino
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy; (L.P.); (P.G.)
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy;
| | - Federica Grillo
- Anatomic Pathology Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy;
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 1632 Genoa, Italy
| | - Manuela Albertelli
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy;
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy
| | - Paola Ghiorzo
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy; (L.P.); (P.G.)
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy;
| | - William Bruno
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy; (L.P.); (P.G.)
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy;
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23
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Kiba T, Oka N. Mutation Status in Phosphatase and Tensin Homolog Deleted on Chromosome 10 Gene in X-ray-Induced Insulinoma Cell Line Rin-5F. Pancreas 2021; 50:e66-e67. [PMID: 34714291 DOI: 10.1097/mpa.0000000000001884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Affiliation(s)
- Takayoshi Kiba
- Department of Life Sciences, Faculty of Science, Okayama University of Science, Okayama, Japan
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24
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Mammarella E, Zampieri C, Panatta E, Melino G, Amelio I. NUAK2 and RCan2 participate in the p53 mutant pro-tumorigenic network. Biol Direct 2021; 16:11. [PMID: 34348766 PMCID: PMC8335924 DOI: 10.1186/s13062-021-00296-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 07/29/2021] [Indexed: 02/04/2023] Open
Abstract
Most inactivating mutations in TP53 gene generates neomorphic forms of p53 proteins that experimental evidence and clinical observations suggest to exert gain-of-function effects. While massive effort has been deployed in the dissection of wild type p53 transcriptional programme, p53 mutant pro-tumorigenic gene network is still largely elusive. To help dissecting the molecular basis of p53 mutant GOF, we performed an analysis of a fully annotated genomic and transcriptomic human pancreatic adenocarcinoma to select candidate players of p53 mutant network on the basis their differential expression between p53 mutant and p53 wild-type cohorts and their prognostic value. We identified NUAK2 and RCan2 whose p53 mutant GOF-dependent regulation was further validated in pancreatic cancer cellular model. Our data demonstrated that p53R270H can physically bind RCan2 gene locus in regulatory regions corresponding to the chromatin permissive areas where known binding partners of p53 mutant, such as p63 and Srebp, bind. Overall, starting from clinically relevant data and progressing into experimental validation, our work suggests NUAK2 and RCan2 as novel candidate players of the p53 mutant pro-tumorigenic network whose prognostic and therapeutic interest might attract future studies.
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Affiliation(s)
- Eleonora Mammarella
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Carlotta Zampieri
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Emanuele Panatta
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Ivano Amelio
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
- School of Life Sciences, University of Nottingham, Nottingham, UK
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25
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RABL6A Promotes Pancreatic Neuroendocrine Tumor Angiogenesis and Progression In Vivo. Biomedicines 2021; 9:biomedicines9060633. [PMID: 34199469 PMCID: PMC8228095 DOI: 10.3390/biomedicines9060633] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are difficult-to-treat neoplasms whose incidence is rising. Greater understanding of pNET pathogenesis is needed to identify new biomarkers and targets for improved therapy. RABL6A, a novel oncogenic GTPase, is highly expressed in patient pNETs and required for pNET cell proliferation and survival in vitro. Here, we investigated the role of RABL6A in pNET progression in vivo using a well-established model of the disease. RIP-Tag2 (RT2) mice develop functional pNETs (insulinomas) due to SV40 large T-antigen expression in pancreatic islet β cells. RABL6A loss in RT2 mice significantly delayed pancreatic tumor formation, reduced tumor angiogenesis and mitoses, and extended survival. Those effects correlated with upregulation of anti-angiogenic p19ARF and downregulation of proangiogenic c-Myc in RABL6A-deficient islets and tumors. Our findings demonstrate that RABL6A is a bona fide oncogenic driver of pNET angiogenesis and development in vivo.
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26
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Kaemmer CA, Umesalma S, Maharjan CK, Moose DL, Narla G, Mott SL, Zamba GKD, Breheny P, Darbro BW, Bellizzi AM, Henry MD, Quelle DE. Development and comparison of novel bioluminescent mouse models of pancreatic neuroendocrine neoplasm metastasis. Sci Rep 2021; 11:10252. [PMID: 33986468 PMCID: PMC8119958 DOI: 10.1038/s41598-021-89866-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic neuroendocrine neoplasms (pNENs) are slow growing cancers of increasing incidence that lack effective treatments once they become metastatic. Unfortunately, nearly half of pNEN patients present with metastatic liver tumors at diagnosis and current therapies fail to improve overall survival. Pre-clinical models of pNEN metastasis are needed to advance our understanding of the mechanisms driving the metastatic process and for the development of novel, targeted therapeutic interventions. To model metastatic dissemination of tumor cells, human pNEN cell lines (BON1 and Qgp1) stably expressing firefly luciferase (luc) were generated and introduced into NSG immunodeficient mice by intracardiac (IC) or intravenous (IV) injection. The efficiency, kinetics and distribution of tumor growth was evaluated weekly by non-invasive bioluminescent imaging (BLI). Tumors formed in all animals in both the IC and IV models. Bioluminescent Qgp1.luc cells preferentially metastasized to the liver regardless of delivery route, mimicking the predominant site of pNEN metastasis in patients. By comparison, BON1.luc cells most commonly formed lung tumors following either IV or IC administration and colonized a wider variety of tissues than Qgp1.luc cells. These models provide a unique platform for testing candidate metastasis genes and anti-metastatic therapies for pNENs.
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Affiliation(s)
- Courtney A Kaemmer
- Department of Neuroscience and Pharmacology, University of Iowa, 2-570 Bowen Science Building, 51 Newton Road, Iowa City, IA, 52242, USA
| | - Shaikamjad Umesalma
- Department of Neuroscience and Pharmacology, University of Iowa, 2-570 Bowen Science Building, 51 Newton Road, Iowa City, IA, 52242, USA
| | - Chandra K Maharjan
- Department of Neuroscience and Pharmacology, University of Iowa, 2-570 Bowen Science Building, 51 Newton Road, Iowa City, IA, 52242, USA
| | - Devon L Moose
- Cancer Biology Graduate Program, University of Iowa, Iowa City, IA, USA
| | - Goutham Narla
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Sarah L Mott
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Gideon K D Zamba
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.,Department of Biostatistics, University of Iowa, Iowa City, IA, USA
| | - Patrick Breheny
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.,Department of Biostatistics, University of Iowa, Iowa City, IA, USA
| | - Benjamin W Darbro
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.,Department of Pediatrics, University of Iowa, Iowa City, IA, USA
| | - Andrew M Bellizzi
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.,Department of Pathology, University of Iowa, Iowa City, IA, USA
| | - Michael D Henry
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.,Department of Pathology, University of Iowa, Iowa City, IA, USA.,Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.,Department of Urology, University of Iowa, Iowa City, IA, USA
| | - Dawn E Quelle
- Department of Neuroscience and Pharmacology, University of Iowa, 2-570 Bowen Science Building, 51 Newton Road, Iowa City, IA, 52242, USA. .,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA. .,Department of Pathology, University of Iowa, Iowa City, IA, USA.
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27
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Antitumoral Activity of the MEK Inhibitor Trametinib (TMT212) Alone and in Combination with the CDK4/6 Inhibitor Ribociclib (LEE011) in Neuroendocrine Tumor Cells In Vitro. Cancers (Basel) 2021; 13:cancers13061485. [PMID: 33807122 PMCID: PMC8004919 DOI: 10.3390/cancers13061485] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/17/2021] [Accepted: 03/17/2021] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES This study assessed the antitumoral activity of the MEK inhibitor trametinib (TMT212) and the ERK1/2 inhibitor SCH772984, alone and in combination with the CDK4/6 inhibitor ribociclib (LEE011) in human neuroendocrine tumor (NET) cell lines in vitro. METHODS Human NET cell lines BON1, QGP-1, and NCI-H727 were treated with trametinib or SCH772984, alone and in combination with ribociclib, to assess cell proliferation, cell cycle distribution, and protein signaling using cell proliferation, flow cytometry, and Western blot assays, respectively. RESULTS Trametinib and SCH772984, alone and in combination with ribociclib, significantly reduced NET cell viability and arrested NET cells at the G1 phase of the cell cycle in all three cell lines tested. In addition, trametinib also caused subG1 events and apoptotic PARP cleavage in QGP1 and NCI-H727 cells. A western blot analysis demonstrated the use of trametinib alone and trametinib in combination with ribociclib to decrease the expression of pERK, cMyc, Chk1, pChk2, pCDK1, CyclinD1, and c-myc in a time-dependent manner in NCI-H727 and QGP-1 cells. CONCLUSIONS MEK and ERK inhibition causes antiproliferative effects in human NET cell lines in vitro. The combination of the MEK inhibitor trametinib (TMT212) with the CDK4/6 inhibitor ribociclib (LEE011) causes additive antiproliferative effects. Future preclinical and clinical studies of MEK inhibition in NETs should be performed.
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28
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Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV. Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocr Rev 2021; 42:133-170. [PMID: 33249439 PMCID: PMC7958143 DOI: 10.1210/endrev/bnaa031] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Indexed: 02/06/2023]
Abstract
Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
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Affiliation(s)
| | | | - Nancy D Perrier
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Gerlof D Valk
- University Medical Center Utrecht, CX Utrecht, the Netherlands
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29
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Modelling Pancreatic Neuroendocrine Cancer: From Bench Side to Clinic. Cancers (Basel) 2020; 12:cancers12113170. [PMID: 33126717 PMCID: PMC7693644 DOI: 10.3390/cancers12113170] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/20/2020] [Accepted: 10/23/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic neuroendocrine tumours (pNETs) are a heterogeneous group of epithelial tumours with neuroendocrine differentiation. Although rare (incidence of <1 in 100,000), they are the second most common group of pancreatic neoplasms after pancreatic ductal adenocarcinoma (PDAC). pNET incidence is however on the rise and patient outcomes, although variable, have been linked with 5-year survival rates as low as 40%. Improvement of diagnostic and treatment modalities strongly relies on disease models that reconstruct the disease ex vivo. A key constraint in pNET research, however, is the absence of human pNET models that accurately capture the original tumour phenotype. In attempts to more closely mimic the disease in its native environment, three-dimensional culture models as well as in vivo models, such as genetically engineered mouse models (GEMMs), have been developed. Despite adding significant contributions to our understanding of more complex biological processes associated with the development and progression of pNETs, factors such as ethical considerations and low rates of clinical translatability limit their use. Furthermore, a role for the site-specific extracellular matrix (ECM) in disease development and progression has become clear. Advances in tissue engineering have enabled the use of tissue constructs that are designed to establish disease ex vivo within a close to native ECM that can recapitulate tumour-associated tissue remodelling. Yet, such advanced models for studying pNETs remain underdeveloped. This review summarises the most clinically relevant disease models of pNETs currently used, as well as future directions for improved modelling of the disease.
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30
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Metabolic Effects of Selective Deletion of Group VIA Phospholipase A 2 from Macrophages or Pancreatic Islet Beta-Cells. Biomolecules 2020; 10:biom10101455. [PMID: 33080873 PMCID: PMC7602969 DOI: 10.3390/biom10101455] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/08/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022] Open
Abstract
To examine the role of group VIA phospholipase A2 (iPLA2β) in specific cell lineages in insulin secretion and insulin action, we prepared mice with a selective iPLA2β deficiency in cells of myelomonocytic lineage, including macrophages (MØ-iPLA2β-KO), or in insulin-secreting β-cells (β-Cell-iPLA2β-KO), respectively. MØ-iPLA2β-KO mice exhibited normal glucose tolerance when fed standard chow and better glucose tolerance than floxed-iPLA2β control mice after consuming a high-fat diet (HFD). MØ-iPLA2β-KO mice exhibited normal glucose-stimulated insulin secretion (GSIS) in vivo and from isolated islets ex vivo compared to controls. Male MØ-iPLA2β-KO mice exhibited enhanced insulin responsivity vs. controls after a prolonged HFD. In contrast, β-cell-iPLA2β-KO mice exhibited impaired glucose tolerance when fed standard chow, and glucose tolerance deteriorated further when introduced to a HFD. β-Cell-iPLA2β-KO mice exhibited impaired GSIS in vivo and from isolated islets ex vivo vs. controls. β-Cell-iPLA2β-KO mice also exhibited an enhanced insulin responsivity compared to controls. These findings suggest that MØ iPLA2β participates in HFD-induced deterioration in glucose tolerance and that this mainly reflects an effect on insulin responsivity rather than on insulin secretion. In contrast, β-cell iPLA2β plays a role in GSIS and also appears to confer some protection against deterioration in β-cell functions induced by a HFD.
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31
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Mpilla GB, Philip PA, El-Rayes B, Azmi AS. Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations. World J Gastroenterol 2020; 26:4036-4054. [PMID: 32821069 PMCID: PMC7403797 DOI: 10.3748/wjg.v26.i28.4036] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/10/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are known to be the second most common epithelial malignancy of the pancreas. PNETs can be listed among the slowest growing as well as the fastest growing human cancers. The prevalence of PNETs is deceptively low; however, its incidence has significantly increased over the past decades. According to the American Cancer Society's estimate, about 4032 (> 7% of all pancreatic malignancies) individuals will be diagnosed with PNETs in 2020. PNETs often cause severe morbidity due to excessive secretion of hormones (such as serotonin) and/or overall tumor mass. Patients can live for many years (except for those patients with poorly differentiated G3 neuroendocrine tumors); thus, the prevalence of the tumors that is the number of patients actually dealing with the disease at any given time is fairly high because the survival is much longer than pancreatic ductal adenocarcinoma. Due to significant heterogeneity, the management of PNETs is very complex and remains an unmet clinical challenge. In terms of research studies, modest improvements have been made over the past decades in the identification of potential oncogenic drivers in order to enhance the quality of life and increase survival for this growing population of patients. Unfortunately, the majority of systematic therapies approved for the management of advanced stage PNETs lack objective response or at most result in modest benefits in survival. In this review, we aim to discuss the broad challenges associated with the management and the study of PNETs.
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Affiliation(s)
- Gabriel Benyomo Mpilla
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
| | - Philip Agop Philip
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
| | - Bassel El-Rayes
- Department of Hematology Oncology, Emory Winship Institute, Atlanta, GA 30322, United States
| | - Asfar Sohail Azmi
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
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32
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Xu EY, Vosburgh E, Wong C, Tang LH, Notterman DA. Genetic analysis of the cooperative tumorigenic effects of targeted deletions of tumor suppressors Rb1, Trp53, Men1, and Pten in neuroendocrine tumors in mice. Oncotarget 2020; 11:2718-2739. [PMID: 32733644 PMCID: PMC7367653 DOI: 10.18632/oncotarget.27660] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/15/2020] [Indexed: 01/29/2023] Open
Abstract
Genetic alterations of tumor suppressor genes (TSGs) are frequently observed to have cumulative or cooperative tumorigenic effects. We examined whether the TSGs Rb1, Trp53, Pten and Men1 have cooperative effects in suppressing neuroendocrine tumors (NETs) in mice. We generated pairwise homozygous deletions of these four genes in insulin II gene expressing cells using the Cre-LoxP system. By monitoring growth and examining the histopathology of the pituitary (Pit) and pancreas (Pan) in these mice, we demonstrated that pRB had the strongest cooperative function with PTEN in suppressing PitNETs and had strong cooperative function with Menin and TRP53, respectively, in suppressing PitNETs and PanNETs. TRP53 had weak cooperative function with PTEN in suppressing pituitary lesions. We also found that deletion of Pten singly led to prolactinomas in female mice, and deletion of Rb1 alone led to islet hyperplasia in pancreas. Collectively, our data indicated that pRB and PTEN pathways play significant roles in suppressing PitNETs, while the Menin-mediated pathway plays a significant role in suppressing PanNETs. Understanding the molecular mechanisms of these genes and pathways on NETs will help us understand the molecular mechanisms of neuroendocrine tumorigenesis and develop effective preclinical murine models for NET therapeutics to improve clinical outcomes in humans.
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Affiliation(s)
- Eugenia Y Xu
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.,Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.,Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Evan Vosburgh
- Department of Medicine, Veterans Administration Hospital, West Haven, CT 06516, USA.,Department of Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Chung Wong
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.,Current address: Regeneron Inc., Tarrytown, NY 10591, USA
| | - Laura H Tang
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Daniel A Notterman
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
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33
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Pan J, Bao Q, Enders G. The Altered Metabolic Molecular Signatures Contribute to the RAD001 Resistance in Gastric Neuroendocrine Tumor. Front Oncol 2020; 10:546. [PMID: 32373532 PMCID: PMC7186336 DOI: 10.3389/fonc.2020.00546] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 03/26/2020] [Indexed: 12/13/2022] Open
Abstract
Although the inhibition of mTOR is a promising treatment for neuroendocrine tumors, several questions are still open for cell specificity and resistance. With the newly characterized gastric neuroendocrine tumor mouse model (CEA424-SV40 T antigen transgenic mice), the anti-tumor efficiency of RAD001 (Everolimus) was tested both in vitro and in vivo. Tumor samples were analyzed for the expression of RNA by cDNA microarrays and also signaling pathways to get more details on the local surviving or selected cells. RAD001 treatment dramatically slowed down tumor growth and prolonged the animals' survival. This inhibitory effect has a preference for tumor cells since gastrointestinal hormone and neuroendocrine tumor specific markers were more reduced than the epithelial ones. While phosphorylation of p70S6K was almost completely blocked both in vitro and in vivo, the phosphorylation of 4EBP1 was only partially inhibited in vitro and unaffected in vivo. RAD001 treatment induced feedback activation of metabolism related pathways like PI(3)K–Akt–mTOR and MEK/ERK signalings. An induction of senescence as well as differential expression of genes responsible for metabolism was also observed, which highlighted the contribution of metabolic molecular signatures to the escape of the tumor cells from the treatment. Together, our data revealed efficient anti-tumor ability of RAD001 in a new gastric neuroendocrine tumor mouse model system and offered new insights into the clinical aspects of the incomplete elimination of tumor cells in patients treated.
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Affiliation(s)
- Jie Pan
- Department of Endocrinology and Metabolism, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, China.,Walter Brendel Centre of Experimental Medicine, University of Munich, Munich, Germany
| | - Qi Bao
- Institution of Gastroenterology, Zhejiang University, Hangzhou, China.,Department of Plastic and Reconstructive Surgery, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Georg Enders
- Walter Brendel Centre of Experimental Medicine, University of Munich, Munich, Germany
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34
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Loss of copy of MIR1-2 increases CDK4 expression in ileal neuroendocrine tumors. Oncogenesis 2020; 9:37. [PMID: 32198354 PMCID: PMC7083839 DOI: 10.1038/s41389-020-0221-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 02/24/2020] [Accepted: 02/25/2020] [Indexed: 12/19/2022] Open
Abstract
Ileal neuroendocrine tumors (I-NETs) are the most common tumors of the small intestine. Although I-NETs are known for a lack of recurrently mutated genes, a majority of tumors do show loss of one copy of chromosome 18. Among the genes on chromosome 18 is MIR1-2, which encodes a microRNA, MIR1-3p, with high complementarity to the mRNA of CDK4. Here we show that transfection of neuroendocrine cell lines with MIR1-3p lowered CDK4 expression and activity, and arrested growth at the G1 stage of the cell cycle. Loss of copy of MIR1-2 in ileal neuroendocrine tumors associated with increased expression of CDK4. Genetic events that attenuated RB activity, including loss of copy of MIR1-2 as well as loss of copy of CDKN1B and CDKN2A, were more frequent in tumors from patients with metastatic I-NETs. These data suggest that inhibitors of CDK4/CDK6 may benefit patients whose I-NETs show loss of copy of MIR1-2, particularly patients with metastatic disease.
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