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Watanabe F, Suzuki K, Noda H, Rikiyama T. Liquid biopsy leads to a paradigm shift in the treatment of pancreatic cancer. World J Gastroenterol 2022; 28:6478-6496. [PMID: 36569270 PMCID: PMC9782840 DOI: 10.3748/wjg.v28.i46.6478] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/25/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most cancers. Its 5-year survival rate is very low. The recent induction of neoadjuvant chemotherapy and improvements in chemotherapy for patients with pancreatic cancer have resulted in improved survival outcomes. However, the prognosis of pancreatic cancer is still poor. To dramatically improve the prognosis, we need to develop more tools for early diagnosis, treatment selection, disease monitoring, and response rate evaluation. Recently, liquid biopsy (circulating free DNA, circulating tumor DNA, circulating tumor cells, exosomes, and microRNAs) has caught the attention of many researchers as a new biomarker that is minimally invasive, confers low-risk, and displays an overall state of the tumor. Thus, liquid biopsy does not employ the traditional difficulties of obtaining tumor samples from patients with advanced PDAC to investigate their molecular biological status. In addition, it allows for long-term monitoring of the molecular profile of tumor progression. These could help in identifying tumor-specific alterations that use the target structure for tailor-made therapy. Through this review, we highlighted the latest discoveries and advances in liquid biopsy technology in pancreatic cancer research and showed how it can be applied in clinical practice.
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Affiliation(s)
- Fumiaki Watanabe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Koichi Suzuki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Hiroshi Noda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Toshiki Rikiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
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2
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Watanabe F, Suzuki K, Tamaki S, Abe I, Endo Y, Takayama Y, Ishikawa H, Kakizawa N, Saito M, Futsuhara K, Noda H, Konishi F, Rikiyama T. Optimal value of CA19-9 determined by KRAS-mutated circulating tumor DNA contributes to the prediction of prognosis in pancreatic cancer patients. Sci Rep 2021; 11:20797. [PMID: 34675229 PMCID: PMC8531317 DOI: 10.1038/s41598-021-00060-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 09/23/2021] [Indexed: 12/24/2022] Open
Abstract
Despite the acceptance of carbohydrate antigen 19-9 (CA19-9) as a valuable predictor for the prognosis of pancreatic ductal adenocarcinoma (PDAC), its cutoff value remains controversial. Our previous study showed a significant correlation between CA19-9 levels and the presence of KRAS-mutated ctDNA in the blood of patients with PDAC. Based on this correlation, we investigated the optimal cutoff value of CA19-9 before surgery. Continuous CA19-9 values and KRAS-mutated ctDNAs were monitored in 22 patients with unresectable PDAC who underwent chemotherapy between 2015 and 2017. Receiver operating characteristic curve analysis identified 949.7 U/mL of CA19-9 as the cutoff value corresponding to the presence of KRAS-mutated ctDNA. The median value of CA19-9 was 221.1 U/mL. Subsequently, these values were verified for their prognostic values of recurrence-free survival (RFS) and overall survival (OS) in 60 patients who underwent surgery between 2005 and 2013. Multivariate analysis revealed that 949.7 U/mL of CA19-9 was an independent risk factor for OS and RFS in these patients (P = 0.001 and P = 0.010, respectively), along with lymph node metastasis (P = 0.008 and P = 0.017), unlike the median CA19-9 level (P = 0.150 and P = 0.210). The optimal CA19-9 level contributes to the prediction of prognosis in patients with PDAC before surgery.
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Affiliation(s)
- Fumiaki Watanabe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Koichi Suzuki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan.
| | - Sawako Tamaki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Iku Abe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Yuhei Endo
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Yuji Takayama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Hideki Ishikawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Nao Kakizawa
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Masaaki Saito
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Kazushige Futsuhara
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Hiroshi Noda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Fumio Konishi
- Nerima Hikarigaoka Hospital, 2-11-1, Hikarigaoka, Nerima-ku, Tokyo, 179-0072, Japan
| | - Toshiki Rikiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
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Anger F, Döring A, van Dam J, Lock JF, Klein I, Bittrich M, Germer CT, Wiegering A, Kunzmann V, van Eijck C, Löb S. Impact of Borderline Resectability in Pancreatic Head Cancer on Patient Survival: Biology Matters According to the New International Consensus Criteria. Ann Surg Oncol 2020; 28:2325-2336. [PMID: 32920720 PMCID: PMC7940298 DOI: 10.1245/s10434-020-09100-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/18/2020] [Indexed: 12/19/2022]
Abstract
Background International consensus criteria (ICC) have redefined borderline resectability for pancreatic ductal adenocarcinoma (PDAC) according to three dimensions: anatomical (BR-A), biological (BR-B), and conditional (BR-C). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumour and vessels but that biological and conditional dimensions also are important. Methods Patients’ tumours were retrospectively defined borderline resectable according to ICC. The study cohort was grouped into either BR-A or BR-B and compared with patients considered primarily resectable (R). Differences in postoperative complications, pathological reports, overall (OS), and disease-free survival were assessed. Results A total of 345 patients underwent resection for PDAC. By applying ICC in routine preoperative assessment, 30 patients were classified as stage BR-A and 62 patients as stage BR-B. In total, 253 patients were considered R. The cohort did not contain BR-C patients. No differences in postoperative complications were detected. Median OS was significantly shorter in BR-A (15 months) and BR-B (12 months) compared with R (20 months) patients (BR-A vs. R: p = 0.09 and BR-B vs. R: p < 0.001). CA19-9, as the determining factor of BR-B patients, turned out to be an independent prognostic risk factor for OS. Conclusions Preoperative staging defining surgical resectability in PDAC according to ICC is crucial for patient survival. Patients with PDAC BR-B should be considered for multimodal neoadjuvant therapy even if considered anatomically resectable.
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Affiliation(s)
- Friedrich Anger
- Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, Julius Maximilians University Wuerzburg, Würzburg, Germany
| | - Anna Döring
- Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, Julius Maximilians University Wuerzburg, Würzburg, Germany
| | - Jacob van Dam
- Department of Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands
| | - Johan Friso Lock
- Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, Julius Maximilians University Wuerzburg, Würzburg, Germany
| | - Ingo Klein
- Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, Julius Maximilians University Wuerzburg, Würzburg, Germany
| | - Max Bittrich
- Department of Internal Medicine II, Julius Maximilians University Wuerzburg, Würzburg, Germany
| | - Christoph-Thomas Germer
- Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, Julius Maximilians University Wuerzburg, Würzburg, Germany.,Comprehensive Cancer Centre Mainfranken, Julius Maximilians University Wuerzburg, Würzburg, Germany
| | - Armin Wiegering
- Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, Julius Maximilians University Wuerzburg, Würzburg, Germany.,Comprehensive Cancer Centre Mainfranken, Julius Maximilians University Wuerzburg, Würzburg, Germany
| | - Volker Kunzmann
- Department of Internal Medicine II, Julius Maximilians University Wuerzburg, Würzburg, Germany.,Comprehensive Cancer Centre Mainfranken, Julius Maximilians University Wuerzburg, Würzburg, Germany
| | - Casper van Eijck
- Department of Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands
| | - Stefan Löb
- Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, Julius Maximilians University Wuerzburg, Würzburg, Germany.
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Wu C, Yang P, Liu B, Tang Y. Is there a CDKN2A-centric network in pancreatic ductal adenocarcinoma? Onco Targets Ther 2020; 13:2551-2562. [PMID: 32273725 PMCID: PMC7108878 DOI: 10.2147/ott.s232464] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 02/19/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer has a high mortality rate and its incidence has risen rapidly in recent years. Meanwhile, the diagnosis and treatment of this cancer remain challenging. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, but, currently, no sufficiently effective modalities for its treatment exist. The early diagnosis rate of pancreatic cancer is low and most patients have reached an advanced stage at the time of diagnosis. PDAC evolves from precancerous lesions and is highly aggressive and metastatic. It is essential to understand how the disease progresses and metastasizes. CDKN2A mutations are very common in PDAC. Therefore, here, we have performed a literature review and discuss the role of CDKN2A and some related genes in the development of PDAC, as well as the basis of gene targeting with a correlation coefficient of CDKN2A above 0.9 on the STRING website. It is noteworthy that the interaction of CDKN2A with each gene has been reported in the literature. The role of these genes and CDKN2A in PDAC may provide new directions that will advance the current knowledge base and treatment options since cancer progression is realized through interactions among cells. Our findings provide new insights into the treatment of PADC that can, to some extent, improve the diagnosis rate and quality of life of patients.
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Affiliation(s)
- Chu Wu
- Cancer Research Institute, Key Laboratory of Tumor Cellular & Molecular Pathology, Medical College of Hengyang, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Ping Yang
- Cancer Research Institute, Key Laboratory of Tumor Cellular & Molecular Pathology, Medical College of Hengyang, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Bingxue Liu
- Cancer Research Institute, Key Laboratory of Tumor Cellular & Molecular Pathology, Medical College of Hengyang, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Yunlian Tang
- Cancer Research Institute, Key Laboratory of Tumor Cellular & Molecular Pathology, Medical College of Hengyang, University of South China, Hengyang, Hunan 421001, People's Republic of China
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De Jesus-Acosta A, Narang A, Mauro L, Herman J, Jaffee EM, Laheru DA. Carcinoma of the Pancreas. ABELOFF'S CLINICAL ONCOLOGY 2020:1342-1360.e7. [DOI: 10.1016/b978-0-323-47674-4.00078-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Liu F, Ma J, Wang K, Li Z, Jiang Q, Chen H, Li W, Xia J. High expression of PDE4D correlates with poor prognosis and clinical progression in pancreaticductal adenocarcinoma. J Cancer 2019; 10:6252-6260. [PMID: 31772658 PMCID: PMC6856734 DOI: 10.7150/jca.35443] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 08/26/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Phosphodiesterase 4D (PDE4D) has recently been reported as an oncogene in various types of human cancers. However, the expression and significance of PDE4D in pancreatic ductal adenocarcinoma (PDAC) have not been elucidated. Methods: Immunohistochemistry (IHC) was used to examine the expression of PDE4D in 104 clinicopathologically characterized PDAC cases. PDE4D expression in paired tumor tissues and adjacent noncancerous tissues were detected by western blotting and real time qRT-PCR. The correlation of PDE4D expression levels with clinicopathological features and prognosis in patients were analyzed by univariate and multivariate methods. Effect of PDE4D on pancreatic cancer cells was detected by cell migration and invasion assays. Results: We found that PDE4D was significantly up-regulated in PDAC tumor tissues compared to those paired adjacent noncancerous tissues at both protein and mRNA levels. High level of PDE4D was significantly associated with clinical stage (P = 0.004), T classification (P = 0.003), lymph node metastasis (P = 0.022) and liver metastasis (P = 0.038). Patients with higher levels of PDE4D had shorter overall survival time contrast with those with lower PDE4D expression (P = 0.002). Multivariate analysis indicated that PDE4D may be an independent prognostic factor for PDAC. PDE4D depletion significantly suppressed β-catenin and Snail expression as well as the migration and invasion abilities of pancreatic cancer cells. Conclusions: Our study reveals that PDE4D up-regulated in PDAC was closely associated with poor prognosis of PDAC patients and multiple aggressive clinicopathological characteristics. PDE4D could be a useful prognostic biomarker and therapeutic target for PDAC.
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Affiliation(s)
- Fude Liu
- Department of General Surgery, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Jieyi Ma
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Kebing Wang
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Zhi Li
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Qingping Jiang
- Department of Pathology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Hui Chen
- Department of Pathology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Wen Li
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Jintang Xia
- Department of General Surgery, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510150, China
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Hernandez MC, Bergquist JR, Leiting JL, Ivanics T, Yang L, Smoot RL, Nagorney DM, Truty MJ. Patient-Derived Xenografts Can Be Reliably Generated from Patient Clinical Biopsy Specimens. J Gastrointest Surg 2019; 23:818-824. [PMID: 30756315 DOI: 10.1007/s11605-019-04109-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 09/17/2018] [Indexed: 01/31/2023]
Abstract
BACKGROUND Patient-derived xenografts (PDX) are clinically relevant human cancer models that can be used to guide individualized medicine. We aimed to generate PDX models from clinically obtained biopsy specimens (surgical or image-guided) hypothesizing that low volume biopsy specimens could provide sufficient viable tissue to successfully engraft PDX models from patients with unresectable or metastatic disease. MATERIALS AND METHODS We maintain a prospective high volume gastrointestinal malignancy PDX program. With informed consent and institutional approval, biopsy specimens (surgical or image-guided) were obtained from patients with unresectable or metastatic tumors: pancreatic adenocarcinoma (PDAC), cholangiocarcinoma, gastric and gallbladder carcinoma. Biopsies were implanted into immunodeficient mice. Tumor growth was monitored, viable tumor was passed into subsequent generations, and histopathology was confirmed. RESULTS In this study, biopsy specimens from 29 patients were used for PDX engraftment. Successful PDX engraftment was variable with highest engraftment rates in gastric and gallbladder carcinoma specimens (100%) compared to engraftment rates of 33% and 29% in PDAC and cholangiocarcinoma respectively. PDX models created from metastasis biopsies compared to unresectable primary tumor tissue demonstrated higher engraftment rates (69% versus 15.4%, p = 0.001). PDX models demonstrated higher engraftment rates when biopsies were obtained during surgical operations (n = 15) compared to image-guided (n = 14) (73% versus 14%, p = 0.003). Patient age, pretreatment status, or ischemic time was not different between biopsy methods. CONCLUSIONS PDX models can be successfully created from clinical biopsy specimens in patients with metastatic or unresectable GI cancers. The use of clinical biopsy specimens for PDX engraftment can expand the repertoire of stage-specific PDX models for downstream basic/translational research.
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Affiliation(s)
- Matthew C Hernandez
- Section of Hepatobiliary and Pancreatic Surgery, Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic, 200 First St. Southwest, Rochester, MN, 55905, USA
| | - John R Bergquist
- Section of Hepatobiliary and Pancreatic Surgery, Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic, 200 First St. Southwest, Rochester, MN, 55905, USA
| | - Jennifer L Leiting
- Section of Hepatobiliary and Pancreatic Surgery, Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic, 200 First St. Southwest, Rochester, MN, 55905, USA
| | - Tommy Ivanics
- Department of Surgery, Henry Ford Medical Center, Detroit, MI, USA
| | - Lin Yang
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
| | - Rory L Smoot
- Section of Hepatobiliary and Pancreatic Surgery, Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic, 200 First St. Southwest, Rochester, MN, 55905, USA
| | - David M Nagorney
- Section of Hepatobiliary and Pancreatic Surgery, Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic, 200 First St. Southwest, Rochester, MN, 55905, USA
| | - Mark J Truty
- Section of Hepatobiliary and Pancreatic Surgery, Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic, 200 First St. Southwest, Rochester, MN, 55905, USA.
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Amaral NS, Resende V, Dos Santos JS, Lima LF, Moraes DC, Friedman E, DE Marco L, Bastos-Rodrigues L. Impact of Ethnicity on Somatic Mutation Rates of Pancreatic Adenocarcinoma. In Vivo 2019; 32:1527-1531. [PMID: 30348712 DOI: 10.21873/invivo.11410] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 09/11/2018] [Accepted: 09/12/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND/AIM Ethnicity has an effect on survival in patients with pancreatic adenocarcinoma (PDAC), which may be reflected in the rate of somatic driver mutations. The Brazilian population represents au extensive interethnic admixture and little is known about the spectrum and rates of somatic driver mutations in Brazilian PDAC cases. MATERIALS AND METHODS Direct sequencing of six genes in 23 PDAC cases was performed and the ancestry of patients was determined using a validated panel of ancestry-informative insertion/deletion DNA polymorphisms. RESULTS KRAS proto-oncogene (KRAS) was the most commonly mutated gene (60%). A novel putatively pathogenic mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (c.2948T>A; p.M983K) was identified. Mutations in epidermal growth factor receptor (EGFR) (4%), PIK3CA (4%), cyclin-dependent kinase inhibitor 2A (CDKN2A) (4%) and TP53 (8%) were noted, in rates that are less frequent than those reported for other populations. Mutations of B-Raf proto-oncogene, serine/threonine kinase (BRAF) were not present. All individuals with high African ancestral component (allelic frequency, >0.45) exhibited KRAS mutations. CONCLUSION Our results highlight the importance of the effect of ethnicity on somatic mutations in Brazilian patients with PDAC.
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Affiliation(s)
- Nayra S Amaral
- Department of Surgery, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Vivian Resende
- Department of Surgery, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Luiz Felipe Lima
- Department of Surgery, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Debora C Moraes
- Department of Surgery, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Eitan Friedman
- The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Luiz DE Marco
- Department of Surgery, Federal University of Minas Gerais, Belo Horizonte, Brazil
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Park J, Han D, Do M, Woo J, Wang JI, Han Y, Kwon W, Kim SW, Jang JY, Kim Y. Proteome characterization of human pancreatic cyst fluid from intraductal papillary mucinous neoplasm by liquid chromatography/tandem mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2017; 31:1761-1772. [PMID: 28815810 DOI: 10.1002/rcm.7959] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/12/2017] [Accepted: 08/11/2017] [Indexed: 06/07/2023]
Abstract
RATIONALE In recent years, the molecular components of pancreatic cyst fluid have been used for diagnosis and prognosis. Because the protein markers that are currently used in clinical tests are unreliable, proteomic studies to find new protein markers are being conducted. However, such researches have been limited due to the complexity of pancreatic cyst fluid and the immaturity of proteomic techniques. METHODS To overcome these limitations and provide a pancreatic cyst proteome dataset, we examined cyst fluid proteome with tandem mass spectrometry. The proteomic analysis was performed using a Orbitrap-based mass spectrometer (Q-Exactive) coupled with a 50-cm-long nano-liquid chromatography column. Protein mutations were identified using mutation sequence database search. RESULTS A total of 5850 protein groups were identified from microliters of cyst fluid. Among those, 3934 protein groups were reported for the first time in pancreatic cyst fluid. Although high-abundance proteins were not depleted in the experiment, our dataset detected almost all pancreatic tumor markers such as mucin family members, S100 proteins, and CEA-related proteins. In addition, 590 protein mutation marker candidates were discovered. CONCLUSIONS We provide a comprehensive cyst proteome dataset that includes cystic cellular proteins and mutated proteins. Our findings would serve as a rich resource for further IPMN studies and clinical applications. The MS data have been deposited in the ProteomeXchange with identifier PXD005671 (http://proteomecentral.proteomexchange.org/dataset/PXD005671).
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MESH Headings
- Amino Acid Sequence
- Biomarkers, Tumor/analysis
- Carcinoma, Pancreatic Ductal/chemistry
- Carcinoma, Pancreatic Ductal/pathology
- Chromatography, Liquid/methods
- Cyst Fluid/chemistry
- Humans
- Neoplasms, Cystic, Mucinous, and Serous/chemistry
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Pancreas/chemistry
- Pancreas/pathology
- Pancreatic Cyst/chemistry
- Pancreatic Cyst/pathology
- Pancreatic Neoplasms/chemistry
- Pancreatic Neoplasms/pathology
- Proteome/analysis
- Proteomics/methods
- Tandem Mass Spectrometry/methods
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Affiliation(s)
- Joonho Park
- Department of Biomedical Engineering, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Dohyun Han
- Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Seoul, Korea
| | - Misol Do
- Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Jongmin Woo
- Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Joseph I Wang
- Department of Biomedical Engineering, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Youngmin Han
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Wooil Kwon
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Sun-Whe Kim
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Jin-Young Jang
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Youngsoo Kim
- Department of Biomedical Engineering, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
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11
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Overbeek KA, Cahen DL, Canto MI, Bruno MJ. Surveillance for neoplasia in the pancreas. Best Pract Res Clin Gastroenterol 2016; 30:971-986. [PMID: 27938791 PMCID: PMC5552042 DOI: 10.1016/j.bpg.2016.10.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 10/25/2016] [Accepted: 10/31/2016] [Indexed: 01/31/2023]
Abstract
Despite its low incidence in the general population, pancreatic cancer is one of the leading causes of cancer-related mortality. Survival greatly depends on operability, but most patients present with unresectable disease. Therefore, there is great interest in the early detection of pancreatic cancer and its precursor lesions by surveillance. Worldwide, several programs have been initiated for individuals at high risk for pancreatic cancer. Their first results suggest that surveillance in high-risk individuals is feasible, but their effectiveness in decreasing mortality remains to be proven. This review will discuss which individuals are eligible for surveillance, which lesions are aimed to be detected, and which surveillance modalities are being used in current clinical practice. Furthermore, it addresses the management of abnormalities found during surveillance and topics for future research.
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Affiliation(s)
- Kasper A. Overbeek
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ‘s Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands,Corresponding author. Fax: +31 10 703 03 31
| | - Djuna L. Cahen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ‘s Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - Marcia Irene Canto
- Division of Gastroenterology and Hepatology, The Johns Hopkins Medical Institutions, 1800 Orleans St., Blalock 407, Baltimore, MD, 21287, USA
| | - Marco J. Bruno
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ‘s Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
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Niccolai E, Cappello P, Taddei A, Ricci F, D'Elios MM, Benagiano M, Bechi P, Bencini L, Ringressi MN, Coratti A, Cianchi F, Bonello L, Di Celle PF, Prisco D, Novelli F, Amedei A. Peripheral ENO1-specific T cells mirror the intratumoral immune response and their presence is a potential prognostic factor for pancreatic adenocarcinoma. Int J Oncol 2016; 49:393-401. [PMID: 27210467 DOI: 10.3892/ijo.2016.3524] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 02/29/2016] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with an average survival of 4-6 months following diagnosis. Surgical resection is the only treatment with curative intent, but resectable PDAC patients are in the minority. Also, unlike other neoplasms, PDAC is resistant to conventional and targeted chemotherapy. Innovative treatments, such as immunotherapy, can be very important and the study of the immune response is fundamental. We previously demonstrated that PDAC patients show tumor-infiltrating T cells specific to α-enolase (ENO1), a glycolytic enzyme over-expressed by pancreatic tumor cells, which plays an important role in promoting cell migration and cancer metastasis. In the present study, we evaluate the functional anticancer proprieties of ENO1-specific T cells isolated from the peripheral blood of PDAC patients. Furthermore, comparing the T cell receptor repertoire of ENO1-specific peripheral and infiltrating tumor T cells from the same patient suggests that ENO1-specific T cells, despite having a different functional profile, can recirculate from the tumor to the periphery. Finally, of clinical relevance, the presence of peripheral ENO1-specific T cells has a prognostic value and significantly correlates with a longer survival.
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Affiliation(s)
- Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Paola Cappello
- Centre for Experimental Research and Medical Studies (CERMS), AOU City of Health and Science of Turin, and Department of Molecular Biotechnology and Health Sciences, University of Turin, I-10126 Turin, Italy
| | - Antonio Taddei
- Department of Surgery and Translational Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Federica Ricci
- Department of Experimental and Clinical Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Mario Milco D'Elios
- Department of Experimental and Clinical Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Marisa Benagiano
- Department of Experimental and Clinical Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Paolo Bechi
- Department of Surgery and Translational Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Lapo Bencini
- Division of General and Oncologic Surgery, Department of Oncology, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Maria Novella Ringressi
- Department of Surgery and Translational Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Andrea Coratti
- Division of General and Oncologic Surgery, Department of Oncology, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Fabio Cianchi
- Department of Surgery and Translational Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Lisa Bonello
- Centre for Experimental Research and Medical Studies (CERMS), AOU City of Health and Science of Turin, and Department of Molecular Biotechnology and Health Sciences, University of Turin, I-10126 Turin, Italy
| | - Paola Francia Di Celle
- General Anatomopathology and Molecular Oncogenetics - AOU City of Health and Science of Turin, I-10126 Turin, Italy
| | - Domenico Prisco
- Department of Experimental and Clinical Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
| | - Francesco Novelli
- Centre for Experimental Research and Medical Studies (CERMS), AOU City of Health and Science of Turin, and Department of Molecular Biotechnology and Health Sciences, University of Turin, I-10126 Turin, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), I-50134 Florence, Italy
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Simões AES, Rodrigues CMP, Borralho PM. The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target. Drug Discov Today 2016; 21:1654-1663. [PMID: 27320690 DOI: 10.1016/j.drudis.2016.06.010] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/18/2016] [Accepted: 06/08/2016] [Indexed: 12/18/2022]
Abstract
Conventional mitogen-activated protein kinase (MAPK) family members are among the most sought-after oncogenic effectors for the development of novel human cancer treatment strategies. MEK5/ERK5 has been the less-studied MAPK subfamily, despite its increasingly demonstrated relevance in the growth, survival, and differentiation of normal cells. MEK5/ERK5 signalling has already been proposed to have pivotal roles in several cancer hallmarks, and to mediate the effects of a range of oncogenes. Accumulating evidence indicates the contribution of MEK5/ERK5 signalling to therapy resistance and the benefits of using MEK5/ERK5 inhibitory strategies in the treatment of human cancer. Here, we explore the major known contributions of MEK5/ERK5 signalling to the onset and progression of several types of cancer, and highlight the potential clinical relevance of targeting MEK5/ERK5 pathways.
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Affiliation(s)
- André E S Simões
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
| | - Pedro M Borralho
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
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Sun L, Chua CYX, Tian W, Zhang Z, Chiao PJ, Zhang W. MicroRNA Signaling Pathway Network in Pancreatic Ductal Adenocarcinoma. J Genet Genomics 2015; 42:563-577. [PMID: 26554910 DOI: 10.1016/j.jgg.2015.07.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 07/16/2015] [Accepted: 07/22/2015] [Indexed: 01/15/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is considered to be the most lethal and aggressive malignancy with high mortality and poor prognosis. Their responses to current multimodal therapeutic regimens are limited. It is urgently needed to identify the molecular mechanism underlying pancreatic oncogenesis. Twelve core signaling cascades have been established critical in PDAC tumorigenesis by governing a wide variety of cellular processes. MicroRNAs (miRNAs) are aberrantly expressed in different types of tumors and play pivotal roles as post-transcriptional regulators of gene expression. Here, we will describe how miRNAs regulate different signaling pathways that contribute to pancreatic oncogenesis and progression.
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Affiliation(s)
- Longhao Sun
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Corrine Ying Xuan Chua
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston 77030, USA
| | - Weijun Tian
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zhixiang Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Paul J Chiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston 77030, USA
| | - Wei Zhang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston 77030, USA; Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
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Frampton AE, Krell J, Jamieson NB, Gall TMH, Giovannetti E, Funel N, Mato Prado M, Krell D, Habib NA, Castellano L, Jiao LR, Stebbing J. microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis. Eur J Cancer 2015; 51:1389-1404. [PMID: 26002251 DOI: 10.1016/j.ejca.2015.04.006] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 04/06/2015] [Accepted: 04/10/2015] [Indexed: 01/17/2023]
Abstract
BACKGROUND Reports have described the prognostic relevance of microRNAs (miRNAs) in patients treated for pancreatic ductal adenocarcinoma (PDAC). However, many of these include small numbers of patients. To increase statistical power and improve translation, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of miRNAs on overall survival (OS) and disease-free survival (DFS) in PDAC. METHODS Eligible studies were identified and quality assessed using multiple search strategies (last search December 2014). Data were collected from studies correlating clinical outcomes with dysregulated tumoural or blood miRNAs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations. RESULTS Twenty studies involving 1525 patients treated for PDAC were included. After correcting for publication bias, OS was significantly shortened in patients with high tumoural miR-21 (adjusted HR = 2.48; 1.96-3.14). This result persisted when only studies adjusting for adjuvant chemotherapy were combined (adjusted HR = 2.72; 1.91-3.89). High miR-21 also predicted reduced DFS (adjusted HR = 3.08; 1.78-5.33). Similarly, we found significant adjusted HRs for poor OS for high miR-155, high miR-203, and low miR-34a; and unadjusted HRs for high miR-222 and high miR-10b. The small number of studies, limited number of miRNAs and paucity of multivariate analyses are the limitations of our study. CONCLUSIONS This is the first rigorous pooled analysis assessing miRNAs as prognostic biomarkers in PDAC. Tumoural miR-21 overexpression emerged as an important predictor of poor prognosis after PDAC resection independent of other clinicopathologic factors, including adjuvant chemotherapy use.
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Affiliation(s)
- Adam E Frampton
- HPB Surgical Unit, Division of Surgery, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK; Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK.
| | - Jonathan Krell
- Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK
| | - Nigel B Jamieson
- Academic Unit of Surgery, Faculty of Medicine, Glasgow Royal Infirmary, Alexandra Parade, University of Glasgow, G31 2ER, UK
| | - Tamara M H Gall
- HPB Surgical Unit, Division of Surgery, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK
| | - Elisa Giovannetti
- Dept. of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Niccola Funel
- Dept. of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Mireia Mato Prado
- Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK
| | - Daniel Krell
- Dept. of Academic Oncology, Royal Free Hospital, Pond Street, London NW3 2QG, UK
| | - Nagy A Habib
- HPB Surgical Unit, Division of Surgery, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK
| | - Leandro Castellano
- Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK
| | - Long R Jiao
- HPB Surgical Unit, Division of Surgery, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK
| | - Justin Stebbing
- Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK.
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16
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Gao D, Gao L, Zhang C, Liu H, Jia B, Zhu Z, Wang F, Liu Z. A near-infrared phthalocyanine dye-labeled agent for integrin αvβ6-targeted theranostics of pancreatic cancer. Biomaterials 2015; 53:229-238. [PMID: 25890722 DOI: 10.1016/j.biomaterials.2015.02.093] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 02/17/2015] [Accepted: 02/21/2015] [Indexed: 02/05/2023]
Abstract
Integrin αvβ6 is widely upregulated in variant malignant cancers but is undetectable in normal organs, making it a promising target for cancer diagnostic imaging and therapy. Using streptavidin-biotin chemistry, we synthesized an integrin αvβ6-targeted near-infrared phthalocyanine dye-labeled agent, termed Dye-SA-B-HK, and investigated whether it could be used for cancer imaging, optical imaging-guided surgery, and phototherapy in pancreatic cancer mouse models. Dye-SA-B-HK specifically bound to integrin αvβ6 in vitro and in vivo with high receptor binding affinity. Using small-animal optical imaging, we detected subcutaneous and orthotopic BxPC-3 human pancreatic cancer xenografts in vivo. Upon optical image-guidance, the orthotopically growing pancreatic cancer lesions could be successfully removed by surgery. Using light irradiation, Dye-SA-B-HK manifested remarkable antitumor effects both in vitro and in vivo. (18)F-FDG positron emission tomography (PET) imaging and ex vivo fluorescence staining validated the observed decrease in proliferation of treated tumors by Dye-DA-B-HK phototherapy. Tissue microarray results revealed overexpression of integrin αvβ6 in over 95% cases of human pancreatic cancer, indicating that theranostic application of Dye-DA-B-HK has clear translational potential. Overall, the results of this study demonstrated that integrin αvβ6-specific Dye-SA-B-HK is a promising theranostic agent for the management of pancreatic cancer.
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Affiliation(s)
- Duo Gao
- Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Liquan Gao
- Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Chenran Zhang
- Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Hao Liu
- Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Bing Jia
- Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Zhaohui Zhu
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing 100857, China
| | - Fan Wang
- Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhaofei Liu
- Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
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Ataxia-telangiectasia-mutated protein kinase levels stratify patients with pancreatic adenocarcinoma into prognostic subgroups with loss being a strong indicator of poor survival. Pancreas 2015; 44:296-301. [PMID: 25423555 DOI: 10.1097/mpa.0000000000000248] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Recently, aberrations in the gene encoding for ataxia-telangiectasia-mutated (ATM) protein kinase have been reported for pancreatic ductal adenocarcinomas (PDAC). These findings argue that ATM deficiency may play a role during carcinogenesis. Therefore, in this study, we investigated the clinical relevance of ATM expression and ATM activation in PDAC. METHODS Both ATM expression and nuclear phosphoSer1981-ATM levels were assessed by immunohistochemistry in a cohort of 133 PDAC and correlated with clinicopathological parameters. RESULTS We found stratification in prognostic subgroups. Complete loss of Ser1981-ATM was indicative of the worst prognosis (median survival, 10.8 vs 14.3 months [low expression] vs 31.1 months [high expression], P < 0.001). Similarly, analysis of ATM expression demonstrated absent expression levels of ATM to be associated with dismal prognosis (median survival, 9.6 months), whereas expression of ATM in general was associated with increased survival (17.7 months, P = 0.001). CONCLUSIONS Our analysis shows that both ATM expression and activated ATM are prognostic markers in PDAC with respect to standard clinicopathological parameters. These results suggest that ATM should be further explored as prognostic as well as predictive factor with respect to conventional chemotherapies and for putative synthetic lethal approaches.
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18
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Clinical implications of miRNAs in the pathogenesis, diagnosis and therapy of pancreatic cancer. Adv Drug Deliv Rev 2015; 81:16-33. [PMID: 25453266 DOI: 10.1016/j.addr.2014.10.020] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 10/12/2014] [Accepted: 10/15/2014] [Indexed: 02/06/2023]
Abstract
Despite considerable progress being made in understanding pancreatic cancer (PC) pathogenesis, it still remains the 10th most often diagnosed malignancy in the world and 4th leading cause of cancer related deaths in the United States with a five year survival rate of only 6%. The aggressive nature, lack of early diagnostic and prognostic markers, late clinical presentation, and limited efficacy of existing treatment regimens make PC a lethal cancer with high mortality and poor prognosis. Therefore, novel reliable biomarkers and molecular targets are urgently needed to combat this deadly disease. MicroRNAs (miRNAs) are short (19-24 nucleotides) non-coding RNA molecules implicated in the regulation of gene expression at post-transcriptional level and play significant roles in various physiological and pathological conditions. Aberrant expression of miRNAs has been reported in several cancers including PC and is implicated in PC pathogenesis and progression, suggesting their utility in diagnosis, prognosis and therapy. In this review, we summarize the role of several miRNAs that regulate various oncogenes (KRAS) and tumor suppressor genes (p53, p16, SMAD4, etc.) involved in PC development, their prospective roles as diagnostic and prognostic markers and as a therapeutic targets.
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Paraneoplastic Ma Antigen-Like 1 as a Potential Prognostic Biomarker in Human Pancreatic Ductal Adenocarcinoma. Pancreas 2015; 44:106-15. [PMID: 25251443 DOI: 10.1097/mpa.0000000000000220] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE The present study aimed to identify novel useful clinical biomarker at early stages and to elucidate the molecular background of carcinogenesis in human pancreatic ductal adenocarcinomas (PDACs). METHODS Proteomes of dissected PDACs and adjacent nontumor pancreatic tissues from formalin-fixed and paraffin-embedded sections from 10 patients were analyzed using QSTAR Elite liquid chromatography-tandem mass spectrometry, ProteinPilot Software, and Ingenuity Pathway Analysis. Expression of potential biomarker candidates was validated immunohistochemically in 50 PDAC patients, followed by survival analyses and statistical comparison of protein expression with clinicopathologic variables. RESULTS Eight hundred five proteins displaying significant quantitative changes were identified in human PDACs by liquid chromatography-tandem mass spectrometry. Based on altered expression of downstream molecules, Ingenuity Pathway Analysis predicted up-regulation and/or activation of nuclear factor β-catenin, SOX11, enolase 1, NFE2L2, SP1, SMAD1, SMAD2, SMAD3, SMAD4, HIF-1, and others. From proteome analysis, paraneoplastic Ma antigen-like 1 was selected as a potential biomarker of human PDAC. Furthermore, paraneoplastic neuronal Ma antigen-like 1 immunohistochemical evaluation in 50 PDAC patients revealed that its positive expression was significantly associated with the better overall survival (log-rank test; P = 0.009) and histological differentiation of PDACs (well, moderate, and poor; P = 0.027) as compared with patients with negative expression. CONCLUSION Paraneoplastic Ma antigen-like 1 is suggested as a novel potential clinically useful prognostic biomarker for patients with PDAC.
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Xia X, Wu W, Huang C, Cen G, Jiang T, Cao J, Huang K, Qiu Z. SMAD4 and its role in pancreatic cancer. Tumour Biol 2014; 36:111-9. [PMID: 25464861 DOI: 10.1007/s13277-014-2883-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 11/19/2014] [Indexed: 12/13/2022] Open
Abstract
Transforming growth factor-β (TGF-β) regulates cell functions and has key roles in pancreatic cancer development. SMAD4, as one of the Smads family of signal transducer from TGF-β, mediates pancreatic cell proliferation and apoptosis and is specifically inactivated in half of advanced pancreatic cancers. In recent years, many advances concerning SMAD4 had tried to unravel the complex signaling mechanisms of TGF-β and its dual role of tumor-suppressive and tumor-promoting efforts in pancreatic cancer initiation and progression through SMAD4-dependent TGF-β signaling and SMAD4-independent TGF-β signaling pathways. Meanwhile, its potential prognostic value based on immunohistochemical expression in surgical sample was variably reported by several studies and short of a systematic analysis. This review aimed to discuss the structure, functions, and regulation of this principal protein and its effects in determining the progression and prognosis of pancreatic cancer.
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Affiliation(s)
- Xiang Xia
- Department of General Surgery, Shanghai Jiaotong University Affiliated First People's Hospital, 100 Hai Ning Road, Shanghai, 200080, People's Republic of China
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Hong TH, Park IY. MicroRNA expression profiling of diagnostic needle aspirates from surgical pancreatic cancer specimens. Ann Surg Treat Res 2014; 87:290-7. [PMID: 25485236 PMCID: PMC4255547 DOI: 10.4174/astr.2014.87.6.290] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 06/30/2014] [Accepted: 07/07/2014] [Indexed: 12/15/2022] Open
Abstract
Purpose MicroRNAs (miRNAs) have been widely investigated as potential biomarkers for several malignancies. To establish the feasibility of miRNA expression profiling of small biopsy samples of pancreatic cancers, we assessed expression profiles in freshly collected aspirates obtained immediately after surgical resection of the pancreas. Methods We used separate fine needles (20-23 gauge) to aspirate the pancreatic cancer and adjacent normal pancreatic tissue. miRNAs that were differentially expressed in pancreatic cancers and matched paraneoplastic normal pancreatic tissues were identified using an miRNA microarray. Results We identified 158 aberrantly expressed miRNAs in pancreatic cancers; 51 were overexpressed and 107 underexpressed compared with normal pancreatic tissue. To confirm the microarray findings, quantitative RT-PCR was performed on individual samples. We chose eight miRNAs for further analysis; of which five were overexpressed (miR-21, miR-27a, miR-146a, miR-200a, and miR-196a) and three underexpressed (miR-217, miR-20a, and miR-96) in pancreatic cancer samples compared to benign pancreatic tissue. Expression of miR-21, miR-27a, miR-146a, miR-200a, and miR-196a was significantly increased in cancer fine-needle aspirates relative to matched controls in all samples. Expression of miR-217, miR-20a, and miR-96 was significantly downregulated in almost all pancreatic cancer tissues. Conclusion We demonstrate the feasibility of performing miRNA profiling on very small specimens obtained using fine-needle aspiration of pancreatic cancers.
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Affiliation(s)
- Tae Ho Hong
- Department of Surgery, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Korea
| | - Il Young Park
- Department of Surgery, The Catholic University of Korea, Bucheon St. Mary's Hospital, Bucheon, Korea
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Zhang LJ, Wang KB, Liu LS, Chen LZ, Peng BG, Liang LJ, Li Z, Xue L, Li W, Xia JT. Overexpression of GOLPH3 is associated with poor prognosis and clinical progression in pancreatic ductal adenocarcinoma. BMC Cancer 2014; 14:571. [PMID: 25104140 PMCID: PMC4133629 DOI: 10.1186/1471-2407-14-571] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 07/30/2014] [Indexed: 02/05/2023] Open
Abstract
Background Golgi phosphoprotein 3 (GOLPH3) has been identified as an oncoprotein in various human cancers; however, its role in pancreatic ductal adenocarcinoma (PDAC) is unknown. We examined GOLPH3 expression levels and relationship with survival in patients with PDAC to establish the significance of GOLPH3 in the development and progression of PDAC. Methods Real-time qPCR and Western blotting were performed to analyze the expression levels of GOLPH3 mRNA and protein in paired PDAC tumor and adjacent non-tumor tissues. Immunohistochemistry was used to analyze the expression levels of GOLPH3 protein in paraffin-embedded tissues from 109 cases of PDAC. Univariate and multivariate analyses were performed to identify correlations between the immunohistochemical data for GOLPH3 expression and the clinicopathologic characteristics in PDAC. Results Expression levels of GOLPH3 mRNA and protein were upregulated in PDAC lesions compared to paired adjacent noncancerous tissues. Expression of GOLPH3 was significantly correlated with clinical stage (P = 0.006), T classification (P = 0.021), N classification (P = 0.049) and liver metastasis (P = 0.035). Patients with high GOLPH3 expression had shorter overall survival times compared to those with low GOLPH3 expression (P = 0.007). Multivariate analysis revealed that GOLPH3 overexpression was an independent prognostic factor in PDAC. Conclusions Our findings suggest that GOLPH3 expression status may be a potential prognostic biomarker and therapeutic target in PCAC.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Wen Li
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
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Ning Z, Wang A, Liang J, Xie Y, Liu J, Feng L, Yan Q, Wang Z. USP22 promotes the G1/S phase transition by upregulating FoxM1 expression via β-catenin nuclear localization and is associated with poor prognosis in stage II pancreatic ductal adenocarcinoma. Int J Oncol 2014; 45:1594-608. [PMID: 24993031 DOI: 10.3892/ijo.2014.2531] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 06/02/2014] [Indexed: 11/05/2022] Open
Abstract
Ubiquitin-specific protease 22 (USP22), a newly discovered member of ubiquitin hydrolase family, exhibits a critical function in cell cycle progression and tumorigenesis. The forkhead box M1 (FoxM1) transcription factor plays a crucial role in cell proliferation, differentiation and transformation. However, the expression and functions of USP22 in pancreatic ductal adenocarcinoma (PDA) and whether FoxM1 is involved in USP22-mediated cell cycle regulation have not been studied. We examined the expression of USP22 and FoxM1 in 136 stage II PDA tissues by immunohistochemistry. Clinical significance was analyzed by multivariate Cox regression analysis, Kaplan-Meier curves and log-rank test. RT-PCR, western blot analysis, luciferase and immunofluorescence assays were used to investigate the molecular function of USP22 and FoxM1 in PDA fresh tissues and cell lines. USP22 and FoxM1 were significantly upregulated in PDA tissues compared with the paired normal carcinoma-adjacent tissues. A statistical correlation was observed between USP22 and FoxM1 expression. The expression of USP/FoxM1 and co-expression of both factors correlated with tumor size, lymph node metastasis and overall survival. Multivariate Cox regression analysis revealed that the expression of USP22/FoxM1, especially the co-expression of both factors, is an independent, unfavorable prognostic factor. USP22 overexpression is accompanied by an increase in FoxM1 expression and USP22 increases FoxM1 expression to promote G1/S transition and cell proliferation through promoting β-catenin nuclear translocation in PDA cell lines. USP22 promotes the G1/S phase transition by upregulating FoxM1 expression via promoting β-catenin nuclear localization. USP22 and FoxM1 may act as prognostic markers and potential targets for PDA.
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Affiliation(s)
- Zhen Ning
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, P.R. China
| | - Aman Wang
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, P.R. China
| | - Jinxiao Liang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, P.R. China
| | - Yunpeng Xie
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, P.R. China
| | - Jiwei Liu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, P.R. China
| | - Lu Feng
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian 116044, P.R. China
| | - Qiu Yan
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, P.R. China
| | - Zhongyu Wang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, P.R. China
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Togashi Y, Sakamoto H, Hayashi H, Terashima M, de Velasco MA, Fujita Y, Kodera Y, Sakai K, Tomida S, Kitano M, Ito A, Kudo M, Nishio K. Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer. Mol Cancer 2014; 13:126. [PMID: 24886203 PMCID: PMC4047430 DOI: 10.1186/1476-4598-13-126] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 05/20/2014] [Indexed: 12/30/2022] Open
Abstract
Background Transforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC); however; the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear. Methods and results We found a homozygous deletion of the activin A receptor, type IB (ACVR1B) gene in 2 out of 8 PC cell lines using array-comparative genomic hybridization, and the absence of ACVR1B mRNA and protein expression was confirmed in these 2 cell lines. Activin A stimulation inhibited cellular growth and increased the phosphorylation level of SMAD2 and the expression level of p21CIP1/WAF1 in the Sui66 cell line (wild-type ACVR1B and SMAD4 genes) but not in the Sui68 cell line (homozygous deletion of ACVR1B gene). Stable ACVR1B-knockdown using short hairpin RNA cancelled the effects of activin A on the cellular growth of the PC cell lines. In addition, ACVR1B-knockdown significantly enhanced the cellular growth and colony formation abilities, compared with controls. In a xenograft study, ACVR1B-knockdown resulted in a significantly elevated level of tumorigenesis and a larger tumor volume, compared with the control. Furthermore, in clinical samples, 6 of the 29 PC samples (20.7%) carried a deletion of the ACVR1B gene, while 10 of the 29 samples (34.5%) carried a deletion of the SMAD4 gene. Of note, 5 of the 6 samples with a deletion of the ACVR1B gene also had a deletion of the SMAD4 gene. Conclusion We identified a homozygous deletion of the ACVR1B gene in PC cell lines and clinical samples and proposed that the deletion of the ACVR1B gene may mediate an aggressive cancer phenotype in PC. Our findings provide novel insight into the role of the activin signal in PC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Kazuto Nishio
- Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.
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25
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Terashima T, Mizukoshi E, Arai K, Yamashita T, Yoshida M, Ota H, Onishi I, Kayahara M, Ohtsubo K, Kagaya T, Honda M, Kaneko S. P53, hTERT, WT-1, and VEGFR2 are the most suitable targets for cancer vaccine therapy in HLA-A24 positive pancreatic adenocarcinoma. Cancer Immunol Immunother 2014; 63:479-89. [PMID: 24633336 PMCID: PMC11029706 DOI: 10.1007/s00262-014-1529-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 02/22/2014] [Indexed: 11/29/2022]
Abstract
Cancer vaccine therapy is one of the most attractive therapies as a new treatment procedure for pancreatic adenocarcinoma. Recent technical advances have enabled the identification of cytotoxic T lymphocyte (CTL) epitopes in various tumor-associated antigens (TAAs). However, little is known about which TAA and its epitope are the most immunogenic and useful for a cancer vaccine for pancreatic adenocarcinoma. We examined the expression of 17 kinds of TAA in 9 pancreatic cancer cell lines and 12 pancreatic cancer tissues. CTL responses to 23 epitopes derived from these TAAs were analyzed using enzyme-linked immunospot (ELISPOT), CTL, and tetramer assays in 41 patients, and factors affecting the immune responses were investigated. All TAAs were frequently expressed in pancreatic adenocarcinoma cells, except for adenocarcinoma antigens recognized by T cells 1, melanoma-associated antigen (MAGE)-A1, and MAGE-A3. Among the epitopes recognized by CTLs in more than two patients in the ELISPOT assay, 6 epitopes derived from 5 TAAs, namely, MAGE-A3, p53, human telomerase reverse transcriptase (hTERT), Wilms tumor (WT)-1, and vascular endothelial growth factor receptor (VEGFR)2, could induce specific CTLs that showed cytotoxicity against pancreatic cancer cell lines. The frequency of lymphocyte subsets correlated well with TAA-specific immune response. Overall survival was significantly longer in patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1, and VEGFR2 were shown to be attractive targets for immunotherapy in patients with pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the prognosis of these patients.
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Affiliation(s)
- Takeshi Terashima
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, 13-1 Takara-Machi, Kanazawa, 920-8641, Ishikawa, Japan,
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26
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Goonesekere NCW, Wang X, Ludwig L, Guda C. A meta analysis of pancreatic microarray datasets yields new targets as cancer genes and biomarkers. PLoS One 2014; 9:e93046. [PMID: 24740004 PMCID: PMC3989178 DOI: 10.1371/journal.pone.0093046] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 02/28/2014] [Indexed: 12/22/2022] Open
Abstract
The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC), which has a five year survival rate of less than 5%. Improved screening for earlier diagnosis, through the detection of diagnostic and prognostic biomarkers provides the best hope of increasing the rate of curatively resectable carcinomas. Though many serum markers have been reported to be elevated in patients with PC, so far, most of these markers have not been implemented into clinical routine due to low sensitivity or specificity. In this study, we have identified genes that are significantly upregulated in PC, through a meta-analysis of large number of microarray datasets. We demonstrate that the biological functions ascribed to these genes are clearly associated with PC and metastasis, and that that these genes exhibit a strong link to pathways involved with inflammation and the immune response. This investigation has yielded new targets for cancer genes, and potential biomarkers for pancreatic cancer. The candidate list of cancer genes includes protein kinase genes, new members of gene families currently associated with PC, as well as genes not previously linked to PC. In this study, we are also able to move towards developing a signature for hypomethylated genes, which could be useful for early detection of PC. We also show that the significantly upregulated 800+ genes in our analysis can serve as an enriched pool for tissue and serum protein biomarkers in pancreatic cancer.
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Affiliation(s)
- Nalin C. W. Goonesekere
- Department of Chemistry and Biochemistry, University of Northern Iowa, Cedar Falls, Iowa, United States of America
| | - Xiaosheng Wang
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Lindsey Ludwig
- Department of Chemistry and Biochemistry, University of Northern Iowa, Cedar Falls, Iowa, United States of America
| | - Chittibabu Guda
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Bioinformatics and Systems Biology Core, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
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27
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Nie S, Lo A, Wu J, Zhu J, Tan Z, Simeone DM, Anderson MA, Shedden KA, Ruffin MT, Lubman DM. Glycoprotein biomarker panel for pancreatic cancer discovered by quantitative proteomics analysis. J Proteome Res 2014; 13:1873-84. [PMID: 24571389 PMCID: PMC3993962 DOI: 10.1021/pr400967x] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
![]()
Pancreatic
cancer is a lethal disease where specific early detection
biomarkers would be very valuable to improve outcomes in patients.
Many previous studies have compared biosamples from pancreatic cancer
patients with healthy controls to find potential biomarkers. However,
a range of related disease conditions can influence the performance
of these putative biomarkers, including pancreatitis and diabetes.
In this study, quantitative proteomics methods were applied to discover
potential serum glycoprotein biomarkers that distinguish pancreatic
cancer from other pancreas related conditions (diabetes, cyst, chronic
pancreatitis, obstructive jaundice) and healthy controls. Aleuria aurantia lectin (AAL) was used to extract
fucosylated glycoproteins and then both TMT protein-level labeling
and label-free quantitative analysis were performed to analyze glycoprotein
differences from 179 serum samples across the six different conditions.
A total of 243 and 354 serum proteins were identified and quantified
by label-free and TMT protein-level quantitative strategies, respectively.
Nineteen and 25 proteins were found to show significant differences
in samples between the pancreatic cancer and other conditions using
the label-free and TMT strategies, respectively, with 7 proteins considered
significant in both methods. Significantly different glycoproteins
were further validated by lectin-ELISA and ELISA assays. Four candidates
were identified as potential markers with profiles found to be highly
complementary with CA 19–9 (p < 0.001).
Obstructive jaundice (OJ) was found to have a significant impact on
the performance of every marker protein, including CA 19–9.
The combination of α-1-antichymotrypsin (AACT), thrombospondin-1
(THBS1), and haptoglobin (HPT) outperformed CA 19–9 in distinguishing
pancreatic cancer from normal controls (AUC = 0.95), diabetes (AUC
= 0.89), cyst (AUC = 0.82), and chronic pancreatitis (AUC = 0.90).
A marker panel of AACT, THBS1, HPT, and CA 19–9 showed a high
diagnostic potential in distinguishing pancreatic cancer from other
conditions with OJ (AUC = 0.92) or without OJ (AUC = 0.95).
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Affiliation(s)
- Song Nie
- Department of Surgery, University of Michigan , Ann Arbor, Michigan 48109, United States
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28
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Raatschen HJ, Fischer S, Zsivcsec B, Schoenfeld CO, Hotz B, Buhr HJ, Hotz HG. Non-invasive quantification of anti-angiogenic therapy by contrast-enhanced MRI in experimental pancreatic cancer. Acta Radiol 2014; 55:131-9. [PMID: 23892234 DOI: 10.1177/0284185113493776] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Currently, early changes of tumor vasculature after angiogenesis inhibition can only be evaluated by histopathology, a method not suitable in a clinical setting. PURPOSE To quantify effects of different angiogenesis inhibitors on the microvasculature of orthotopically implanted pancreatic cancers by contrast-enhanced magnetic resonance imaging (MRI) in order to establish a non-invasive technique for monitoring antiangiogenic cancer treatment. MATERIAL AND METHODS DSL-6A/C1 pancreatic cancers were implanted in the pancreas of 109 Lewis rats. Three weeks later, antiangiogenic treatment was initiated by administration of Bevacizumab (n = 38) or Suramin (n = 27) while the control group (n = 44) remained untreated. Dynamic MRI was performed 24 h, 1 week, and 4 weeks after treatment initiation. Fractional tumor plasma volume (fPV, %) and vascular permeability (K(PS), mL/min/100 cc) were calculated based on the MRI data by using a pharmacokinetic model. RESULTS Twenty-four hours after the initial dose, a significant decline in K(PS) was observed in the Bevacizumab group compared to the control and Suramin group (0.002 ± 0.008; 0.057 ± 0.046 and 0.064 ± 0.062 (mean ± SD); P < 0.05). At 1 week, fPV was significantly smaller in Bevacizumab and Suramin treated tumors compared to control tumors (6.25 ± 2.74, 7.47 ± 3.44, and 15.10 ± 9.97, respectively; P < 0.05). Differences in tumor volumes were first observed after 4 weeks of treatment with significantly larger control tumors (4380.3 ± 1590.6 vs. 869.6 ± 717.2 and 1676.5 ± 2524.1 mm(3); P < 0.05). CONCLUSION Dynamic MRI can quantify antiangiogenic effects on tumor microvasculature before changes in tumor volumes are detectable. Thus, this technique is a reasonable addition to morphological MRI and may be applied as an alternative to histopathology.
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Affiliation(s)
- Hans-Juergen Raatschen
- Department of Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany
| | - Susanne Fischer
- Department of Radiology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Benjamin Zsivcsec
- Department of Radiology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | - Birgit Hotz
- Department of General, Vascular and Thoracic Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Heinz J Buhr
- Department of General, Vascular and Thoracic Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Hubert G Hotz
- Department of General, Vascular and Thoracic Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
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29
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Xiao W, Hong H, Awadallah A, Yu S, Zhou L, Xin W. CRABP-II is a highly sensitive and specific diagnostic molecular marker for pancreatic ductal adenocarcinoma in distinguishing from benign pancreatic conditions. Hum Pathol 2014; 45:1177-83. [PMID: 24709110 DOI: 10.1016/j.humpath.2014.01.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 01/13/2014] [Accepted: 01/15/2014] [Indexed: 01/05/2023]
Abstract
CRABP-II, a retinoic acid binding protein, shuffles retinoic acid from cytoplasm into nucleus and forms a complex with nuclear retinoic acid receptor to facilitate transcriptional activities of retinoic acid. In this study, we studied the expression patterns of CRABP-II in pancreatic ductal adenocarcinoma (PDAC) compared with those in normal pancreas, chronic pancreatitis, and precancerous lesions. We showed no detectable expressions of CRABP-II in normal pancreatic parenchyma, normal ductal epithelium, and chronic pancreatitis. In contrast, the expression of CRABP-II was readily detected in all PDACs including metastatic PDACs. CRABP-II staining was also observed and progressively increased from pancreatic intraepithelial neoplasia 1 to 3. In addition, when fine needle aspiration specimens were evaluated from patients with PDAC, CRABP-II was positive in 55.6% cases if cytology diagnosis was "atypia," and in 87.5% cases, if "malignancy." Our study suggests that CRABP-II is highly and specifically expressed in PDAC and is more commonly expressed in high-grade precursor cancerous lesions than in low-grade lesions. Therefore, overexpression of CRABP-II is a late event of pancreatic carcinogenesis, and it could be used as a diagnostic marker to distinguish PDAC from other benign pancreatic conditions in both resection and cytology specimens.
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Affiliation(s)
- Wenbin Xiao
- Department of Pathology, University Hospitals Case Medical Center, Cleveland, OH 44106
| | - Hong Hong
- Department of Pathology, University Hospitals Case Medical Center, Cleveland, OH 44106
| | - Amad Awadallah
- Department of Pathology, University Hospitals Case Medical Center, Cleveland, OH 44106
| | - Shuiliang Yu
- Case Western Reserve University, Cleveland, OH 44106
| | - Lan Zhou
- Department of Pathology, University Hospitals Case Medical Center, Cleveland, OH 44106; Case Western Reserve University, Cleveland, OH 44106
| | - Wei Xin
- Department of Pathology, University Hospitals Case Medical Center, Cleveland, OH 44106; Case Western Reserve University, Cleveland, OH 44106.
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Zhu Z, Xu Y, Du J, Tan J, Jiao H. Expression of microRNA-218 in human pancreatic ductal adenocarcinoma and its correlation with tumor progression and patient survival. J Surg Oncol 2013; 109:89-94. [PMID: 24166773 DOI: 10.1002/jso.23475] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Accepted: 09/29/2013] [Indexed: 01/18/2023]
Abstract
BACKGROUND Our aim was to analyze clinicopathologic and prognostic values of microRNA (miR)-218 in pancreatic ductal adenocarcinima (PDAC). METHODS TaqMan quantitative RT-PCR was used to determine the expression of miR-218 in human PDAC cells and tissue samples. The association of miR-218 expression with clinicopathologic variables was analyzed. Kaplan-Meier survival analysis was performed to analyze the association of miR-218 expression with recurrence-free survival or overall survival of patients. Univariate and multivariate Cox regression analyses were performed. RESULTS The relative level of miR-218 in PDAC cells was significantly lower than that in normal human pancreatic duct epithelial cell line. Also, the mean level of miR-218 in PDAC tissues was significantly lower than that in normal pancreatic tissues. Statistical analyses indicated that low miR-218 expression was closely associated with poor tumor differentiation, advanced tumor stage, higher incidence of lymph node metastasis, and tumor recurrence. Kaplan-Meier survival analyses showed that patients with low miR-218 expression had lower recurrence-free and overall survival than those with high miR-218 expression. Univariate and multivariate Cox regression analyses showed that miR-218 might be an independent prognostic factor. CONCLUSION Reduced miR-218 in PDAC tissues was correlated with tumor progression, and might be an independent poor prognostic factor for patients.
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Affiliation(s)
- Ziman Zhu
- Department of Hepatobiliary Surgery, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, People's Republic of China
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31
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Stenzinger A, Endris V, Klauschen F, Sinn B, Lorenz K, Warth A, Goeppert B, Ehemann V, Muckenhuber A, Kamphues C, Bahra M, Neuhaus P, Weichert W. High SIRT1 expression is a negative prognosticator in pancreatic ductal adenocarcinoma. BMC Cancer 2013; 13:450. [PMID: 24088390 PMCID: PMC3850795 DOI: 10.1186/1471-2407-13-450] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 09/25/2013] [Indexed: 01/05/2023] Open
Abstract
Background Several lines of evidence indicate that Sirt1, a class III histone deacetylase (HDAC) is implicated in the initiation and progression of malignancies and thus gained attraction as druggable target. Since data on the role of Sirt1 in pancreatic ductal adenocarcinoma (PDAC) are sparse, we investigated the expression profile and prognostic significance of Sirt1 in vivo as well as cellular effects of Sirt1 inhibition in vitro. Methods Sirt1 expression was analyzed by immunohistochemistry in a large cohort of PDACs and correlated with clinicopathological and survival data. Furthermore, we investigated the impact of overexpression and small molecule inhibition on Sirt1 in pancreatic cancer cell culture models including combinatorial treatment with chemotherapy and EGFR-inhibition. Cellular events were measured quantitatively in real time and corroborated by conventional readouts including FACS analysis and MTT assays. Results We detected nuclear Sirt1 expression in 36 (27.9%) of 129 PDACs. SIRT1 expression was significantly higher in poorly differentiated carcinomas. Strong SIRT1 expression was a significant predictor of poor survival both in univariate (p = 0.002) and multivariate (HR 1.65, p = 0.045) analysis. Accordingly, overexpression of Sirt1 led to increased cell viability, while small molecule inhibition led to a growth arrest in pancreatic cancer cells and impaired cell survival. This effect was even more pronounced in combinatorial regimens with gefitinib, but not in combination with gemcitabine. Conclusions Sirt1 is an independent prognosticator in PDACs and plays an important role in pancreatic cancer cell growth, which can be levered out by small molecule inhibition. Our data warrant further studies on SIRT1 as a novel chemotherapeutic target in PDAC.
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Affiliation(s)
- Albrecht Stenzinger
- Institute of Pathology, and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
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Foygel K, Wang H, Machtaler S, Lutz AM, Chen R, Pysz M, Lowe AW, Tian L, Carrigan T, Brentnall TA, Willmann JK. Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1. Gastroenterology 2013; 145:885-894.e3. [PMID: 23791701 PMCID: PMC3783557 DOI: 10.1053/j.gastro.2013.06.011] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2012] [Revised: 05/14/2013] [Accepted: 06/14/2013] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging. METHODS Thymocyte differentiation antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Up-regulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC. RESULTS Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P = .007) or normal tissue samples (P < .0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC. CONCLUSIONS We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients.
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Affiliation(s)
- Kira Foygel
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS); Stanford University, Stanford, California, USA
| | - Huaijun Wang
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS); Stanford University, Stanford, California, USA
| | - Steven Machtaler
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS); Stanford University, Stanford, California, USA
| | - Amelie M. Lutz
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS); Stanford University, Stanford, California, USA
| | - Ru Chen
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Marybeth Pysz
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS); Stanford University, Stanford, California, USA
| | - Anson W. Lowe
- Department of Medicine, Stanford University, Stanford, California, USA
| | - Lu Tian
- Department of Health, Research & Policy, Stanford University, Stanford, California, USA
| | - Tricia Carrigan
- Translational Diagnostics, Ventana Medical Systems, INC, Tucson, Arizona, USA
| | | | - Jürgen K. Willmann
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS); Stanford University, Stanford, California, USA
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Park S, Park JY, Bang S, Park SW, Chung JB, Song SY. Radiotherapy prolongs biliary metal stent patency in malignant pancreatobiliary obstructions. Gut Liver 2013; 7:480-485. [PMID: 23898391 PMCID: PMC3724039 DOI: 10.5009/gnl.2013.7.4.480] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 08/25/2012] [Accepted: 09/23/2012] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND/AIMS Biliary stenting is the most effective decompressive method for treating malignant biliary obstructive jaundice. Although the main cause of stent occlusion is tumor growth, few studies have investigated whether stent patency is affected by the combination of cancer-treatment modalities. The aim of this study was to evaluate the effects of local radiotherapy on metal-stent patency in patients with malignant biliary obstruction. METHODS Patients who underwent self-expandable biliary metallic stenting for malignant biliary obstruction from 1999 to 2007 were included. Forty patients received chemotherapy and radiation therapy (radiation group, RG), and 31 patients received only chemotherapy (nonradiation group, NRG). RESULTS The cumulative median stent patency was significantly longer in the RG than in the NRG (17.7 months; 95% confidence interval [CI], 1.8 to 33.6 months vs 8.7 months; 95% CI, 4.9 to 12.5 months; p=0.025). Stent occlusion caused by tumor growth or stent migration occurred in two (5%) and three (7.5%) cases in the RG and in six (19.3%) and two (6.5%) cases in the NRG, respectively. CONCLUSIONS The patency of biliary metal stents in pancreatobiliary cancer patients who receive chemoradiation therapy is significantly longer than that in patients who do not receive radiotherapy, which suggests that local cancer control significantly affects stent patency.
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Affiliation(s)
- Semi Park
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
- Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeong Youp Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Seungmin Bang
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Woo Park
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Bock Chung
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Si Young Song
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
- Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
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Kosanam H, Prassas I, Chrystoja CC, Soleas I, Chan A, Dimitromanolakis A, Blasutig IM, Rückert F, Gruetzmann R, Pilarsky C, Maekawa M, Brand R, Diamandis EP. Laminin, gamma 2 (LAMC2): a promising new putative pancreatic cancer biomarker identified by proteomic analysis of pancreatic adenocarcinoma tissues. Mol Cell Proteomics 2013; 12:2820-32. [PMID: 23798558 DOI: 10.1074/mcp.m112.023507] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
In pancreatic cancer, the incidence and mortality curves coincide. One major reason for this high mortality rate in pancreatic ductal adenocarcinoma (PDAC) patients is the dearth of effective diagnostic, prognostic, and disease-monitoring biomarkers. Unfortunately, existing tumor markers, as well as current imaging modalities, are not sufficiently sensitive and/or specific for early-stage diagnosis. There is, therefore, an urgent need for improved serum markers of the disease. Herein, we performed Orbitrap® mass spectrometry proteomic analysis of four PDAC tissues and their adjacent benign tissues and identified a total of 2190 nonredundant proteins. Sixteen promising candidates were selected for further scrutiny using a systematic scoring algorithm. Our preliminary serum verification of the top four candidates (DSP, LAMC2, GP73, and DSG2) in 20 patients diagnosed with pancreatic cancer and 20 with benign pancreatic cysts, showed a significant (p < 0.05) elevation of LAMC2 in pancreatic cancer serum. Extensive validation of LAMC2 in healthy, benign, and PDAC sera from geographically diverse cohorts (n = 425) (Japan, Europe, and USA) demonstrated a significant increase in levels in early-stage PDAC compared with benign diseases. The sensitivity of LAMC2 was comparable to CA19.9 in all data sets, with an AUC value greater than 0.85 in discriminating healthy patients from early-stage PDAC patients. LAMC2 exhibited diagnostic complementarity with CA19.9 by showing significant (p < 0.001 in two out of three cohorts) elevation in PDAC patients with clinically low CA19.9 levels.
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Affiliation(s)
- Hari Kosanam
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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Mahawithitwong P, Ohuchida K, Ikenaga N, Fujita H, Zhao M, Kozono S, Shindo K, Ohtsuka T, Mizumoto K, Tanaka M. Kindlin-2 expression in peritumoral stroma is associated with poor prognosis in pancreatic ductal adenocarcinoma. Pancreas 2013; 42:663-9. [PMID: 23508013 DOI: 10.1097/mpa.0b013e318279bd66] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Kindlin-2 is a novel focal adhesion protein reported to be expressed in breast, lung, and gastric cancers. This study aimed to investigate the significance of kindlin-2 expression in pancreatic ductal adenocarcinomas (PDACs). METHODS We performed immunohistochemical analysis on kindlin-2 on PDAC samples from 95 patients. We investigated the association between kindlin-2 expression and clinicopathological parameters of PDAC and the survival time of patients with PDAC who underwent pancreatectomy. RESULTS Kindlin-2 was highly expressed in the peritumoral stroma of PDACs. Stromal kindlin-2 expression was related to nodal metastasis (P = 0.03). Univariate analysis showed that patients with positive kindlin-2 expression had significantly shorter survival times than those with negative kindlin-2 expression (P = 0.01). In addition, multivariate analysis revealed that kindlin-2 expression was an independent factor of poor prognosis in patients with PDAC after R0 resection (RR = 2.15; P = 0.04). CONCLUSIONS Kindlin-2 expression in stromal components is significantly associated with poor prognosis of patients with PDAC, suggesting that kindlin-2 is a prognostic marker for patients with PDAC.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Female
- Humans
- Male
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Middle Aged
- Multivariate Analysis
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Prognosis
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Stromal Cells/metabolism
- Stromal Cells/pathology
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36
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Metalloproteinase 2 and 9 activity in the development of pancreatic cancer. POLISH JOURNAL OF SURGERY 2013; 84:377-82. [PMID: 22985699 DOI: 10.2478/v10035-012-0064-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
UNLABELLED Pancreatic adenocarcinoma is the fourth most common cancer occurring in both women and men. In Poland, within the past ten years the number of deaths from pancreatic cancer increased by 29%.The aim of the study was to determine the correlation between the activity of metalloproteinase (MMP) 2 and 9 and progression and aggressiveness of pancreatic cancer. MATERIAL AND METHODS Tissue samples were collected from 36 patients with diagnosed pancreatic adenocarcinoma who underwent Whipple resection. Tumor tissues were analyzed by gel zymography, zymography in situ and immunohistochemistry. RESULTS The activity of MMPs was found mainly in cancer cells. Active form of MMP2 (62 kDa) was present in 88% of cases and MMP9 (83 kDa) in 38% of cases. By contrast, immunohistochemical staining revealed the presence of metalloproteinase 9 in all studied tissues. MMP activity was assessed against histological grade of the tumor. In the case of group G1 there was no activity of matrix metalloproteinase 9. By comparing the activity we concluded that the activity of MMPs in tumors with the highest degree of differentiation is significantly lower than in G2 and G3. Metalloproteinase 9 expression analysis revealed no significant differences between the groups of various degrees of histological maturity. The level of expression did not differ between the groups N0 and N1. CONCLUSION Lack of metalloproteinase 9 activity in group G1 may indicate that MMP9 is activated only in higher tumor grades. We have shown that an active form of MMP2 is found in all histological grades, which supports its involvement in the development of pancreatic cancer. Metalloproteinases are attractive target of anticancer therapy but not only the level of expression of metalloproteinases should be taken into account but also their level of activity and factors associated with their activation.
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Xu HN, Nioka S, Li LZ. Imaging heterogeneity in the mitochondrial redox state of premalignant pancreas in the pancreas-specific PTEN-null transgenic mouse model. Biomark Res 2013; 1:6. [PMID: 24252270 PMCID: PMC3776248 DOI: 10.1186/2050-7771-1-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Accepted: 12/18/2012] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Metabolic alteration is one of the hallmarks of carcinogenesis. We aimed to identify certain metabolic biomarkers for the early detection of pancreatic cancer (PC) using the transgenic PTEN-null mouse model. Pancreas-specific deletion of PTEN in mouse caused progressive premalignant lesions such as highly proliferative ductal metaplasia. We imaged the mitochondrial redox state of the pancreases of the transgenic mice approximately eight months old using the redox scanner, i.e., the nicotinamide adenine dinucleotide/oxidized flavoproteins (NADH/Fp) fluorescence imager at low temperature. Two different approaches, the global averaging of the redox indices without considering tissue heterogeneity along tissue depth and the univariate analysis of multi-section data using tissue depth as a covariate were adopted for the statistical analysis of the multi-section imaging data. The standard deviations of the redox indices and the histogram analysis with Gaussian fit were used to determine the tissue heterogeneity. RESULTS All methods show consistently that the PTEN deficient pancreases (Pdx1-Cre;PTENlox/lox) were significantly more heterogeneous in their mitochondrial redox state compared to the controls (PTENlox/lox). Statistical analysis taking into account the variations of the redox state with tissue depth further shows that PTEN deletion significantly shifted the pancreatic tissue to an overall more oxidized state. Oxidization of the PTEN-null group was not seen when the imaging data were analyzed by global averaging without considering the variation of the redox indices along tissue depth, indicating the importance of taking tissue heterogeneity into account for the statistical analysis of the multi-section imaging data. CONCLUSIONS This study reveals a possible link between the mitochondrial redox state alteration of the pancreas and its malignant transformation and may be further developed for establishing potential metabolic biomarkers for the early diagnosis of pancreatic cancer.
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Affiliation(s)
- He N Xu
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Shoko Nioka
- Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lin Z Li
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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38
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SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/β-catenin signaling. Oncogene 2013; 33:279-88. [PMID: 23318427 DOI: 10.1038/onc.2012.595] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 10/23/2012] [Accepted: 11/02/2012] [Indexed: 12/19/2022]
Abstract
Pancreatic cancer is among the top five deadliest cancers in developed countries. Better knowledge of the molecular mechanisms contributing to its tumorigenesis is imperative to improve patient prognosis. Identification of novel tumor suppressor genes (TSGs) in pancreatic cancer will reveal new mechanisms of pathway deregulation and will ultimately help improve our understanding of this aggressive disease. According to Knudson's two-hit model, TSGs are classically disrupted by two concerted genetic events. In this study, we combined DNA methylation profiling with copy number and mRNA expression profiling to identify novel TSGs in a set of 20 pancreatic cancer cell lines. These data sets were integrated for each of ∼12 000 genes in each cell line enabling the elucidation of those genes that undergo DNA hypermethylation, copy-number loss and mRNA downregulation simultaneously in multiple cell lines. Using this integrative genomics strategy, we identified SOX15 (sex determining region Y-box 15) as a candidate TSG in pancreatic cancer. Expression of SOX15 in pancreatic cancer cell lines with undetectable expression resulted in reduced viability of cancer cells both in vitro and in vivo demonstrating its tumor suppressive capability. We also found reduced expression, homozygous deletion and aberrant DNA methylation of SOX15 in clinical pancreatic tumor data sets. Furthermore, we deduced a novel role for SOX15 in suppressing the Wnt/β-catenin signaling pathway, which we hypothesize is a pathway through which SOX15 may exert its tumor suppressive effects in pancreatic cancer.
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39
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Hartwig W, Strobel O, Hinz U, Fritz S, Hackert T, Roth C, Büchler MW, Werner J. CA19-9 in potentially resectable pancreatic cancer: perspective to adjust surgical and perioperative therapy. Ann Surg Oncol 2012; 20:2188-96. [PMID: 23247983 DOI: 10.1245/s10434-012-2809-1] [Citation(s) in RCA: 213] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Indexed: 12/28/2022]
Abstract
PURPOSE In pancreatic cancer, genetic markers to aid clinical decision making are still lacking. The present study was designed to determine the prognostic role of perioperative serum tumor marker carbohydrate antigen 19-9 (CA19-9) in pancreatic adenocarcinoma, with a focus on implications for pre- and postoperative therapeutic consequences. METHODS Of a total of 1,626 consecutive patients who underwent surgery for primary pancreatic adenocarcinoma, data from 1,543 patients with preoperative serum levels of CA19-9 were evaluated for tumor stage, resectability, and prognosis. Preoperative to postoperative CA19-9 changes were analyzed for long-term survival. A control cohort of 706 patients with chronic pancreatitis was used to assess the predictability of malignancy by CA19-9 and the effects of hyperbilirubinemia on CA19-9 levels. RESULTS The more that preoperative CA19-9 increased, the lower were tumor resectability and survival rates. Resectability and 5-year survival varied from 80 to 38 % and from 27 to 0 % for CA19-9 <37 versus ≥4,000 U/ml, respectively. The R0 resection rate was as low as 15 % in all patients with CA19-9 levels ≥1,000 U/ml. CA19-9 increased with the stage of the disease and was highest in AJCC stage IV. Patients with an early postoperative CA19-9 increase had a dismal prognosis. Hyperbilirubinemia did not markedly affect CA19-9 levels (correlation coefficient ≤0.135). CONCLUSIONS In patients with pancreatic adenocarcinoma, CA19-9 predicts resectability, stage of disease, as well as survival. Highly elevated preoperative or increasing postoperative CA19-9 levels are associated with low resectability and poor survival rates, and demand the adjustment of surgical and perioperative therapy.
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Affiliation(s)
- Werner Hartwig
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany
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40
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Hu Y, Ou Y, Wu K, Chen Y, Sun W. miR-143 inhibits the metastasis of pancreatic cancer and an associated signaling pathway. Tumour Biol 2012; 33:1863-70. [PMID: 23070684 DOI: 10.1007/s13277-012-0446-8] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 06/21/2012] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is characterized by early metastasis and high mortality. In this study, the role of miR-143 in invasion and metastasis was investigated in pancreatic cancer cells. miR-143 expression was established by an adenovirus-carried miR-143 expression cassette. mRNA and protein levels of gene expression were examined by RT-PCR and Western blot assay, respectively. Rho GTPases activity was measured by the pull down assay. The role of miR-143 in migration and invasion of Panc-1 cells was tested in vitro. The antimetastatic effect of miR-143 was tested in a liver metastasis model, while its antitumor growth effect was tested in a xenograft Panc-1 tumor model. Results demonstrated that ARHGEF1 (GEF1), ARHGEF2 (GEF2), and K-RAS genes are the targets of miR-143. miR-143 expression significantly decreased mRNA and protein levels of GEF1, GEF2, and K-RAS genes; lowered the constitutive activities of RhoA, Rac1, and Cdc42 GTPases; decreased the protein levels of MMP-2 and MMP-9; but significantly increased the protein level of E-cadherin. miR-143 expression also significantly inhibited the migration and invasion of Panc-1 cells in vitro, liver metastasis, and xenograft tumor growth in vivo. Our study suggested that miR-143 plays a central role in the invasion and metastasis of pancreatic cancer and miR-143 is a potential target for pancreatic cancer therapy.
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Affiliation(s)
- Yongjun Hu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, PR China
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41
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Pezzilli R, Fabbri D, Imbrogno A. Pancreatic ductal adenocarcinoma screening: New perspectives. World J Gastroenterol 2012; 18:4973-7. [PMID: 23049204 PMCID: PMC3460322 DOI: 10.3748/wjg.v18.i36.4973] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 04/20/2012] [Accepted: 05/26/2012] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma accounts for more than 90% of all pancreatic cancers and its incidence has increased significantly worldwide. Patients with pancreatic ductal adenocarcinoma have a poor outcome and more than 95% of the people affected die from the disease within 12 mo after diagnosis. Surgery is the first-line treatment in the case of resectable neoplasm, but only 20% of patients are candidates for this approach. One of the reasons there are few candidates for surgery is that, during the early phases of the disease, the symptoms are poor or non-specific. Early diagnosis is of crucial importance to improve patient outcome; therefore, we are looking for a good screening test. The screening test must identify the disease in an early stage in order to be effective; having said this, a need exists to introduce the concept of “early” ductal adenocarcinoma. It has been reported that at least five additional years after the occurrence of the initiating mutation are required for the acquisition of metastatic ability of pancreatic adenocarcinoma and patients die an average of two years thereafter. We have reviewed the most recent literature in order to evaluate the present and future perspectives of screening programs of this deadly disease.
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Giovinazzo F, Turri G, Zanini S, Butturini G, Scarpa A, Bassi C. Clinical implications of biological markers in Pancreatic Ductal Adenocarcinoma. Surg Oncol 2012; 21:e171-82. [PMID: 22981281 DOI: 10.1016/j.suronc.2012.07.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Revised: 07/17/2012] [Accepted: 07/26/2012] [Indexed: 12/29/2022]
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a malignant neoplasm and is the fourth leading cause of cancer-related deaths in US with a 5-year survival rate less than 5%. Surgery is the only potentially curative treatment even though the result is a palliation in the majority of cases and the majority of lesions are lately diagnosed. Progression from normal pancreatic epithelium to metastatic disease is now a well-characterized sequence of events. Research has shown that pancreatic cancer is fundamentally a genetic disease with several biological pathway implied in apoptosis, cell proliferation and self-sufficiency in growth signaling, but how those findings could be applied in daily clinical practice remain unknown. Several studies tried to characterize diagnostic and prognostic biomarkers in PDAC to make it possible an earlier diagnosis, guarantee a more effective treatment and reach a better prognosis even though the results remain contrasting. The main limit of the published researches is the small number of patients studied, but even the heterogeneity of the used methods of analysis. Examining critically the research of the last years future trials may be addressed toward a translational models integrating "the bench and the bed" with the clinical experience and drive the basic research toward the clinical applications.
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Affiliation(s)
- Francesco Giovinazzo
- Laboratory of Translational Surgery, University Laboratories of Medical Research (LURM), G.B. Rossi Hospital, University of Verona, Piazzale L.A. Scuro 10, Verona 37134, Italy
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Luo Y, Tian L, Feng Y, Yi M, Chen X, Huang Q. The predictive role of p16 deletion, p53 deletion, and polysomy 9 and 17 in pancreatic ductal adenocarcinoma. Pathol Oncol Res 2012; 19:35-40. [PMID: 22782330 DOI: 10.1007/s12253-012-9555-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 06/26/2012] [Indexed: 12/22/2022]
Abstract
In this study, we investigated p53 and p16 deletions, and chromosome 9 and 17 amplifications in pancreatic ductal adenocarcinoma (PDAC), and further analyzed their associations with clinical characteristics and prognosis of PDAC. A total of 32 PDAC and 23 peritumoral tissues were collected. Molecular abnormalities of CEP9/p16 and CEP17/p53 were detected using Fluorescence in situ hybridization (FISH). Deletions of p16 and p53 were detected in 50 % and 65.7 % of PDAC, respectively. Polysomy 9 and 17 were identified in 75 % and 71.8 % of PDAC, respectively. No p16 and p53 deletion, polysomy 9 and 17 were identified in peritumoral tissues. We also observed significant correlations of p16 deletion, polysomy 9 and 17 with shorter survival of PDAC. P16 deletion, polysomy 9 and 17 are predictive markers for poor prognosis of PDAC patients, but p53 deletion is not associated with the clinical characteristics and prognosis of PDAC.
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Affiliation(s)
- Yanli Luo
- Experimental Research Center, First People's Hospital, Shanghai Jiaotong University, 85 Wujin Road, Shanghai 200080, China
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44
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Abrams RA. Radiotherapy in the adjuvant management of pancreatic adenocarcinoma: is it helpful? Expert Rev Gastroenterol Hepatol 2012; 6:149-61. [PMID: 22375521 DOI: 10.1586/egh.12.3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Curative-intent management for pancreatic adenocarcinoma requires gross total resection. Only 15-20% of patients are eligible for resection and of these only approximately 20% are long-term survivors. Adjuvant and neoadjuvant approaches have been, and are being, sought to improve upon surgical results. Radiotherapy has a role in the adjuvant management of many gastrointestinal malignancies and historically has also had a role in the adjuvant management of pancreatic adenocarcinoma. However, the role of radiotherapy in the management of pancreatic adenocarcinoma has been called into question. This review examines this controversy and the underlying issues and considers current efforts towards resolving them, as well as some likely future developments.
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Affiliation(s)
- Ross A Abrams
- Department of Radiation Oncology, Rush University Medical Center, Atrium Bldg, Ground Floor, 500 S. Paulina, Chicago, IL 60612, USA.
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45
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PDGFRβ expression in tumor stroma of pancreatic adenocarcinoma as a reliable prognostic marker. Med Oncol 2012; 29:2824-30. [PMID: 22403002 DOI: 10.1007/s12032-012-0193-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Accepted: 02/14/2012] [Indexed: 01/08/2023]
Abstract
Pancreatic adenocarcinoma is a lethal disease that often develops a desmoplastic reaction in tumor stroma. In general, desmoplasia is thought to promote tumor growth. However, its molecular pathology and prognostic potential have not been fully investigated. Here, we investigate 26 cases of pancreatic ductal adenocarcinoma and examine the clinicopathological association between survival and expression levels of several molecular markers for stromal cells. These include alpha-smooth muscle actin (SMA) and platelet-derived growth factor (PDGF) receptor β (PDGFRβ). Both are markers of activated fibroblasts or pancreatic stellate cells (PSCs) that play an important role in desmoplasia. The staining patterns of both molecular markers were not uniform, so we categorized them into 3 grades (high, middle, and low) according to intensity. Interestingly, Kaplan-Meier analysis revealed that higher expression of PDGFRβ matched shorter prognosis (p=0.0287, log-rank test) as well as lymphatic invasion and lymph node metastasis, whereas SMA did not (p=0.6122). Our results suggest the prognostic potential of cancer stroma via PDGF-B signaling. Regulation of PDGF-B-associated signaling crosstalk between cancer cells and stroma cells, therefore, may indicate a possible therapeutic target for desmoplastic malignant tumors such as pancreatic adenocarcinoma.
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Singh P, Srinivasan R, Wig JD, Radotra BD. A study of Smad4, Smad6 and Smad7 in Surgically Resected Samples of Pancreatic Ductal Adenocarcinoma and Their Correlation with Clinicopathological Parameters and Patient Survival. BMC Res Notes 2011; 4:560. [PMID: 22195733 PMCID: PMC3268768 DOI: 10.1186/1756-0500-4-560] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Accepted: 12/23/2011] [Indexed: 12/11/2022] Open
Abstract
Background Smad4 is the common mediator of the tumor suppressive functions of TGF-beta. Smad6 and Smad7 are the antagonists of the TGF-beta pathway. This study investigates the differential protein expressions of Smad4, Smad6 and Smad7 in tumor as compared to normal tissue of pancreatic ductal adenocarcinoma (PDAC) and compares them with clinicopathological parameters and patient survival. Results There was a significant difference in protein expressions of Smad4 (p = 0.0001), Smad6 (p = 0.0015) and Smad7 (p = 0.0005) protein in tumor as compared to paired normal samples. Loss of Smad7 expression correlated significantly with tumor size (r = 0.421, p < 0.036) and margin status (r = 0.431; p < .032). Patients with moderate to high Smad4 protein expression had a better survival (median survival = 14.600 ± 2.112 months) than patients with absent or weak Smad4 protein expression (median survival = 7.150 ± 0.662). In addition, advanced disease stage correlated significantly with poor prognosis. Conclusion Loss of Smad4 significantly correlated with poor survival of PDAC patients. In the cases where Smad4 is expressed, Smad6 inhibition is possibly a novel mechanism for Smad4 inactivation. Smad7 has a role in pathobiology of PDAC. Further investigation in the roles of Smad6 and Smad7 would help in the identification of novel therapeutic targets for PDAC.
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Affiliation(s)
- Puneet Singh
- Department of General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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