Pancreatic ductal adenocarcinoma has a poor prognosis due to late diagnosis and a lack of effective therapeutic options. Thus, it is important to better understand its molecular mechanisms and to develop more effective treatments for the disease. The ternary complex factor Net, which exerts its strong inhibitory function on transcription of proto-oncogene gene c-fos by forming ternary complexes with a second transcription factor, has been suspected of being involved in pancreatic cancer and other tumors biology. In this study, we found that the majority of pancreatic ductal adenocarcinoma tissues and cell lines had weak or no expression of Net, whereas significantly high level of Net expression occurred in paired adjacent normal tissues we studied. Furthermore, using in vitro and in vivo model systems, we found that overexpression of Net inhibited cell growth and survival and induced cell apoptosis in human pancreatic ductal adenocarcinoma cell PL45; the mechanisms by which Net inhibited the cell cycle
TY - JOUR. T1 - Ex vivo organotypic culture system of precision-cut slices of human pancreatic ductal adenocarcinoma. AU - Misra, Sougat. AU - Moro, Carlos F.. AU - Del Chiaro, Marco. AU - Pouso, Soledad. AU - Sebestyén, A.. AU - Löhr, Matthias. AU - Björnstedt, Mikael. AU - Verbeke, Caroline S.. PY - 2019/12/1. Y1 - 2019/12/1. N2 - Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, which is mainly due to late diagnosis and profound resistance to treatment. The latter is to a large extent attributed to the tumor stroma that is exceedingly prominent in PDAC and engages in complex interactions with the cancer cells. Hence, relevant preclinical models of PDAC should also include the tumor stroma. We herein describe the establishment and functional validation of an ex vivo organotypic culture of human PDAC that is based on precision-cut tissue slices from surgical specimens and reproducibly recapitulates the complex cellular and acellular composition of PDAC, including its ...
In the present study, we found that the centrosomes in nearly all pancreatic ductal carcinomas displayed structural abnormalities, such as an increase in their number and size, and an irregular distribution. Quantitative analysis demonstrated a significant difference in centrosome number between normal and cancer cells. In addition, double-labeled immunofluorescence analysis of MIA PaCa-2 pancreatic cancer cells suggest that these aberrant centrosomes contribute to the assembly of multipolar spindles, which may result in the improper segregation of chromosomes during mitosis. These results are consistent with previous studies describing centrosome abnormalities in human malignant tumors of the breast, prostate, brain, lung, and colon (10 , 11) . To our knowledge, however, this is the first report to demonstrate centrosome abnormalities in pancreatic carcinoma.. The centrosome plays a key role in the organization of cytoplasmic microtubules, in the determination of cell polarity, and in the ...
TY - JOUR. T1 - Co-expression of mesothelin and CA125 correlates with unfavorable patient outcome in pancreatic ductal adenocarcinoma. AU - Einama, Takahiro. AU - Kamachi, Hirofumi. AU - Nishihara, Hiroshi. AU - Homma, Shigenori. AU - Kanno, Hiromi. AU - Takahashi, Kenta. AU - Sasaki, Ayami. AU - Tahara, Munenori. AU - Okada, Kuniaki. AU - Muraoka, Shunji. AU - Kamiyama, Toshiya. AU - Matsuno, Yoshihiro. AU - Ozaki, Michitaka. AU - Todo, Satoru. PY - 2011/11. Y1 - 2011/11. N2 - Objectives: Recent studies have shown that the high affinity of mesothelin-CA125 interaction might cause intracavitary tumor metastasis. We examined the clinicopathologic significance and prognostic implication of mesothelin and CA125 expression in pancreatic ductal adenocarcinoma. Methods: Tissue samples from 66 pancreatic ductal adenocarcinomas were immunohistochemically examined. Proportion and intensity of constituent tumor cells with mesothelin and CA125 expression were analyzed and classified as high-level ...
Osteopontin (OPN) is a secreted phospho-protein that confers on cancer cells a migratory phenotype. We have recently shown that nicotine, a risk factor in pancreatic ductal adenocarcinoma (PDA), induces an alpha7-nicotine acetylcholine receptor (α7-nAChR)-mediated increase of OPN in PDA cells. In this study, we tested nicotines effect on the expression of OPN splice variants (OPNa, b, c) in PDA cells. We also analyzed the correlation between patients smoking history with OPN and α7-nAChR levels. RT-PCR and UV-light-illumination of ethidium-bromide staining were used to examine the mRNA expression in tissue and PDA cells treated with or without nicotine (3-300 nM). Localization of total OPN, OPNc and α7-nAChR was analyzed by immunohistochemistry, and their mRNA tissue expression levels were correlated with the patients smoking history. PDA cells expressed varying levels of OPNa, OPNb, and α7-nAChR. Nicotine treatment selectively induced denovo expression of OPNc and increased α7-nAChR expression
Avarol is a sesquiterpenoid hydroquinone with potent cytotoxicity. Although resolving endoplasmic reticulum (ER) stress is essential for intracellular homeostasis, erratic or excessive ER stress can lead to apoptosis. Here, we reported that avarol selectively induces cell death in pancreatic ductal adenocarcinomas (PDAC), which are difficult to treat owing to the availability of few chemotherapeutic agents. Analyses of the molecular mechanisms of avarol-induced apoptosis indicated upregulation of ER stress marker BiP and ER stress-dependent apoptosis inducer CHOP in PDAC cells but not in normal cells, suggesting that avarol selectively induces ER stress responses. We also showed that avarol activated the PERK-eIF2α pathway but did not affect the IRE1 and ATF6 pathways. Moreover, CHOP downregulation was significantly suppressed by avarol-induced apoptosis. Thus, the PERK-eIF2α-CHOP signaling pathway may be a novel molecular mechanism of avarol-induced apoptosis. The present data indicate that avarol
Glycolytic cancer cells produce large quantities of lactate that must be removed to sustain metabolism in the absence of oxidative phosphorylation. The only venting mechanism described to do this at an adequate rate is H+-coupled lactate efflux on monocarboxylate transporters (MCTs). Outward MCT activity is, however, thermodynamically inhibited by extracellular acidity, a hallmark of solid tumours. This inhibition would feedback unfavourably on metabolism and growth, raising the possibility that other venting mechanisms become important in under-perfused tumours. We investigated connexin-assembled gap junctions as an alternative route for discharging lactate from pancreatic ductal adenocarcinoma (PDAC) cells. Diffusive coupling (calcein transmission) in vitro was strong between Colo357 cells, weaker yet hypoxia-inducible between BxPC3 cells, and very low between MiaPaCa2 cells. Coupling correlated with levels of connexin-43 (Cx43), a protein previously linked to late-stage disease. Evoked lactate
In February of this year the U.S. National Cancer Institute published an important overview of the state of the science and medicine of pancreatic cancer. We will comment on aspects of it from time to time in the future, but as it so comprehensive and precise, in a departure from our usual practice, we will show a copy it here (sans bibliography and figures) in our pancreatic cancer blog. The term "Pancreatic Ductal Carcinoma" is accurate and abbreviated PDAC in the original paper; here in the interests of a potential lay reader we will add in parentheses the term: pancreatic cancer.. Scientific Framework for Pancreatic Ductal Carcinoma Executive Summary Significant scientific progress has been made in the last decade in understanding the biology and natural history of pancreatic ductal adenocarcinoma (PDAC, pancreatic cancer); major clinical advances, however, have not occurred. Although PDAC (pancreatic cancer) shares some of the characteristics of other solid malignancies, such as mutations ...
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude ...
Telomerase activity was measured in surgically resected tissues of 20 human pancreatic ductal carcinomas, 12 adenomas, 5 pancreatitis tissues, 14 normal pancreatic ducts, and 13 normal pancreatic tissues (primarily made up of acinar cells) using a PCR-based telomerase assay. Relative telomerase activity was expressed as the equivalent telomerase intensity of the number of cells of a human pancreatic cancer cell line, MIA PaCa-2, per microgram of protein in the tissue samples. The median value (25th percentile, 75th percentile) of relative telomerase activity in pancreatic carcinomas was 13.2 (3.58, 244), which was significantly higher relative to normal tissues, normal ducts, pancreatitis tissues, and adenomas (P , 0.0001). When the cutoff value of relative telomerase activity was set at 1.00 and 3.00, the positivity rates of telomerase activity in pancreatic ductal carcinomas were 100 and 80%, respectively. Some of the adenoma samples displayed a weak telomerase ladder. However, when ...
TY - JOUR. T1 - Integrated stress response is critical for gemcitabine resistance in pancreatic ductal adenocarcinoma. AU - Palam, L. R.. AU - Gore, J.. AU - Craven, K. E.. AU - Wilson, J. L.. AU - Korc, M.. PY - 2015/10/1. Y1 - 2015/10/1. N2 - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with marked chemoresistance and a 5-year survival rate of 7%. The integrated stress response (ISR) is a cytoprotective pathway initiated in response to exposure to various environmental stimuli. We used pancreatic cancer cells (PCCs) that are highly resistant to gemcitabine (Gem) and an orthotopic mouse model to investigate the role of the ISR in Gem chemoresistance. Gem induced eIF2 phosphorylation and downstream transcription factors ATF4 and CHOP in PCCs, and these effects occurred in an eIF2a-S51 phosphorylation-dependent manner as determined using PANC-1 cells, and wild type and S51 mutant mouse embryo fibroblasts. Blocking the ISR pathway in PCCs with the ISR inhibitor ISRIB or ...
Growing tumors are hypoxic and respond to microenvironmental stress through increased expression of the hypoxia inducible factor-1α (HIF-1α) transcription factor, resulting in an adaptive switch to glycolytic metabolism, angiogenic signaling, survival, and metastasis. HIF-1α expression is associated with tumor resistance to cytotoxic therapy and inferior patient outcomes. Pancreatic cancer is the most hypoxic of all solid tumors and remains refractory to current chemoradiotherapy. We have seen nuclear HIF-1α in 88% of human pancreatic ductal carcinoma but in only 16% of normal pancreas. Stroma adjacent to the pancreatic ductal carcinoma also showed HIF-1α in 43% of cases. We investigated the novel selective HIF-1α inhibitor PX-478 on in vitro and in vivo radiation response of human pancreatic cancer models. Inhibition of HIF-1α by PX-478 increased cell killing by radiation. In mice with Panc-1, CF-PAC-1, or SU.86.86 pancreatic xenografts, concurrent administration of PX-478 potentiated ...
The Wnt/β-catenin pathway has a key role in regulating cellular processes and its aberrant signaling can lead to cancer development. The role of β-catenin expression in pancreatic ductal adenocarcinoma is somewhat controversial. Transcription factor PROX1 is a target of Wnt/β-catenin signaling and it is involved in carcinogenesis through alterations in its expression. The actions can be either oncogenic or tumor suppressive depending on the tissue. The aim of this study was to investigate PROX1 and β-catenin expression in pancreatic ductal adenocarcinoma (PDAC). Expression of PROX1 and β-catenin were evaluated in 156 patients by immunohistochemistry of tissue microarrays. Associations between tumor marker expression and clinicopathological parameters were assessed by the Fischers exact-test or the linear-by-linear association test. The Kaplan-Meier method and log-rank test were used for survival analysis. Uni- and multivariate survival analyses were carried out by the Cox regression proportional
TY - JOUR. T1 - Pancreatic ductal adenocarcinoma radiology reporting template. T2 - Consensus statement of the society of abdominal radiology and the american pancreatic association. AU - Al-Hawary, Mahmoud M.. AU - Francis, Isaac R.. AU - Chari, Suresh T. AU - Fishman, Elliot K.. AU - Hough, David M.. AU - Lu, David S.. AU - Macari, Michael. AU - Megibow, Alec J.. AU - Miller, Frank H.. AU - Mortele, Koenraad J.. AU - Merchant, Nipun B.. AU - Minter, Rebecca M.. AU - Tamm, Eric P.. AU - Sahani, Dushyant V.. AU - Simeone, Diane M.. PY - 2014/1. Y1 - 2014/1. N2 - Pancreatic ductal adenocarcinoma is an aggressive malignancy with a high mortality rate. Proper determination of the extent of disease on imaging studies at the time of staging is one of the most important steps in optimal patient management. Given the variability in expertise and definition of disease extent among different practitioners as well as frequent lack of complete reporting of pertinent imaging findings at radiologic ...
Pancreatic cancer is among the most lethal malignancies worldwide. This study aimed to identify a novel prognostic biomarker, facilitating treatment selection, using mass spectrometry (MS)-based proteomic analysis with formalin-fixed paraffin-embedded (FFPE) tissue. The two groups with poor prognosis (n = 4) and with better prognosis (n = 4) had been carefully chosen among 96 resected cases of pancreatic cancer during 1998 to 2007 in Tohoku University Hospital. Although those 2 groups had adjusted background (UICC-Stage IIB, Grade2, R0, gemcitabine adjuvant), there was a significant difference in postoperative mean survival time (poor 21.0 months, better 58.1 months, P = 0.0067). Cancerous epithelial cells collected from FFPE tissue sections by laser micro-dissection (LMD) were processed for liquid chromatography-tandem mass spectrometry (LC-MS/MS). In total, 1099 unique proteins were identified and 6 proteins showed different expressions in the 2 groups by semi-quantitative comparison. Among these 6
A pancreatic adenocarcinoma cell line (Paca44) was treated with trichostatin-A (TSA), a potent inhibitor of histone deacetylases, in order to evaluate the effect of this drug on protein expression. Master maps of control and treated Paca44 cells were generated by analysis with the PDQuest software. The comparison between such maps showed up- and downregulation of 51 polypeptide chains, out of a total of 700 spots detected by a medium-sensitivity stain, micellar Coomassie Brilliant Blue. Fingerprinting by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)-mass spectrometry analysis enabled the identification of 22 of these spots. Among these proteins, of particular interest are the two downregulated proteins nucleophosmin and translationally controlled tumor protein, as well as the upregulated proteins programmed cell death protein 5 (also designated as TFAR19) and stathmin (oncoprotein 18). The modulation of these four proteins is consistent with our observation that TSA is ...
Pancreatic ductal adenocarcinoma (PDAC) remains amongst the most lethal human cancers. PDAC is characterized by the tumor mass containing a paucity of malignant cells in association with a large desmoplastic reaction comprised of a variety of stromal components. Sporadic PDAC oncogenesis occurs as a result of the sequential acquisition of genetic aberrations occurring in core genetic pathways. Unfortunately, the average PDAC contains a large number of genetic aberrations that are not uniform between individual cancers. The interplay between the complex genetics and stromal component may represent a significant barrier to the development of effective therapy for this disease and ultimately be an important factor in PDAC lethality. The Wnt pathway has been identified as a one of the common pathways undergoing genetic alterations in PDAC. Wnt is a complex signal transduction pathway utilizing both a b-catenin dependent (canonical) and b-catenin independent (noncanonical) signals to affect a wide array of
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma - a process that can take up to 15-20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging ...
Background Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer worldwide, as a result of a late diagnosis and limited therapeutic options. Tumour microenvironment (or stroma) plays a key role in cancer onset and progression and constitutes an intrinsic histological hallmark of PDAC. Thus we hypothesised that relevant prognostic biomarkers and therapeutic targets can be identified in the stroma. Methods Laser microdissection of the stroma from freshly frozen PDAC was combined to gene expression profiling. Protein expression of candidate biomarkers was evaluated by immunohistochemistry on tissue microarrays (n = 80 tumours) and by ELISA in plasma samples (n = 51 patients). Results A signature made of 1256 genes that significantly discriminate the stroma from the non-tumour fibrous tissue was identified. Upregulated genes were associated with inflammation and metastasis processes and linked to NF-Kappa B and TGF beta pathways. TMA analysis validated an increased expression of SFN, ADAMTS12 and CXCL3
The best treatment strategy for patients with locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC) remains the subject of considerable debate. This report presents a case of a 58-year-old woman with locally advanced unresectable PDAC who was treated with sequential FOLFIRINOX for 8 cycles followed by chemoradiation, and continues to show durable disease control 18 months later. The respective roles of systemic therapy and chemoradiation for locally advanced PDAC are discussed, including optimal sequencing of these modalities, recent improvements in chemotherapy, and the question of whether radiotherapy improves survival outcomes in this disease context. ...
Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear. Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival. Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019. Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine. Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence. Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9
Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumours with dismal prognosis. Although curative resection with adjuvant chemoradiotherapy is the most effective treatment, the
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with an overall five-year survival rate of 8%. Due to subtle texture changes of PDAC, pancreatic dual-phase imaging is...
TY - JOUR. T1 - The personalized medicine for pancreatic ductal adenocarcinoma patients: The oncologist perspective. AU - Peretti, U. AU - Zanon, Silvia. AU - Reni, M. PY - 2017. Y1 - 2017. N2 - No abstract available. AB - No abstract available. U2 - 10.4103/eus.eus_62_17. DO - 10.4103/eus.eus_62_17. M3 - Article. VL - 6. SP - S66-S68. JO - Endoscopic Ultrasound. JF - Endoscopic Ultrasound. SN - 2303-9027. IS - Suppl.3. ER - ...
Background Pancreatic ductal adenocarcinoma frequently recurs despite curative surgical resection. This study aims to investigate the patterns of recu..
... , Sia Kim, Malinda Itchins, Jennifer Arena, Chris Nahm, Nick
Enhancement parameters of contrast-enhanced computed tomography for pancreatic ductal adenocarcinoma: Correlation with pathologic grading
Chronic pancreatitis increases by 16 fold the risk of developing pancreatic ductal adenocarcinoma (PDAC), one of the deadliest human cancers. Activating Kras mutations have been detected in 30% of early pancreatic intraepithelial neoplasias (PanINs), increasing to 100% in advanced pancreatic ductal adenocarcinoma (PDAC).. We hypothesize that inflammatory cells recruited to the pancreas in response to chronic injury can interact with epithelial cells harboring activated KrasG12D and affect the progression of PanIN lesions. To test this hypothesis, we have used the inducible transgenic Mist1:CreERT2; LSL-KrasG12D (KCiMist1) adult mice in which the LSL KrasG12D allele is activated specifically in the acinar compartment. This model leads to rapid formation of PanINs with a classic "ductal" phenotype and the progression of lesions is further accelerated with the induction of chronic pancreatitis (CP) generated by recurrent injections of cerulein.. We have found that TH17 cells, a subtype of CD4+ ...
TY - JOUR. T1 - Phase 2 study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer. AU - Herman, Joseph M.. AU - Fan, Katherine Y.. AU - Wild, Aaron T.. AU - Hacker-Prietz, Amy. AU - Wood, Laura D.. AU - Blackford, Amanda L.. AU - Ellsworth, Susannah. AU - Zheng, Lei. AU - Le, Dung T.. AU - De Jesus-Acosta, Ana. AU - Hidalgo, Manuel. AU - Donehower, Ross C.. AU - Schulick, Richard D.. AU - Edil, Barish H.. AU - Choti, Michael A.. AU - Hruban, Ralph H.. AU - Pawlik, Timothy M.. AU - Cameron, John L.. AU - Laheru, Daniel A.. AU - Wolfgang, Christopher L.. PY - 2013/7/15. Y1 - 2013/7/15. N2 - Purpose: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine- erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of ...
Pancreatic cancer is lethal, as it is often detected late. Thus, novel biomarkers of precursor lesions are needed to devise timely therapies. Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) are major precursors of pancreatic cancer. In normal gastric mucosa, gastric gland mucin-specific O-glycans are unique in having α1,4-linked N-acetylglucosamine (αGlcNAc) residues attached to MUC6. Recently we reported that αGlcNAc functions as a tumor suppressor for differentiated-type gastric adenocarcinoma (Karasawa et al., J Clin Invest 122, 923, 2012). MUC6 is also expressed in pancreatic neoplasms, including PanIN and IPMN, but the role of αGlcNAc expression in pancreatic neoplasms remains unknown. Here, we analyze expression patterns of αGlcNAc, MUC6 and MUC5AC in pancreatic neoplasms and compare them with progression from PanIN to invasive ductal adenocarcinoma (IDAC) (the PanIN-IDAC sequence; 20 cases) and from IPMN to IPMN with associated invasive
Introduction IPMN is characterized by a predominantly noninvasive growth pattern with mucin production and cystic duct dilatation. The distinction between IPMN and pancreatic intraepithelial neoplasia (PanIN) ,which is the common precursor of invasive carcinomas
There is a lack of well-established clinical tools for predicting dendritic cell (DC) vaccination response of pancreatic ductal adenocarcinoma (PDAC). DC vaccine treatment efficiency was demonstrated using histological analysis in pre-clinical studies; however, its usage was limited due to invasiveness. In this study, we aimed to investigate the potential of MRI texture features for detection of early immunotherapeutic response as well as overall survival (OS) of PDAC subjects following dendritic cell (DC) vaccine treatment in LSL-KrasG12D;LSL-Trp53R172H;Pdx-1-Cre (KPC) transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC). KPC mice were treated with DC vaccines, and tumor growth was dynamically monitored. A total of a hundred and fifty-two image features of T2-weighted MRI images were analyzed using a kernel-based support vector machine model to detect treatment effects following the first and third weeks of the treatment. Moreover, univariate analysis was performed to describe the
There is a lack of well-established clinical tools for predicting dendritic cell (DC) vaccination response of pancreatic ductal adenocarcinoma (PDAC). DC vaccine treatment efficiency was demonstrated using histological analysis in pre-clinical studies; however, its usage was limited due to invasiveness. In this study, we aimed to investigate the potential of MRI texture features for detection of early immunotherapeutic response as well as overall survival (OS) of PDAC subjects following dendritic cell (DC) vaccine treatment in LSL-KrasG12D;LSL-Trp53R172H;Pdx-1-Cre (KPC) transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC). KPC mice were treated with DC vaccines, and tumor growth was dynamically monitored. A total of a hundred and fifty-two image features of T2-weighted MRI images were analyzed using a kernel-based support vector machine model to detect treatment effects following the first and third weeks of the treatment. Moreover, univariate analysis was performed to describe the
We immunohistochemically examined material from 36 pancreata (adenocarcinomas, 30 lesions; pancreatic intraepithelial neoplasia [PanIN], 65; normal pancreatic ducts, 30) for cyclooxygenase 2 (COX-2) with an automated platform. We analyzed 7 to 10 discrete foci and generated an average percentage of …
There will be two phases to this study. The lead-in phase will evaluate the safety, pharmacokinetics, and define the maximum tolerated dose (MTD) of momelotinib (MMB) combined with nab-paclitaxel and gemcitabine (nab-P + G) in adults with previously untreated metastatic pancreatic ductal adenocarcinoma. The randomized treatment phase will evaluate the efficacy, safety, and tolerability of nab-P + G with either MMB administered at the MTD or placebo in adults with previously untreated metastatic pancreatic ductal adenocarcinoma. Participants will continue study treatment until disease progression, unacceptable toxicity, consent withdrawal, or participants refusal of treatment. Following treatment, participants will be followed for safety for 30 days and for survival approximately every 3 months for up to 3 years ...
BACKGROUND & AIMS: Small nucleolar noncoding RNAs (snoRNAs) regulate function of ribosomes, and specific snoRNAs are dysregulated in some cancer cells. We investigated dysregulation of snoRNAs in pancreatic ductal adenocarcinoma (PDAC) cells. METHODS: We investigated snoRNA expression in PDAC cell lines by complementary DNA microarray and quantitative reverse transcription polymerase chain reaction. In PDAC (n = 133), intraductal papillary mucinous neoplasm (n = 16), mucinous cystic neoplasm-associated PDAC (n = 1), and non-tumor pancreas (n = 8) and liver (n = 3) tissues from subjects who underwent surgical resection, levels of snoRNA were measured by quantitative reverse transcription polymerase chain reaction and compared with clinicopathologic parameters and survival times determined by Kaplan-Meier analysis ...
BACKGROUND: The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results. METHODS: In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation. RESULTS: The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8
Depending on the cellular context, transforming growth factor β (TGFβ) has been observed to exert protumorigenic functions, such as inducing an epithelial-mesenchymal transition (EMT), or inhibit tumorigenesis by activating apoptosis. The proapoptotic functions of TGFβ have been linked with the transcription factor SMAD4, which acts downstream of TGFβ and is frequently deleted in pancreatic ductal carcinoma (PDAC). To elucidate the mechanism by which TGFβ promotes apoptosis, David and colleagues used a Kras-mutant/Smad4-deleted PDAC murine model and found that reintroduction of SMAD4 sensitized cells to TGFβ treatment and promoted changes in cell morphology and loss of E-cadherin consistent with EMT. Moreover, SNAIL was shown to be upregulated following TGFβ treatment, and genetic depletion of SNAIL inhibited TGFβ-induced EMT, apoptosis, and accelerated pancreatic carcinogenesis in SMAD4-wild-type cells, raising the unexpected possibility that EMT precedes apoptosis and is required for ...
One of the hallmarks of human pancreatic ductal adenocarcinoma (PDAC) is its pronounced type I collagen-rich fibrotic reaction. Although recent reports have shown that the fibrotic reaction can limit the efficacy of gemcitabine chemotherapy, the underlying mechanisms remain poorly understood. In this article, we show that the type I collagen allows PDAC cells to override checkpoint arrest induced by gemcitabine. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3-dimensional collagen microenvironment have minimal Chk1 phosphorylation and continue to proliferate in the presence of gemcitabine. Collagen increases membrane type 1 matrix metalloproteinase (MT1-MMP)-dependent ERK1/2 phosphorylation to limit the effect of gemcitabine. Collagen also increases MT1-MMP-dependent high mobility group A2 (HMGA2) expression, a nonhistone DNA-binding nuclear protein involved in chromatin remodeling and gene transcription, to attenuate the effect of gemcitabine. Overexpression of MT1-MMP ...
BAG3 Directly Stabilizes Hexokinase 2 mRNA and Promotes Aerobic Glycolysis in Pancreatic Cancer Cells Scientists showed that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in pancreatic ductal adenocarcinoma cells. [J Cell Biol] Abstract Long Noncoding RNA NORAD, a Novel Competing Endogenous RNA, Enhances the Hypoxia-Induced Epithelial-Mesenchymal Transition to Promote Metastasis in Pancreatic Cancer NORAD expression was measured in 33 paired cancerous and noncancerous tissue samples by real-time PCR. The effects of NORAD on pancreatic cancer cells were studied by overexpression and knockdown in vitro. [Mol Cancer] Full Article A New Panel of Pancreatic Cancer Biomarkers Discovered Using a Mass Spectrometry-Based Pipeline Scientists developed a coherent, high-throughput and non-discriminatory pipeline for the novel clinical biomarker discovery of pancreatic carcinoma. [Br J Cancer] Abstract Alternative Polyadenylation of ZEB1 Promotes Its ...
HuR (Hu protein antigen R) is an mRNA binding protein previously described as a predictive biomarker for selecting pancreatic ductal adenocarcinoma patients for gemcitabine-based therapy. In an independent, validating sample set, high HuR cytoplasmic expression strongly correlated with patients response to gemcitabine, and cytoplasmic HuR status correlated with adverse pathologic characteristics of pancreatic ductal adenocarcinoma better than vascular endothelial growth factor and cyclooxygenase-2. This study supports the notion that cytoplasmic HuR status can help guide the treatment of pancreatic ductal adenocarcinoma ...
Epigenetic alterations have been recognized as important contributors to the pathogenesis of PDAC. However, the role of histone variants in pancreatic tumor progression is still not completely understood. The aim of this study was to explore the expression and prognostic significance of histone protein variants in PDAC patients. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed for qualitative analysis of histone variants and histone related post-translational modifications (PTMs) in PDAC and normal pancreatic tissues. Survival analysis was conducted using the Kaplan-Meier method and Cox proportional hazards regression. Histone variant H1.3 was found to be differentially expressed (p = 0.005) and was selected as a PDAC specific histone variant candidate. The prognostic role of H1.3 was evaluated in an external cohort of patients with resected PDAC using immunohistochemistry. Intratumor expression of H1.3 was found to be an important risk factor for overall survival in PDAC, with an
Qian ZR, Rubinson DA, Nowak JA, Morales-Oyarvide V, Dunne RF, Kozak MM, Welch MW, Brais LK, Da Silva A, Li T, Li W, Masuda A, Yang J, Shi Y, Gu M, Masugi Y, Bui J, Zellers CL, Yuan C, Babic A, Khalaf N, Aguirre A, Ng K, Miksad RA, Bullock AJ, Chang DT, Tseng JF, Clancy TE, Linehan DC, Findeis-Hosey JJ, Doyle LA, Thorner AR, Ducar M, Wollison B, Laing A, Hahn WC, Meyerson M, Fuchs CS, Ogino S, Hornick JL, Hezel AF, Koong AC, Wolpin BM. Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma. JAMA Oncol. 2017 Nov 02. PMID: 29098284. ...
Pancreatic ductal adenocarcinoma (PDAC) ranks as the fourth leading cause of cancer mortality in the United States and causes ,200,000 deaths worldwide annually (1, 2). Histopathological analyses have identified precursor lesions, pancreatic intraepithelial neoplasias (PanIN), which appear to progress through increasingly severe stages of cellular atypia leading to invasive PDAC (3). These lesions show multistep molecular progression that includes early activating KRAS mutations and telomere attrition, and subsequent inactivation of p16Ink4a , p14ARF , p53, and/or SMAD4 tumor suppressors in a high percentage of cases (4-6).. The Ink4a/Arf locus (hereafter denoted p16Ink4a /p19Arf ) encodes tumor suppressors p16INK4A and p14ARF (p19Arf in the mouse). p16INK4A is a G1 cyclin-dependent kinase (CDK) inhibitor that binds to CDK4 and CDK6 and prevents their association with D-type cyclins (7), thereby facilitating CDK4/6-cyclin D-mediated phosphorylation and inactivation of retinoblastoma protein (RB) ...
In HeLa (cervical adenocarcinoma), HEK293T (kidney), HepG2 (hepatocellular carcinoma), Huh-7 (hepatocellular carcinoma), and CFPAC-1 (pancreatic ductal adenocarcinoma) cells, depletion of SQSTM1 with si-SQSTM1 h3 consistently resulted in a increase in the basal protein level of Keap1 (Fig. 2A ...
Rushika M. Perera, PhD, University of California, San Francisco. Dr. Perera has characterized cancer-specific lysosomal proteins and showed that these proteins confer upon pancreatic ductal adenocarcinoma cells two key properties: the ability to rapidly repair cell membranes in the face of sustained mechanical and chemical insults and to alter cell membrane composition to evade recognition by the host immune system. Collectively, these results suggest largely unexplored roles for the lysosome and highlight novel vulnerabilities ...
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers worldwide, partly because methods are lacking to detect disease at an early, operable stage. Noninvasive PDAC precursors called intraductal papillary mucinous neoplasms (IPMN) exist, and strategies are needed to aid in their proper diagnosis and management. Data support the importance of miRNAs in the progression of IPMNs to malignancy, and we hypothesized that miRNAs may be shed from IPMN tissues and detected in blood. Our primary goals were to measure the abundance of miRNAs in archived preoperative plasma from individuals with pathologically confirmed IPMNs and healthy controls and discover plasma miRNAs that distinguish between IPMN patients and controls and between "malignant" and "benign" IPMNs. Using novel nCounter technology to evaluate 800 miRNAs, we showed that a 30-miRNA signature distinguished 42 IPMN cases from 24 controls [area underneath the curve (AUC) = 74.4; 95% confidence interval (CI), 62.3-86.5, P = ...
Although my undergraduate research explored language perception in human subjects, my training has been largely in the fields of basic neuroscience and pain neurobiology. My graduate training focused on channel-channel and channel-receptor interactions involved in the development of masseter hypersensitivity as well as analgesia. My current interests involve exploring how communication between neurons, immune cells, and their target organs not only regulate homeostasis but also how these interactions drive the development of pathophysiological states. My main research program employs a mouse model of human pancreatic ductal adenocarcinoma (PDAC) to study the role of the nervous system in cancer, both with respect to pain and neurogenic inflammation as well as tumorigenesis itself. Our most recent studies focus on how denervation of the pancreas can slow or halt development of tumors. We are currently interested in elucidating the mechanisms underlying the efficacy of denervation. Toward this ...
Background : Carcinoma of the pancreas is a fatal malignant disease with limited therapeutic options. Cyclooxygenase-2 (COX-2) and c-erbB-2 are known to be involved in the carcinogenesis, differentiation and invasiveness of various neoplasms. We studied the immunohistochemical expressions of c-erbB-2 and COX-2 and the correlation between these expressions and the clinicopathologic parameters and the relation between the expressions. Methods : Immunohistochemical staining for c-erbB-2 and COX-2 were performed on the paraffin embedded sections of 36 cases of surgically resected ductal adenocarcinoma of the pancreas and 10 cases of non-neoplastic pancreas tissue. Results : The non-neoplastic control group showed a c-erbB-2 expression in the acini (8/10) and ducts (2/10), and a COX-2 expression in the acini (6/10) and ducts (3/10). The overexpression of c-erbB-2 was observed in 58% (21/36) of the carcinoma specimens. No significant correlation was found between c-erbB-2 and age, gender, tumor size, ...
Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of