1960-1970
Freisen, S. R.; Tracy, H. J.; Grecory, R. A. Mechanism of the Gastric Hypersecretion in the Zollinger-Ellison Syndrome: Successful Extraction of Gastrin-Like Activity from Metastases and Primary Pancreatico-Duodenal Islet Cell Carcinoma. Annals of Surgery 1962, 155 (2), 167–174. https://doi.org/10.1097/00000658-196200000-00001.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1466056/pdf/annsurg00850-0005.pdf
This paper is one of the first papers that reports patients having Zollinger-Ellison syndrome to islet tumor cells. It establishes the base that pancreatic islet cells have the ability to release hormones that result in other issues throughout the body, demonstrated by the release of gastrin that results in Zollinger-Ellison syndrome.
Murraylyon, I. TREATMENT OF MULTIPLE-HORMONE-PRODUCING MALIGNANT ISLET-CELL TUMOUR WITH STREPTOZOTOCIN. The Lancet 1968, 292 (7574), 895–898. https://doi.org/10.1016/S0140-6736(68)91058-1. (Landmark)
This paper is a landmark paper that connects patients suffering from hyperglycemia to malignant islet tumors. It was shown that islet tumors can still produce insulin and glucagon along with the previously established gastrin. Streptozotocin can be used as a drug to reduce the symptoms of hyperglycemia that were observed.
Sandler, M.; Karim, S. M. M.; Williams, E. D. PROSTAGLANDINS IN AMINE-PEPTIDE-SECRETING TUMOURS. The Lancet 1968, 292 (7577), 1053–1055. https://doi.org/10.1016/S0140-6736(68)91528-6.
This paper helps to reinforce the idea of protein secreting tumors that result in adverse effects throughout the body. Tumors in this paper specifically secrete 4 isoforms of prostaglandin.
1971-1980
Goldfine, I. D.; Perlman, R.; Roth, J. Inhibition of Cyclic 3′,5′-AMP Phosphodiesterase in Islet Cells and Other Tissues by Tolbutamide. Nature 1971, 234 (5327), 295–297. https://doi.org/10.1038/234295a0.
This paper introduces molecules that are used to increase insulin production in the pancreas. These drugs are two different types of sulphonylureas; tolbutamide and chlorpropamide. These molecules appear to be connected to the regulation of cyclic-AMP, which is a mechanism that can be used as a potential drug target for islet tumors
Schein, P. S.; O’Connell, M. J.; Blom, J.; Hubbard, S.; Magrath, I. T.; Bergevin, P.; Wiernik, P. H.; Ziegler, J. L.; Devita, V. T. Clinical Antitumor Activity and Toxicity of Streptozotocin (NSC-85998). Cancer 1974, 34 (4), 993–1000. https://doi.org/10.1002/1097-0142(197410)34:4<993::AID-CNCR2820340404>3.0.CO;2-T.
This paper tests the established drug, streptozotocin on a variety of different cancers in the pancreas including islet tumors. In contrast to previous studies, they reported that there was no metastatic difference within tumors while past papers reported remission. They also reported on the first successful response in a serotonin producing islet tumor.
Moertel, C. G.; Hanley, J. A.; Johnson, L. A. Streptozotocin Alone Compared with Streptozocin plus Fluorouracil in the Treatment of Advanced Islet-Cell Carcinoma. N Engl J Med 1980, 303 (21), 1189–1194. https://doi.org/10.1056/NEJM198011203032101. (Landmark)
This landmark paper reports that a combination of streptozotocin and fluorouracil results in an increased survival rate from 16 months when treated with only streptozotocin to 26 months when treated with the chemical mixture. This mixture also resulted in nausea and vomiting, mild and reversible renal toxicity, and bone-marrow depression, which caused the authors to stress that these issues must be solved in order to further the treatment.
1981-1990
*Knepel, W.; Jepeal, L.; Habener, J. F. A Pancreatic Islet Cell-Specific Enhancer-like Element in the Glucagon Gene Contains Two Domains Binding Distinct Cellular Proteins. J Biol Chem 1990, 265 (15), 8725–8735. https://pubmed.ncbi.nlm.nih.gov/2160464/
This paper identifies genes that code for gene enhancers that help produce insulin, somatostatin, and glucagon within islet cells. These enhancers can be used to help further understand how the tumor cells upregulate the production of hormones that cause outside issues outside of the tumor/
*Sanke, T.; Bell, G. I.; Sample, C.; Rubenstein, A. H.; Steiner, D. F. An Islet Amyloid Peptide Is Derived from an 89-Amino Acid Precursor by Proteolytic Processing. J Biol Chem 1988, 263 (33), 17243–17246. https://pubmed.ncbi.nlm.nih.gov/3053705/
This paper builds further on previous reports of amyloid deposits present in islet tumor cells by identifying proteins that are present in the tumors. These proteins include islet amyloid polypeptide (IAPP) and diabetes-associated peptide (DAP). The paper concludes that there may be created through a similar process as proinsulin and that the peptide might be carboxyamidated.
*Tada, M.; Yokosuka, O.; Omata, M.; Ohto, M.; Isono, K. Analysis of Ras Gene Mutations in Biliary and Pancreatic Tumors by Polymerase Chain Reaction and Direct Sequencing. Cancer 1990, 66 (5), 930–935. https://doi.org/10.1002/1097-0142(19900901)66:5<930::AID-CNCR2820660519>3.0.CO;2-W.
This paper took a set of different pancreatic tumors and compared them to known mutations in cancers, specifically point mutations occurring in codon 12,13, or 6 in the ras family of oncogenes. They were able to show a point mutation at codon 12 in the ras gene of the pancreatic tumors, but no other mutations.
*Larsson, C.; Skogseid, B.; Öberg, K.; Nakamura, Y.; Nordenskjöld, M. Multiple Endocrine Neoplasia Type 1 Gene Maps to Chromosome 11 and Is Lost in Insulinoma. Nature 1988, 332 (6159), 85–87. https://doi.org/10.1038/332085a0. (Landmark)
This letter focuses on the gene map on chromosome 11 throughout a family, specifically looking for multiple endocrine neoplasia type I (MEN-1) mutations. It was shown that recessive carriers of the MNE-1 locus on chromosome 11 results in the mutation that allows for the formation of multiple different types of insulin based tumors.
Hanahan, D. Heritable Formation of Pancreatic β-Cell Tumors in Transgenic Mice Expressing Recombinant Insulin/Simian Virus 40 Oncogenes. Nature 1985, 315 (6015), 115–122. https://doi.org/10.1038/315115a0. (Landmark)
This paper used mice to determine the creation of simian virus antigens in oncogenes but ended up finding that α, ß, and δ cells are disorder in mic and can result in inheriting genes that are inherited and can result in pancreatic based tumors.
1991-2000
*Robinson, G. L.; Cordle, S. R.; Henderson, E.; Weil, P. A.; Teitelman, G.; Stein, R. Isolation and Characterization of a Novel Transcription Factor That Binds to and Activates Insulin Control Element-Mediated Expression. Mol Cell Biol 1994, 14 (10), 6704–6714. https://doi.org/10.1128/mcb.14.10.6704-6714.1994.
This paper looks into healthy ß islet cells to understand how insulin is signaled to be produced. They concluded that there are a number of DNA sequences that can be used to express insulin in islet cells. These sequences can be used to further understand the up or down regulation of islet cells in tumors
Moertel, C. G.; Kvols, L. K.; O’Connell, M. J.; Rubin, J. Treatment of Neuroendocrine Carcinomas with Combined Etoposide and Cisplatin. Evidence of Major Therapeutic Activity in the Anaplastic Variants of These Neoplasms. Cancer 1991, 68 (2), 227–232. https://doi.org/10.1002/1097-0142(19910715)68:2<227::AID-CNCR2820680202>3.0.CO;2-I. (Landmark)
This paper uses the drugs etoposide and cisplatin to treat neuroendocrine and islet tumors in the pancreas. The paper concluded that the mixture resulted in n67% of their 45 patients entering remission when given this treatment.
*Giannoukakis, N.; Rudert, W. A.; Trucco, M.; Robbins, P. D. Protection of Human Islets from the Effects of Interleukin-1β by Adenoviral Gene Transfer of an IκB Repressor. Journal of Biological Chemistry 2000, 275 (47), 36509–36513. (Landmark) https://doi.org/10.1074/jbc.M005943200.
This paper looks at healthy ß islet cells in order to understand the effects of interleukin-1ß on cellular apoptosis. They found that an IκB repressor can be used to successfully avoid the induced apoptosis. Understanding the genome of an islet cell is helpful in understanding how the cells go out of control to become tumors
2001-2010
Pelengaris, S.; Khan, M. Oncogenic Co-Operation in Beta-Cell Tumorigenesis. Endocrine-related cancer 2001, 307–314. https://doi.org/10.1677/erc.0.0080307.
Building off the establishment of the hereditary factor of the MEN-1 locus, this paper aims to further understand other oncogenes present. Specifically it looks at the early induced apoptosis by c-mys, another prolific oncogene in tumor growth. It was found that inhibiting myc resulted in the unregulated proliferation of cell growth, potentially leading to tumor growth.
Jonkers, Y.; Ramaekers, F.; Speel, E. Molecular Alterations during Insulinoma Tumorigenesis. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer 2007, 1775 (2), 313–332. https://doi.org/10.1016/j.bbcan.2007.05.004.
This paper looks to further understand the effects that MEN1 mutations have on the tumors at the molecular level. Specifically, they look to find how the menin protein interacts with the cell and it’s expected functions when the mutation is present.
Brom, M.; Oyen, W. J. G.; Joosten, L.; Gotthardt, M.; Boerman, O. C. 68Ga-Labelled Exendin-3, a New Agent for the Detection of Insulinomas with PET. Eur J Nucl Med Mol Imaging 2010, 37 (7), 1345–1355. https://doi.org/10.1007/s00259-009-1363-y. (Landmark)
Tumor detection is extremely important, this paper sets out to use the radioactive agonist exendin-3 labeled with 68Ga. This agonist is common to the glucagon-like peptide 1 receptor (GLP-1R), which is found in about 90% of pancreatic tumors. The group was able to show that exendin-3 labeled with 68Ga is a viable target for detection.
2011-Now
*Hong, X.; Qiao, S.; Li, F.; Wang, W.; Jiang, R.; Wu, H.; Chen, H.; Liu, L.; Peng, J.; Wang, J.; Jia, C.; Liang, X.; Dai, H.; Jiang, J.; Zhang, T.; Liao, Q.; Dai, M.; Cong, L.; Han, X.; Guo, D.; Liang, Z.; Li, D.; Zheng, Z.; Ye, C.; Li, S.; Zhao, Y.; Wu, K.; Wu, W. Whole-Genome Sequencing Reveals Distinct Genetic Bases for Insulinomas and Non-Functional Pancreatic Neuroendocrine Tumours: Leading to a New Classification System. Gut 2020, 69 (5), 877–887. https://doi.org/10.1136/gutjnl-2018-317233.
This paper aimed to find the difference between insulinomas and non-functional pancreatic neuroendocrine tumors. It did this successfully by group pancreatic tumors into new molecular subtypes using whole genome sequencing (WGS) as a guide for the grouping.
Zhang, H.; Zhu, C.; Sun, Z.; Yan, X.; Wang, H.; Xu, H.; Ma, J.; Zhang, Y. Linderane Protects Pancreatic β Cells from Streptozotocin (STZ)-Induced Oxidative Damage. Life Sciences 2019, 233, 116732. https://doi.org/10.1016/j.lfs.2019.116732.
It’s been established that streptozotocin is a viable drug to reduce the effects of islet cell tumors on the body, however, it was established in the 80s that the drug causes bad side effects. This paper focuses on dealing with those side effects by using linderane to reduce the effects of oxidative stress brought onto healthy islet cells from streptozotocin.
Niitsu, Y.; Minami, I.; Izumiyama, H.; Hashimoto, K.; Yoshimoto, T.; Satou, F.; Tsujino, M.; Ota, K.; Kudo, A.; Tanabe, M.; Yamada, T.; Ogawa, Y. Clinical Outcomes of 20 Japanese Patients with Insulinoma Treated with Diazoxide. Endocr J 2019, 66 (2), 149–155. https://doi.org/10.1507/endocrj.EJ18-0353.
This paper aimed to further the understanding of possible drugs to help combat against insulinomas like islet cell tumors. Diazoxide, a known treatment option with adverse effects, was the molecule of interest in order to better understand its effects. This study showed that the side effects occurred more frequently in women and were able to reduce tumor size
Soucek, L.; Buggy, J. J.; Kortlever, R.; Adimoolam, S.; Monclús, H. A.; Allende, M. T. S.; Swigart, L. B.; Evan, G. I. Modeling Pharmacological Inhibition of Mast Cell Degranulation as a Therapy for Insulinoma. Neoplasia 2011, 13 (11), 1093-IN43. https://doi.org/10.1593/neo.11980.
Continuing to understand the myc oncogene, this paper presents an alternative way to trigger apoptosis when myc gets mutated. This involves inhibiting bruton tyrosine kinase, a known degranulation protein, with a synthetic molecule that inhibits BtK and allows for apoptosis to be signaled to start.
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