scholarly journals Gα15 in early onset of pancreatic ductal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Giulio Innamorati ◽  
Thomas M. Wilkie ◽  
Giorgio Malpeli ◽  
Salvatore Paiella ◽  
Silvia Grasso ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
De Novo ◽  
Ectopic Expression ◽  
Human Tumor ◽  
Biological Data ◽  
Ductal Adenocarcinoma ◽  
Preneoplastic Lesions ◽  
Oncogenic Signaling

AbstractThe GNA15 gene is ectopically expressed in human pancreatic ductal adenocarcinoma cancer cells. The encoded Gα15 protein can promiscuously redirect GPCR signaling toward pathways with oncogenic potential. We sought to describe the distribution of GNA15 in adenocarcinoma from human pancreatic specimens and to analyze the mechanism driving abnormal expression and the consequences on signaling and clinical follow-up. We detected GNA15 expression in pre-neoplastic pancreatic lesions and throughout progression. The analysis of biological data sets, primary and xenografted human tumor samples, and clinical follow-up shows that elevated expression is associated with poor prognosis for GNA15, but not any other GNA gene. Demethylation of the 5′ GNA15 promoter region was associated with ectopic expression of Gα15 in pancreatic neoplastic cells, but not in adjacent dysplastic or non-transformed tissue. Down-modulation of Gα15 by shRNA or CRISPR/Cas9 affected oncogenic signaling, and reduced adenocarcimoma cell motility and invasiveness. We conclude that de novo expression of wild-type GNA15 characterizes transformed pancreatic cells. The methylation pattern of GNA15 changes in preneoplastic lesions coincident with the release a transcriptional blockade that allows ectopic expression to persist throughout PDAC progression. Elevated GNA15 mRNA correlates with poor prognosis. In addition, ectopic Gα15 signaling provides an unprecedented mechanism in the early steps of pancreas carcinogenesis distinct from classical G protein oncogenic mutations described previously in GNAS and GNAQ/GNA11.

scholarly journals How pancreatic adenocarcinoma might cause diabetes? The role of TGF- β

2021 ◽  
pp. 05-10
Author(s):  
Hanan F. Aly
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Adenocarcinoma ◽  
De Novo ◽  
Ductal Adenocarcinoma ◽  
Preneoplastic Lesions ◽  
Β Cells ◽  
Selective Depletion ◽  
New Onset

Pancreatic ductal adenocarcinoma (PDAC) is a deadly sickness that stays incurable due to past due diagnosis, which renders any healing intervention challenging. Most PDAC sufferers expand de novo diabetes, which exacerbates their morbidity and mortality. How PDAC triggers diabetes continues to be unfolding. Using a mouse version of KrasG12D-pushed PDAC, which faithfully recapitulates the development of the human sickness, we determined a large and selective depletion of β-cells, taking place very early on the degrees of preneoplastic lesions. Mechanistically, it turned into observed that accelerated TGF beta (TGF-β) signaling throughout PDAC development induced erosion of β-mobileular mass thru apoptosis. Suppressing TGF-β signaling, both pharmacologically thru TGF-β immunoneutralization or genetically thru deletion of Smad4 or TGF-β kind II receptor (TβRII), afforded size able safety in opposition to PDAC-pushed β-mobileular depletion. From a translational perspective, each activation of TGF-β signaling and depletion of β-cells often arise in human PDAC, imparting a mechanistic cause of the pathogenesis of diabetes in PDAC sufferers, and similarly implicating new- onset diabetes as a capability early prognostic marker for PDAC. In this mini review we try to analyze the principle relationships between pancreatic cancer and diabetes and vice versa in addition to the implication of TGF-β signaling as a likely goal for attenuating diabetes in pancreatic most cancers patients.

scholarly journals Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 14 (3) ◽  
pp. 280
Author(s):  
Rita Rebelo ◽  
Bárbara Polónia ◽  
Lúcio Lara Santos ◽  
M. Helena Vasconcelos ◽  
Cristina P. R. Xavier
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Pancreatic Ductal Adenocarcinoma ◽  
De Novo ◽  
Drug Repurposing ◽  
Metastatic Tumor ◽  
Therapeutic Options ◽  
Ductal Adenocarcinoma ◽  
Clinical Indication ◽  
Novel Treatments

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials.

scholarly journals Incidence and frequency of cancer cachexia during chemotherapy for advanced pancreatic ductal adenocarcinoma

2020 ◽  
Vol 28 (11) ◽  
pp. 5271-5279 ◽  
Author(s):  
Shuichi Mitsunaga ◽  
Eiji Kasamatsu ◽  
Koji Machii
Keyword(s):  
Overall Survival ◽  
Weight Loss ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cachexia ◽  
Ductal Adenocarcinoma ◽  
Cancer Therapies ◽  
First Line ◽  
Timing Of Onset ◽  
Line Chemotherapy

Abstract Purpose Cachexia influences the patient’s physical wellbeing and quality of life, and the patient’s ability to tolerate their cancer therapies, especially cytotoxic chemotherapy. The purpose of this study was to investigate the frequency and timing of onset of cancer cachexia during chemotherapy and its association with prognosis and toxicity in patients with pancreatic ductal adenocarcinoma (PDAC). Methods We performed a retrospective study in patients who underwent first-line chemotherapy after diagnosis of advanced PDAC between 6 June 2008 and 31 March 2017. Base cachexia (weight loss up to 6 months before starting first-line chemotherapy) and follow-up cachexia (after starting first-line chemotherapy) were defined as weight loss > 2% with a body mass index (BMI) < 20 kg/m2 or weight loss > 5%. Results A total of 150 patients were registered. The median age and BMI were 65 years and 21.7 kg/m2, respectively. Base cachexia occurred in 50% of patients. Follow-up cachexia occurred in 32% within 12 weeks of starting first-line chemotherapy, reaching 64% at 1 year. Overall survival was not significantly different between patients with and without follow-up cachexia, regardless of whether cancer cachexia occurred within 12, 24, or 48 weeks of starting first-line treatment. Appetite loss, fatigue, nausea, and diarrhea were more frequent in patients with follow-up cachexia than in those without follow-up cachexia. Conclusion Follow-up cachexia had an early onset, but was not a prognostic factor for overall survival in patients with PDAC. Some adverse events tended to be more frequent in patients with follow-up cachexia than in those without follow-up cachexia.

scholarly journals Aberrant methylation ofReprimo correlates with genetic instability and predicts poor prognosis in pancreatic ductal adenocarcinoma

Cancer ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 251-257 ◽  
Author(s):  
Norihiro Sato ◽  
Noriyoshi Fukushima ◽  
Hiroyuki Matsubayashi ◽  
Christine A. Iacobuzio-Donahue ◽  
Charles J. Yeo ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Genetic Instability ◽  
Poor Prognosis ◽  
Ductal Adenocarcinoma ◽  
Aberrant Methylation

High expression of ErbB3 binding protein 1 (EBP1) predicts poor prognosis of pancreatic ductal adenocarcinoma (PDAC)

Tumor Biology ◽  
2015 ◽  
Vol 36 (12) ◽  
pp. 9189-9199 ◽  
Author(s):  
Chen Gong ◽  
Yixin Zhang ◽  
Yinji Chen ◽  
Haifeng Zhang ◽  
Xiaorong Liu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
Binding Protein ◽  
High Expression ◽  
Ductal Adenocarcinoma

Precursors of pancreatic cancer in background of chronic opisthorchiasis

2021 ◽  
Vol 22 (1) ◽  
pp. 118-121
Author(s):  
V. U. Rayn ◽  
◽  
M. A. Persidskiy ◽  
E. V. Malakhova ◽  
I. V. Anuchina ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Free Survival ◽  
Morphological Data ◽  
Small Samples ◽  
Ductal Adenocarcinoma ◽  
Preneoplastic Lesions ◽  
Opisthorchis Felineus ◽  
Disease Free

Aim. To establish the association between pancreatic cancer precursor lesions and chronic opisthorchiasis. Materials and methods. A single center case-control study was conducted at a low-volume pancreatic surgery center in Khanty-Mansiysk. We retrospectively collected morphological data from 47 pancreatoduodenectomies performed for pancreatic ductal adenocarcinoma. The study group included 23 cases of pancreatic ductal adenocarcinoma with concomitant chronic Opisthorchis felineus invasion which were compared to 24 controls consisting of “pure” cancer. Qualitative analysis was performed using χ2 Pearson criterion. Exact Fisher test was used for small samples. Time to progression and overall survival rates were calculated using Kaplan-Meier survival analysis. Data were collected and analyzed in Statistica 7.0. Results. PanINs were seen in 41,7% pancreata resected for ductal adenocarcinoma of the head and in 95,7% cases of pancreatic cancer in background of chronic opisthorchiasis (р = 0,000; 95% CI 3,5-268). PanIN high grade were observed only in opisthorchiasis group. In mixed pathology invasive cancer component tended to be more dedifferentiated and advanced when compared to pure cancer group (p = 0,029). Median disease free survival was 9 mo. in both groups and overall survival was 13 mo. in non-opisthorchiasis group and 15,3 mo. in opisthorchiasis group (р = 0,437). Conclusion. Chronic opisthorchiasis is associated with pancreatic intraepithelial neoplasia. Pancreatic ductal adenocarcinoma in background of opisthorchiasis with preneoplastic lesions tend to be more advanced in stage and poorly differentiated. Disease free and overall survival have no statistically significant differences in patients with and without Opisthorchis felineus invasion.

SLC39A1 Contributes to Gemcitabine Resistance of Pancreatic Ductal Adenocarcinoma by Activating AMPK Signaling

2021 ◽  
Author(s):  
Hao Yu ◽  
Xiaoping Mei ◽  
Xueming Zhang ◽  
Neng Qian ◽  
Qingjiang Yu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Western Blotting ◽  
Poor Prognosis ◽  
Ductal Adenocarcinoma ◽  
Tumor Type ◽  
Ampk Signaling ◽  
Gemcitabine Resistance ◽  
Mrna And Protein Expression

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) serves as a prevailing tumor type with high mortality and poor prognosis. The study aims to explore the mechanism of gemcitabine resistance in PDAC patients. Methods: Immunohistochemistry(IHC)was used to analyze the expression of SLC39A1 in PDAC samples. PDAC cells were culture and transfected with siSLC39A1 and siNC, respectively. Cell proliferation analysis was performed using CCK-8 assay. And qPCR and Western blotting was used to analysis the expression level of SLC39A1 and related signal molecular in cells. Results: IHC results demonstrated that the SLC39A1 expression was significantly up-regulated in the gemcitabine-resistant PDAC samples compared with gemcitabine-sensitive PDAC samples. The treatment of gemcitabine dose-dependently inhibited the viability of the PDAC cells. Meanwhile, the mRNA and protein expression of SLC39A1 were elevated in the gemcitabine-resistant PDAC. The treatment of gemcitabine remarkably decreased viability of PDACs, in which SLC39A1 depletion could reverse this effect. SLC39A1 knockdown could reverse the gemcitabine-induced phosphorylation of AMPK enhanced and gemcitabine-inhibited S6K expression. Conclusion: SLC39A1 contributed to gemcitabine resistance of PDAC by activating AMPK signaling.

Adipophilin expression is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma: An immunohistochemical analysis

Pancreatology ◽  
2019 ◽  
Vol 19 (3) ◽  
pp. 443-448 ◽  
Author(s):  
Yuki Hashimoto ◽  
Mitsuaki Ishida ◽  
Hironori Ryota ◽  
Tomohisa Yamamoto ◽  
Hisashi Kosaka ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
Immunohistochemical Analysis ◽  
Ductal Adenocarcinoma
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