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Nuclear receptors and pathogenesis of pancreatic cancer

World Journal of Gastroenterology 2014年第34期20卷 12062-12081页

作者： simone polvani Mirko Tarocchi Sara Tempesti Andrea Galli Department of Experimental and Clinical Biomedical Sciences University of Florence50134 FlorenceItaly

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.

关键词： Peroxisome proliferator activated receptor Pancreatic intraepithelial neoplasia COUP-TFⅡ Nuclear receptors Orphan nuclear receptor Nuclear receptors 4A2 Nuclear receptors 2F2 Pancreatic cancer Retinoid X receptor Testicular receptor 3

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Molecular mechanism of hepatitis B virus-induced hepatocarcinogenesis

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World Journal of Gastroenterology 2014年第33期20卷 11630-11640页

作者： Mirko Tarocchi simone polvani Giada Marroncini Andrea Galli Department of Experimental and Clinical Biomedical Sciences University of Florence 50139 Florence Italy FiorGen Foundation 50139 Florence Italy

Hepatitis B virus(HBV) infection is a global public health problem with approximately 2 billion people that have been exposed to the virus. HBV is a member of a family of small, enveloped DNA viruses called hepadnaviruses, and has a preferential tropism for hepatocytes of mammals and birds. Epidemiological studies have proved a strong correlation between chronic hepatitis B virus infection and the development of hepatocellular carcinoma(HCC). HCC is the fifth most common malignancy with about 700000 new cases each year, and more than 50% of them arise in HBV carriers. A large number of studies describe the way in which HBV can contribute to HCC development. Multiple mechanisms have been proposed, including the accumulation of genetic damage due to immune-mediated hepatic inflammation and the induction of oxidative stress. There is evidence of the direct effects of the viral proteins HBx and HBs on the cell biology. Integration of HBV-DNAinto the human genome is considered an early event in the carcinogenic process and can induce, through insertional mutagenesis, the alteration of gene expression and chromosomal instability. HBV has also epigenetic effects through the modification of the genomic methylation status. Furthermore, the virus plays an important role in the regulation of microRNA expression. This review will summarize the many mechanisms involved in HBV-related liver carcinogenesis.

关键词： Hepatocellular carcinoma Hepatocarcino-genesis Hepatitis B Virus Chronic hepatitis B infection Cell biology

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Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer

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World Journal of Gastroenterology 2016年第8期22卷 2441-2459页

作者： simone polvani Mirko Tarocchi Sara Tempesti Lapo Bencini Andrea Galli Department of Experimental and Clinical Biomedical Sciences "Mario Serio" University of Florence Chirurgia Generale Oncologica Azienda Ospedaliero Universitaria Careggi

Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.

关键词： Insulin Pancreatic cancer Adipose tissue Metformin Nuclear receptor Leptin Adiponectin Inflammation Thiazolidinediones

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Telomerase reactivation is associated with hepatobiliary and pancreatic cancers

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Hepatobiliary & Pancreatic Diseases International 2020年第5期19卷 420-428页

作者： Vito Sansone Marco Le Grazie Jenny Roselli simone polvani Andrea Galli Francesco Tovoli Mirko Tarocchi Department of Medical and Surgical Sciences University of BolognaBolognaItaly Department of Experimental and Clinical Biomedical Sciences"Mario Serio" University of Florence50139 FirenzeItaly

Background:Human telomerase reverse transcriptase(hTERT)and its components play a significant role in cancer progression,but recent data demonstrated that telomeres and telomerase alterations could be found in other diseases;increasing evidence suggests a key role of this enzyme in the fields of hepatobiliary and pancreatic *** sources:We performed a PubMed search with the following keywords:telomerase,hepatocellular carcinoma,cholangiocarcinoma,pancreatic adenocarcinoma by December *** reviewed the relevant publications that analyzed the correlation between telomerase activity and hepatobiliary and pancreatic ***:Telomerase reactivation plays a significant role in the development and progression of hepatobiliary and pancreatic tumors and could be used as a diagnostic biomarker for hepatobiliary and pancreatic cancers,as a predictor for prognosis and a promising therapeutic ***:Our review summarized the evidence about the critical role of hTERT in cancerous and precancerous lesions of the alteration and its activity in hepatobiliary and pancreatic diseases.

关键词： Telomerase Telomere Cancer Hepatobiliary and pancreatic disease

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Chemotherapy for hepatocellular carcinoma:The present and the future

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World Journal of Hepatology 2017年第21期9卷 907-920页

作者： Marco Le Grazie Maria Rosa Biagini Mirko Tarocchi simone polvani Andrea Galli Gastroenterology Research Unit Department of Experimental and Clinical Biochemical Sciences"Mario Serio"University of Florence50139 FlorenceItaly

Hepatocellular carcinoma(HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it's still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatinand gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

关键词： Hepatocellular carcinoma Systemic therapy Chemotherapy Molecular targeted therapy Cytotoxic therapy Immunotherapy Perspectives

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Telomerase activity: An attractive target for cancer therapeutics

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World Journal of Pharmacology 2014年第4期3卷 86-96页

作者： Lucia Picariello Cecilia Grappone simone polvani Andrea Galli Gastroenterology Unit Department of Experimental and Clinical Biomedical Sciences University of Florence 50139 Florence Italy

Telomeres are non-coding tandem repeats of 1000-2000 TTAGGG nucleotide DNA sequences on the 3’ termini of human chromosomes where they serve as protective “caps” from degradation and loss of genes. The “cap” at the end of chromosome required to protect its integ-rity is a 150-200 nucleotide-long single stranded G-rich 3’ overhang that forms two higher order structures, a T-loop with Sheltering complex, or a G-quadruplex com-plex. Telomerase is a human ribonucleoprotein reverse transcriptase that continually added single stranded TTAGGG DNA sequences onto the single strand 3’ of telomere in the 5’ to 3’ direction. Telomerase activity is detected in male germ line cells, proliferative cells of renewal tissues, some adult pluripotent stem cells, embryonic cells, but in most somatic cells is not de-tected. Re-expression or up-regulation of telomerase in tumours cells is considered as a critical step in cell tumorigenesis and telomerase is widely considered as a tumour marker and a target for anticancer drugs. Dif-ferent approaches have been used in anticancer thera-peutics targeting telomerase. Telomerase inhibitors can block directly Human TElomerase Reverse Transcrip-tase （hTERT） or Human TElomerase RNA telomerase subunits activity, or G-quadruplex and Sheltering complex components, shortening telomeres and inhibiting cell proliferation. Telomerase can become an immune target and GV1001, Vx-001, I540 are the most wide-spread vaccines used with encouraging results. Another method is to use hTERT promoter to drive suicide gene expression or to control a lytic virus replication. Recently telomerase activity was used to activate pro-drugs such as Acycloguanosyl 5’-thymidyltriphosphate, a synthetic ACV-derived molecule when it is activated by telomer-ase it does not require any virus or host active immune response to induce suicide gene therapy. Advantage of all these therapies is that target only neoplastic cells without any effects in normal cells, avoiding toxicity and

关键词： Human telomerase reverse transcriptase Immunotherapy Suicide gene therapy Acycloguanosyl 5'-thymidyltriphosphate Telomerase inhibition

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Gastric and duodenal polyps in familial adenomatous polyposis patients: Conventional endoscopy vs virtual chromoendoscopy(fujinon intelligent color enhancement) in dysplasia evaluation

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World Journal of Clinical Oncology 2017年第2期8卷 168-177页

作者： Gabriele Lami Andrea Galli Giuseppe Macrì Emanuele Dabizzi Maria Rosa Biagini Mirko Tarocchi Luca Messerini Rosa Valanzano Stefano Milani simone polvani Gastroenterology Research Unit Department of Experimental and Clinical Biomedical Sciences "Mario Serio"University of Florence Clinical Gastroenterology Unit Careggi University Hospital Gastroenterology and Gastrointestinal Endoscopy San Raffaele Hospital Division of Pathological Anatomy Department of Experimental and Clinical MedicineUniversity of Florence Surgical Unit Department of Translational Surgery and MedicineUniversity of Florence

AIM To test the fujinon intelligent color enhancement(FICE) in identifying dysplastic or adenomatous polyps in familial adenomatous polyposis(FAP) *** Seventy-six consecutive FAP patients, already treated by colectomy and members of sixty-five families, were enrolled. A FICE system for the upper gastro-intestinal tract with an electronic endoscope system and a standard duodenoscope(for side-viewing examination) were used by two expert examiners. Endoscopic resection was performed with diathermic loop for polyps ≥ 6 mm and with forceps for polyps < 6 mm. Formalin-fixed biopsy specimens were analyzed by two expert gastrointestinal pathologists blinded to size, location and number of FAPassociated fundic gland *** Sixty-nine(90.8%) patients had gastric polyps(34 only in the corpus-fundus, 7 only in the antrum and 28 in the whole stomach) and 52(68.4%) in duodenum(7 in the bulb, 35 in second/third duodenal portion, 10 both in the bulb and the second portion of duodenum). In the stomach fundus after FICE evaluation, 10 more polyps were removed from 10 patients for suspicious features of dysplasia or adenomas, but they were classified as cystic fundic gland after histology. In the antrum FICE identified more polyps than traditional endoscopy, showing a better tendency to identify adenomas and displastic areas. In the duodenum FICE added a significant advantage in identifying adenomas in the bulb and identified more polyps in the Ⅱ/Ⅲ *** FICE significantly increases adenoma detection rate in FAP patients but does not change any Spigelman stage and thus does not modify patient's prognosis and treatment strategies.

关键词： Fujinon intelligent color enhancement Familial adenomatous polyposis Spigelman Endoscopy Polyp Adenoma Stomach Duodenum

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