MicroRNA-21 Is Induced Early in Pancreatic Ductal Adenocarcinoma Precursor Lesions

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has the poorest overall prognosis among gastrointestinal cancers; however, curative resection in early-stage PDAC greatly improves survival rates, indicating the importance of early detection. Because abnormal microRNA production is commonly detected in cancer, we investigated noninvasive precursor pancreatic intraepithelial neoplasia (PanIN) lesions for microRNA production as a potential early biomarker of PDAC. Methods: Pathologists identified and classified ductal lesions. We extracted total RNA from laser-capture microdissected PanIN tissue samples from a conditional KRAS(G12D) mouse model (n = 29) or of human origin (n = 38) (KRAS is v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). MicroRNA production was quantified by quantitative real-time PCR. Internal controls included 5S and U6 RNAs. Results: Production of microRNAs miR-21, miR-205, and miR-200 paralleled PanIN progression in the KRAS(G12D) mouse model, compared with microRNA production in samples of nonpathologic ducts. miR-21 demonstrated the highest relative concentrations in the precursor lesions. Interestingly, miR-205 and miR-21 up-regulation preceded phenotypic changes in the ducts. The production of microRNAs miR-21, miR-221, miR-222, and let-7a increased with human PanIN grade, with peak production occurring in hyperplastic PanIN-2/3 lesions. In situ hybridization analysis indicated miR-21 production to be concentrated in pathologic ductal cells. miR-21 production was regulated by KRAS(G12D) and epidermal growth factor receptor in PDAC-derived cell lines. Conclusions: Aberrant microRNA production is an early event in the development of PanIN. Our findings indicate that miR-21 warrants further investigation as a marker for early detection of PDAC.

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Panel of serum miRNAs as potential non-invasive biomarkers for pancreatic ductal adenocarcinoma

Scientific Reports ◽

10.1038/s41598-021-82266-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Imteyaz Ahmad Khan ◽

Safoora Rashid ◽

Nidhi Singh ◽

Sumaira Rashid ◽

Vishwajeet Singh ◽

...

Keyword(s):

Next Generation Sequencing ◽

Pancreatic Ductal Adenocarcinoma ◽

Early Stage ◽

Ductal Adenocarcinoma ◽

Next Generation ◽

Serum Samples ◽

Tissue Samples ◽

Non Invasive ◽

Specific Symptoms ◽

Generation Sequencing

AbstractEarly-stage diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to non-specific symptoms. Circulating miRNAs in body fluids have been emerging as potential non-invasive biomarkers for diagnosis of many cancers. Thus, this study aimed to assess a panel of miRNAs for their ability to differentiate PDAC from chronic pancreatitis (CP), a benign inflammatory condition of the pancreas. Next-generation sequencing was performed to identify miRNAs present in 60 FFPE tissue samples (27 PDAC, 23 CP and 10 normal pancreatic tissues). Four up-regulated miRNAs (miR-215-5p, miR-122-5p, miR-192-5p, and miR-181a-2-3p) and four down-regulated miRNAs (miR-30b-5p, miR-216b-5p, miR-320b, and miR-214-5p) in PDAC compared to CP were selected based on next-generation sequencing results. The levels of these 8 differentially expressed miRNAs were measured by qRT-PCR in 125 serum samples (50 PDAC, 50 CP, and 25 healthy controls (HC)). The results showed significant upregulation of miR-215-5p, miR-122-5p, and miR-192-5p in PDAC serum samples. In contrast, levels of miR-30b-5p and miR-320b were significantly lower in PDAC as compared to CP and HC. ROC analysis showed that these 5 miRNAs can distinguish PDAC from both CP and HC. Hence, this panel can serve as a non-invasive biomarker for the early detection of PDAC.

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Acinar transformed ductal cells exhibit differential mucin expression in a tamoxifen-induced pancreatic ductal adenocarcinoma mouse model

Biology Open ◽

10.1242/bio.052878 ◽

2020 ◽

Vol 9 (9) ◽

pp. bio052878

Author(s):

Kavita Mallya ◽

Dhanya Haridas ◽

Parthasarathy Seshacharyulu ◽

Ramesh Pothuraju ◽

Wade M. Junker ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Pancreatic Ductal Adenocarcinoma ◽

Intraepithelial Neoplasia ◽

Ductal Adenocarcinoma ◽

Chemotherapy Response ◽

Pancreatic Intraepithelial Neoplasia ◽

Ductal Cells ◽

Mucin Expression ◽

Acinar To Ductal Metaplasia

ABSTRACTPancreatic cancer (PC) is acquired postnatally; to mimic this scenario, we developed an inducible KrasG12D; Ptf1a-CreER™ (iKC) mouse model, in which Kras is activated postnatally at week 16 upon tamoxifen (TAM) administration. Upon TAM treatment, iKC mice develop pancreatic intraepithelial neoplasia (PanIN) lesions and PC with metastasis at the fourth and fortieth weeks, respectively, and exhibited acinar-to-ductal metaplasia (ADM) and transdifferentiation. Kras activation upregulated the transcription factors Ncoa3, p-cJun and FoxM1, which in turn upregulated expression of transmembrane mucins (Muc1, Muc4 and Muc16) and secretory mucin (Muc5Ac). Interestingly, knockdown of KrasG12D in multiple PC cell lines resulted in downregulation of MUC1, MUC4, MUC5AC and MUC16. In addition, iKC mice exhibited ADM and transdifferentiation. Our results show that the iKC mouse more closely mimics human PC development and can be used to investigate pancreatic ductal adenocarcinoma (PDAC) biomarkers, early onset of PDAC, and ADM. The iKC model can also be used for preclinical strategies such as targeting mucin axis alone or in combination with neo-adjuvant, immunotherapeutic approaches and to monitor chemotherapy response.

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The Impact of Biomarkers in Pancreatic Ductal Adenocarcinoma on Diagnosis, Surveillance and Therapy

Cancers ◽

10.3390/cancers14010217 ◽

2022 ◽

Vol 14 (1) ◽

pp. 217

Author(s):

Niklas Sturm ◽

Thomas J. Ettrich ◽

Lukas Perkhofer

Keyword(s):

Early Detection ◽

Pancreatic Ductal Adenocarcinoma ◽

Early Stage ◽

Therapy Response ◽

Ductal Adenocarcinoma ◽

Current State ◽

Novel Biomarkers ◽

State Of Research ◽

Noninvasive Biomarkers ◽

The Impact

Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer.

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Incidentally discovered pancreatic ductal adenocarcinoma: Is detection of asymptomatic cancer associated with better outcomes than symptomatic cancer?

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.243 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 243-243

Author(s):

Yoshinori Takeda ◽

Akio Saiura ◽

Yoshihiro Mise ◽

Takeaki Ishizawa ◽

Yosuke Inoue ◽

...

Keyword(s):

Early Detection ◽

Pancreatic Ductal Adenocarcinoma ◽

Surgical Resection ◽

Early Stage ◽

Ductal Adenocarcinoma ◽

Incomplete Resection ◽

Long Term Outcomes ◽

Potential Implication ◽

Treatment Type

243 Background: The number of incidentally discovered asymptomatic pancreatic ductal adenocarcinoma (APDAC) has been increasing along with recent wide spread use of imaging studies in general practice. However, the clinical implication in early detection of asymptomatic pancreatic cancer remains yet to be determined. In this study, we reviewed our experience of patients with PDAC in high volume cancer center and compared the characteristics and long-term outcomes between those with APDAC and symptomatic PDAC (SPDAC). Methods: This retrospective study included 569 consecutive patients with PDAC initially treated in our institution from January 2007 to December 2012. Median follow-up period was 29 months for the survivors. Two hundred and fifty patients underwent surgical resection and 319 patients were deemed unresectable. The patient’s demographics, tumor locations, pathologic stages, and treatment type received, and the overall survival (OS) were compared between the patients with APDAC and those with SPDAC. Results: One hundred and sixty-three patients (29%) presented without any subjective symptoms. When compared with SPDAC, APDAC was associated with early stage (stage I, 6% vs. 1%, p<0.01). Among 163 patients with APDAC, 104 patients (64%) underwent surgical resection, while only 146 patients (36%) out of 406 SPDAC underwent resection ( p<0.01). The 5-year OS rate of the patients with APDAC was 18%, comparing with 7% for those with SPDAC ( p<0.01). Among the patients who underwent resection, the presence of symptoms did not affect the chance of incomplete resection (R1, 12% vs. 22% for patients with APDAC and SPDAC, respectively, p=0.06) and the 5-year OS rate (23% vs. 22%, p=0.09). However, the patients with SPDAC required complex operation (concomitant vascular resection and reconstruction 56% vs. 29% for those with APDAC, p<0.01). Conclusions: Asymptomatic PDAC is associated with better long-term outcomes than symptomatic PDAC due to early stage at presentation and higher chance of resectability. Our findings highlight the potential implication of screening program for early detection of PDAC for selected high-risk patient population.

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Differentiation of Pancreatic Ductal Adenocarcinoma From Chronic Pancreatitis by PAM4 Immunohistochemistry

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2013-0056-oa ◽

2014 ◽

Vol 138 (2) ◽

pp. 220-228 ◽

Cited By ~ 12

Author(s):

Chanjuan Shi ◽

Nipun Merchant ◽

Guy Newsome ◽

David M. Goldenberg ◽

David V. Gold

Keyword(s):

Monoclonal Antibody ◽

Chronic Pancreatitis ◽

Pancreatic Ductal Adenocarcinoma ◽

Early Stage ◽

High Specificity ◽

Intraepithelial Neoplasia ◽

Tissue Microarrays ◽

Ductal Adenocarcinoma ◽

Precursor Lesions ◽

Pancreatic Intraepithelial Neoplasia

Context.—PAM4 is a monoclonal antibody that shows high specificity for pancreatic ductal adenocarcinoma (PDAC) and its neoplastic precursor lesions. A PAM4-based serum immunoassay is able to detect 71% of early-stage patients and 91% with advanced disease. However, approximately 20% of patients diagnosed with chronic pancreatitis (CP) are also positive for circulating PAM4 antigen. The specificity of the PAM4 antibody is critical to the interpretation of the serum-based and immunohistochemical assays for detection of PDAC. Objective.—To determine whether PAM4 can differentiate PDAC from nonneoplastic lesions of the pancreas. Design.—Tissue microarrays of PDAC (N = 43) and surgical specimens from CP (N = 32) and benign cystic lesions (N = 19) were evaluated for expression of the PAM4 biomarker, MUC1, MUC4, CEACAM5/6, and CA19-9. Results.—PAM4 and monoclonal antibodies (MAbs) to MUC1, MUC4, CEACAM5/6, and CA19-9 were each reactive with the majority of PDAC cases; however, PAM4 was the only monoclonal antibody not to react with adjacent, nonneoplastic parenchyma. Although PAM4 labeled 19% (6 of 32) of CP specimens, reactivity was restricted to pancreatic intraepithelial neoplasia associated with CP; inflamed tissues were negative in all cases. In contrast, MUC1, MUC4, CEACAM5/6, and CA19-9 were detected in 90%, 78%, 97%, and 100% of CP, respectively, with reactivity also present in nonneoplastic inflamed tissue. Conclusions.—PAM4 was the only monoclonal antibody able to differentiate PDAC (and pancreatic intraepithelial neoplasia precursor lesions) from benign, nonneoplastic tissues of the pancreas. These results suggest the use of PAM4 for evaluation of tissue specimens, and support its role as an immunoassay for detection of PDAC.

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Advances in Early Detection of Pancreatic Cancer

Diagnostics ◽

10.3390/diagnostics9010018 ◽

2019 ◽

Vol 9 (1) ◽

pp. 18 ◽

Cited By ~ 7

Author(s):

Atsushi Kanno ◽

Atsushi Masamune ◽

Keiji Hanada ◽

Masataka Kikuyama ◽

Masayuki Kitano

Keyword(s):

Pancreatic Cancer ◽

Early Detection ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Early Stage ◽

Epidemiological Data ◽

The United States ◽

Ductal Adenocarcinoma ◽

Intraductal Papillary Mucinous Neoplasms ◽

Mucinous Neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. PDAC is the fourth leading cause of death in the United States and Japan based on epidemiological data. Early detection of PDAC is very important to improve the prognosis of PDAC. Early detection of pancreatic ductal adenocarcinoma (PDAC) requires further examination after selecting cases with risk factors for the condition, such as family history, hereditary pancreatic carcinoma syndrome, intraductal papillary mucinous neoplasms, or chronic pancreatitis. The Japan Study Group on the Early Detection of Pancreatic Cancer has investigated and clarified the clinicopathological features for the early diagnosis of PDAC. In Japan, an algorithm for the early diagnosis of PDAC, which utilized the cooperation of local clinics and regional general hospitals, has been a breakthrough in the detection of early-stage PDAC. Further approaches for the early diagnosis of PDAC are warranted.

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Primary pancreatic ductal adenocarcinoma cell cultures represent the features of native tumours

Biologija ◽

10.6001/biologija.v65i1.3983 ◽

2019 ◽

Vol 65 (1) ◽

Author(s):

Marija Ger ◽

Eglė Žalytė ◽

Algirdas Kaupinis ◽

Benediktas Kurlinkus ◽

Marius Petrulionis ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Cell Cultures ◽

Early Stage ◽

Focal Adhesions ◽

Chemotherapeutic Agents ◽

Ductal Adenocarcinoma ◽

Diagnostic Tools ◽

Pdgf Receptor ◽

Tissue Samples ◽

Low Efficiency

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer due to the lack of diagnostic tools at the early stage and low efficiency of current chemotherapeutic approaches. The anticancer compounds with proven efficiency in established cell cultures often fail validation in further research. In this study, we employed PDAC patient-derived primary cell cultures to evaluate the efficiency of chemotherapeutic agents. Alongside, patients’ tissue samples were analysed by high-throughput differential proteomic analysis. We have shown that main firstline chemotherapeutic agents gemcitabine and FOLFIRINOX have little to no effect on the viability of patient-derived primary PDAC cells. The comparative proteomic and bioinformatic analysis of PDAC tumours shows an increase in the components of the extracellular matrix and focal adhesions and also overexpression of the downstream signaling from a variety of receptors, most notably PDGF receptor β and ErbB1 receptor. Consistently, all tumour-derived cell cultures assayed express a high level of PDGF receptor β. The enhancement of multiple signaling pathways leads to the increase in cell survival, proliferation, and resistance to apoptosis. Here we demonstrated the promising value of patient-derived primary PDAC cultures as a model for anticancer drug research and evaluation for individualized therapy.

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New Onset of DiabetEs in aSsociation with pancreatic ductal adenocarcinoma (NODES Trial): protocol of a prospective, multicentre observational trial

BMJ Open ◽

10.1136/bmjopen-2020-037267 ◽

2020 ◽

Vol 10 (11) ◽

pp. e037267

Author(s):

Dóra Illés ◽

Emese Ivány ◽

Gábor Holzinger ◽

Klára Kosár ◽

M Gordian Adam ◽

...

Keyword(s):

High Risk ◽

Early Detection ◽

Pancreatic Ductal Adenocarcinoma ◽

Clinical Symptoms ◽

Risk Group ◽

High Risk Group ◽

Ductal Adenocarcinoma ◽

Onset Diabetes ◽

Dismal Prognosis ◽

New Onset

IntroductionPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with an overall 5-year survival of approximately 8%. The success in reducing the mortality rate of PDAC is related to the discovery of new therapeutic agents, and to a significant extent to the development of early detection and prevention programmes. Patients with new-onset diabetes mellitus (DM) represent a high-risk group for PDAC as they have an eightfold higher risk of PDAC than the general population. The proposed screening programme may allow the detection of PDAC in the early, operable stage. Diagnosing more patients in the curable stage might decrease the morbidity and mortality rates of PDAC and additionally reduce the burden of the healthcare.Methods and analysisThis is a prospective, multicentre observational cohort study. Patients ≥60 years old diagnosed with new-onset (≤6 months) diabetes will be included. Exclusion criteria are (1) Continuous alcohol abuse; (2) Chronic pancreatitis; (3) Previous pancreas operation/pancreatectomy; (4) Pregnancy; (5) Present malignant disease and (6) Type 1 DM. Follow-up visits are scheduled every 6 months for up to 36 months. Data collection is based on questionnaires. Clinical symptoms, body weight and fasting blood will be collected at each, carbohydrate antigen 19–9 and blood to biobank at every second visit. The blood samples will be processed to plasma and analysed with mass spectrometry (MS)-based metabolomics. The metabolomic data will be used for biomarker validation for early detection of PDAC in the high-risk group patients with new-onset diabetes. Patients with worrisome features will undergo MRI or endoscopic ultrasound investigation, and surgical referral depending on the radiological findings. One of the secondary end points is the incidence of PDAC in patients with newly diagnosed DM.Ethics and disseminationThe study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (41085-6/2019). We plan to disseminate the results to several members of the healthcare system includining medical doctors, dietitians, nurses, patients and so on. We plan to publish the results in a peer-reviewed high-quality journal for professionals. In addition, we also plan to publish it for lay readers in order to maximalise the dissemination and benefits of this trial.Trial registration numberClinicalTrials.gov NCT04164602

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