|
1
|
Calistri S, Ottaviano G, Ubaldini A. Radiopharmaceuticals for Pancreatic Cancer: A Review of Current Approaches and Future Directions. Pharmaceuticals (Basel) 2024; 17:1314. [PMID: 39458955 PMCID: PMC11510189 DOI: 10.3390/ph17101314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/28/2024] Open
Abstract
The poor prognosis of pancreatic cancer requires novel treatment options. This review examines the evolution of radiopharmaceuticals in the treatment of pancreatic cancer. Established strategies such as peptide receptor radionuclide therapy (PRRT) offer targeted and effective treatment, compared to conventional treatments. However, there are currently no radiopharmaceuticals approved for the treatment of pancreatic cancer in Europe, which requires further research and novel approaches. New radiopharmaceuticals including radiolabeled antibodies, peptides, and nanotechnological approaches are promising in addressing the challenges of pancreatic cancer therapy. These new agents may offer more specific targeting and potentially improve efficacy compared to traditional therapies. Further research is needed to optimize efficacy, address limitations, and explore the overall potential of these new strategies in the treatment of this aggressive and harmful pathology.
Collapse
Affiliation(s)
- Sara Calistri
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy
- ENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, C.R. Bologna, Via Martiri di Monte Sole 4, 40129 Bologna, Italy; (G.O.); (A.U.)
| | - Giuseppe Ottaviano
- ENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, C.R. Bologna, Via Martiri di Monte Sole 4, 40129 Bologna, Italy; (G.O.); (A.U.)
| | - Alberto Ubaldini
- ENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, C.R. Bologna, Via Martiri di Monte Sole 4, 40129 Bologna, Italy; (G.O.); (A.U.)
| |
Collapse
|
|
2
|
Menadi S, Kucuk B, Cacan E. Promoter Hypomethylation Upregulates ANXA2 Expression in Pancreatic Cancer and is Associated with Poor Prognosis. Biochem Genet 2024; 62:2721-2742. [PMID: 38001391 DOI: 10.1007/s10528-023-10577-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 10/26/2023] [Indexed: 11/26/2023]
Abstract
Pancreatic cancer (PC) is one of the world's most aggressive and deadly cancers, owing to non-specific early clinical symptoms, late-stage diagnosis, and poor survival. Therefore, it is critical to identify specific biomarkers for its early diagnosis. Annexin A2 (ANXA2) is a calcium-dependent phospholipid-binding protein that has been reported to be upregulated in several cancer types, making it an emerging biomarker and potential cancer therapeutic target. However, the mechanism underlying the regulation of ANXA2 overexpression is still unclear. It is well established that genetic and epigenetic alterations may lead to widespread dysregulation of gene expression. Hence, in this study, we focused on exploring the regulatory mechanism of ANXA2 by investigating the transcriptional profile, methylation pattern, somatic mutation, and prognostic value of ANXA2 in PC using several bioinformatics databases. Our results revealed that the expression levels of ANXA2 were remarkably increased in PC tissues comparing to normal tissues. Furthermore, the high expression of ANXA2 was significantly related to the poor prognosis of PC patients. More importantly, we demonstrated for the first time that the ANXA2 promoter is hypomethylated in PC tissues compared to normal tissues which may result in ANXA2 overexpression in PC. However, more experimental research is required to corroborate our findings.
Collapse
Affiliation(s)
- Soumaya Menadi
- Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, 60250, Tokat, Turkey
| | - Burak Kucuk
- Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, 60250, Tokat, Turkey
| | - Ercan Cacan
- Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, 60250, Tokat, Turkey.
| |
Collapse
|
|
3
|
Alausa A, Lawal KA, Babatunde OA, Obiwulu ENO, Oladokun OC, Fadahunsi OS, Celestine UO, Moses EU, Akaniro IR, Adegbola PI. Overcoming immunotherapeutic resistance in PDAC: SIRPα-CD47 blockade. Pharmacol Res 2022; 181:106264. [PMID: 35597384 DOI: 10.1016/j.phrs.2022.106264] [Citation(s) in RCA: 10] [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: 05/10/2022] [Accepted: 05/15/2022] [Indexed: 11/25/2022]
Abstract
A daily increase in the number of new cases of pancreatic ductal adenocarcinoma remains an issue of contention in cancer research. The data revealed that a global cumulated case of about 500, 000 have been reported. This has made PDAC the fourteenth most occurring tumor case in cancer research. Furthermore, PDAC is responsible for about 466,003 deaths annually, representing the seventh prevalent type of cancer mortality. PDAC has no salient symptoms in its early stages. This has exasperated several attempts to produce a perfect therapeutic agent against PDAC. Recently, immunotherapeutic research has shifted focus to the blockade of checkpoint proteins in the management and of some cancers. Investigations have centrally focused on developing therapeutic agents that could at least to a significant extent block the SIRPα-CD47 signaling cascade (a cascade which prevent phagocytosis of tumors by dendritic cells, via the deactivation of innate immunity and subsequently resulting in tumor regression) with minimal side effects. The concept on the blockade of this interaction as a possible mechanism for inhibiting the progression of PDAC is currently being debated. This review examined the structure--function activity of SIRPα-CD47 interaction while discussing in detail the mechanism of tumor resistance in PDAC. Further, this review details how the blockade of SIRPα-CD47 interaction serve as a therapeutic option in the management of PDAC.
Collapse
Affiliation(s)
- Abdullahi Alausa
- Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo state, Nigeria.
| | - Khadijat Ayodeji Lawal
- Heamtalogy and Blood Transfusion Unit, Department of Medical Laboratory Science, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | | | - E N O Obiwulu
- Department of Chemical Science, University of Delta, Agbor, Delta State, Nigeria
| | | | - Olumide Samuel Fadahunsi
- Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo state, Nigeria
| | - Ugwu Obiora Celestine
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Enugu State University of Science and Technology, Nigeria
| | | | | | - Peter Ifeoluwa Adegbola
- Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo state, Nigeria.
| |
Collapse
|
|
4
|
Molecular aspects of pancreatic cancer: focus on reprogrammed metabolism in a nutrient-deficient environment and potential therapeutic targets. Cent Eur J Immunol 2021; 46:258-263. [PMID: 34764796 PMCID: PMC8568029 DOI: 10.5114/ceji.2021.107027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 04/08/2021] [Indexed: 11/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is still burdened with high mortality (5-year survival rate < 9%) due to late diagnosis, aggressiveness, and a lack of more effective treatment methods. Early diagnosis and new therapeutic approaches based on the reprogrammed metabolism of the tumor in a nutrient-deficient environment are expected to improve the future treatment of PDAC patients. Research results suggest that genetic and metabolic disorders may precede the onset of neoplastic changes, which should allow for earlier appropriate treatment. Glycolysis and glutaminolysis are the most investigated pathways associated with the highest aggressiveness of pancreatic tumors. Blocking of selected metabolic pathways related to the local adaptive metabolic activity of pancreatic cancer cells improving nutrient acquisition and metabolic crosstalk within the microenvironment to sustain proliferation may inhibit cancer development, increase cancer cells death, and increase sensitivity to other forms of treatment (e.g., chemotherapy). Depriving cancer cells of important nutrients (glucose, glutamine) revealed tumor “checkpoints” for the mechanisms that drive cell proliferation and metastasis formation in order to determine its accuracy for individualization of the therapeutic approach. The present review highlights selected metabolic signaling pathways and their regulators aimed at inhibiting the neoplastic process. Particular attention has been paid to the adaptive metabolism of pancreatic cancer, which promotes its development in an oxygen-deficient and nutrient-poor environment.
Collapse
|
|
5
|
Xiong C, Zhu Y, Xue M, Jiang Y, Zhong Y, Jiang L, Shi M, Chen H. Tumor-associated macrophages promote pancreatic ductal adenocarcinoma progression by inducing epithelial-to-mesenchymal transition. Aging (Albany NY) 2021; 13:3386-3404. [PMID: 33428605 PMCID: PMC7906203 DOI: 10.18632/aging.202264] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 09/28/2020] [Indexed: 12/14/2022]
Abstract
In this study, we investigated the role of tumor-associated macrophages (TAMs) in the progression of pancreatic ductal adenocarcinoma (PDAC). PDAC patients with higher levels of CD68+ TAMs exhibited shorter overall survival. In Transwell assays, PDAC cells incubated with TAMs or conditioned media from TAM cells (TAM-CM) showed higher migration and invasion rates than controls. PET/CT scan analysis of orthotopic PDAC model mice revealed greater primary tumor growth and liver metastasis in the TAM-CM treatment group than the controls. H&E staining of liver tissues showed significantly higher numbers of metastatic nodules in the TAM-CM treatment group. Heat inactivation of TAM-CM significantly reduced Transwell migration by PDAC cells, suggesting the involvement of one or more secreted proteins in PDAC progression. Transcriptome sequencing analysis of PDAC cells treated with TAM-CM revealed significant enrichment of transforming growth factor-β (TGF-β) signaling pathway genes. Western blot and qRT-PCR analysis showed that TAM-CM enhanced PDAC migration cells by inducing epithelial-to-mesenchymal transition through the TGF-β-Smad2/3/4-Snail signaling axis. The pro-tumorigenic effects of TAMs or TAM-CM were abolished by TGF-β signaling pathway inhibitors and neutralizing TGF-β antibody. These results demonstrate that TAMs promote PDAC progression through the TGF-β signaling pathway.
Collapse
Affiliation(s)
- Cheng Xiong
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai, China.,Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Youwei Zhu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai, China.,Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Meilin Xue
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai, China.,Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yongsheng Jiang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai, China.,Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yiming Zhong
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai, China.,Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Lingxi Jiang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai, China.,Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Minmin Shi
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai, China.,Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Hao Chen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai, China.,Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| |
Collapse
|
|
6
|
Tarabay J, Li X, Chandan VS. Adenosquamous carcinoma of the pancreas. Clin Res Hepatol Gastroenterol 2020; 44:796-798. [PMID: 32107164 DOI: 10.1016/j.clinre.2020.01.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 01/22/2020] [Indexed: 02/04/2023]
Affiliation(s)
- Jana Tarabay
- Department of Pathology and Laboratory Medicine, University of California-Irvine, Orange, CA 92868, United States
| | - Xiaodong Li
- Department of Pathology and Laboratory Medicine, University of California-Irvine, Orange, CA 92868, United States
| | - Vishal S Chandan
- Department of Pathology and Laboratory Medicine, University of California-Irvine, Orange, CA 92868, United States.
| |
Collapse
|
|
7
|
Dhar D, Raina K, Kumar D, Wempe MF, Bagby SM, Pitts TM, Orlicky DJ, Agarwal C, Messersmith WA, Agarwal R. Bitter melon juice intake with gemcitabine intervention circumvents resistance to gemcitabine in pancreatic patient-derived xenograft tumors. Mol Carcinog 2020; 59:1227-1240. [PMID: 32816368 DOI: 10.1002/mc.23251] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/18/2022]
Abstract
Chemoresistance to gemcitabine (GEM)-a frontline chemotherapeutic, resulting from its dysfunctional uptake and metabolism in cancer cells, is a major contributing factor for failed therapy in pancreatic cancer (PanC) patients. Therefore, there is an urgent need for agents that could reverse GEM resistance and allow continued chemosensitivity to the drug. We employed natural nontoxic agent (with anti-PanC potential) bitter melon juice (BMJ) and GEM to examine their combinatorial benefits against tumorigenesis of PanC patient-derived xenograft (PDX)-pancreatic ductal adenocarcinomas explants PDX272 (wild-type KRAS), PDX271 (mutant KRAS and SMAD4), and PDX266 (mutant KRAS). Anti-PanC efficacy of single agents vs combination in the three tumor explants, both at the end of active dosing regimen and following a drug-washout phase were compared. In animal studies, GEM alone treatment significantly inhibited PDX tumor growth, but effects were not sustained, as GEM-treated tumors exhibited regrowth posttreatment termination. However, combination-regimen displayed enhanced and sustained efficacy. Mechanistic assessments revealed that overcoming GEM resistance by coadministration with BMJ was possibly due to modulation of GEM transport/metabolism pathway molecules (ribonucleotide reductase regulatory subunit M1, human equilibrative nucleoside transporter 1, and deoxycytidine kinase). Study outcomes, highlighting significantly higher and sustained efficacy of GEM in combination with BMJ, make a compelling case for a clinical trial in PanC patients, wherein BMJ could be combined with GEM to target and overcome GEM resistance. In addition, given their specific effectiveness against KRAS-mutant tumors, this combination could be potentially beneficial to a broader PanC patient population.
Collapse
Affiliation(s)
- Deepanshi Dhar
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado
| | - Komal Raina
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado.,Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota
| | - Dileep Kumar
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado
| | - Michael F Wempe
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado
| | - Stacey M Bagby
- Division of Medical Oncology, School of Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado
| | - Todd M Pitts
- Division of Medical Oncology, School of Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado
| | - David J Orlicky
- Department of Pathology, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado
| | - Chapla Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado
| | - Wells A Messersmith
- Division of Medical Oncology, School of Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado.,University of Colorado Cancer Center, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado.,University of Colorado Cancer Center, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado
| |
Collapse
|
|
8
|
Nguyen AV, Trompetto B, Tan XHM, Scott MB, Hu KHH, Deeds E, Butte MJ, Chiou PY, Rowat AC. Differential Contributions of Actin and Myosin to the Physical Phenotypes and Invasion of Pancreatic Cancer Cells. Cell Mol Bioeng 2020; 13:27-44. [PMID: 32030106 PMCID: PMC6981337 DOI: 10.1007/s12195-019-00603-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/04/2019] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Metastasis is a fundamentally physical process in which cells deform through narrow gaps and generate forces to invade surrounding tissues. While it is commonly thought that increased cell deformability is an advantage for invading cells, we previously found that more invasive pancreatic ductal adenocarcinoma (PDAC) cells are stiffer than less invasive PDAC cells. Here we investigate potential mechanisms of the simultaneous increase in PDAC cell stiffness and invasion, focusing on the contributions of myosin II, Arp2/3, and formins. METHOD We measure cell invasion using a 3D scratch wound invasion assay and cell stiffness using atomic force microscopy (AFM). To determine the effects of actin- and myosin-mediated force generation on cell stiffness and invasion, we treat cells with pharmacologic inhibitors of myosin II (blebbistatin), Arp2/3 (CK-666), and formins (SMIFH2). RESULTS We find that the activity of myosin II, Arp2/3, and formins all contribute to the stiffness of PDAC cells. Interestingly, we find that the invasion of PDAC cell lines is differentially affected when the activity of myosin II, Arp2/3, or formins is inhibited, suggesting that despite having similar tissue origins, different PDAC cell lines may rely on different mechanisms for invasion. CONCLUSIONS These findings deepen our knowledge of the factors that regulate cancer cell mechanotype and invasion, and incite further studies to develop therapeutics that target multiple mechanisms of invasion for improved clinical benefit.
Collapse
Affiliation(s)
- Angelyn V. Nguyen
- Department of Integrative Biology and Physiology, University of California, 610 Charles E Young Dr. East, Los Angeles, CA 90095 USA
| | - Brittany Trompetto
- Department of Integrative Biology and Physiology, University of California, 610 Charles E Young Dr. East, Los Angeles, CA 90095 USA
| | | | - Michael B. Scott
- Department of Integrative Biology and Physiology, University of California, 610 Charles E Young Dr. East, Los Angeles, CA 90095 USA
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, USA
- Present Address: Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, USA
- Department of Biomedical Engineering, Northwestern McCormick School of Engineering, Evanston, USA
| | | | - Eric Deeds
- Department of Integrative Biology and Physiology, University of California, 610 Charles E Young Dr. East, Los Angeles, CA 90095 USA
- Institute for Quantitative and Computational Biology, University of California, Los Angeles, USA
| | - Manish J. Butte
- Department of Pediatrics, University of California, Los Angeles, USA
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, USA
| | - Pei Yu Chiou
- Department of Bioengineering, University of California, Los Angeles, USA
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, USA
| | - Amy C. Rowat
- Department of Integrative Biology and Physiology, University of California, 610 Charles E Young Dr. East, Los Angeles, CA 90095 USA
- Department of Bioengineering, University of California, Los Angeles, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, USA
| |
Collapse
|
|
9
|
Metabolic Alterations in Pancreatic Cancer Progression. Cancers (Basel) 2019; 12:cancers12010002. [PMID: 31861288 PMCID: PMC7016676 DOI: 10.3390/cancers12010002] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 12/12/2019] [Accepted: 12/14/2019] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is the third leading cause of cancer-related deaths in the USA. Pancreatic tumors are characterized by enhanced glycolytic metabolism promoted by a hypoxic tumor microenvironment and a resultant acidic milieu. The metabolic reprogramming allows cancer cells to survive hostile microenvironments. Through the analysis of the principal metabolic pathways, we identified the specific metabolites that are altered during pancreatic cancer progression in the spontaneous progression (KPC) mouse model. Genetically engineered mice exhibited metabolic alterations during PanINs formation, even before the tumor development. To account for other cells in the tumor microenvironment and to focus on metabolic adaptations concerning tumorigenic cells only, we compared the metabolic profile of KPC and orthotopic tumors with those obtained from KPC-tumor derived cell lines. We observed significant upregulation of glycolysis and the pentose phosphate pathway metabolites even at the early stages of pathogenesis. Other biosynthetic pathways also demonstrated a few common perturbations. While some of the metabolic changes in tumor cells are not detectable in orthotopic and spontaneous tumors, a significant number of tumor cell-intrinsic metabolic alterations are readily detectable in the animal models. Overall, we identified that metabolic alterations in precancerous lesions are maintained during cancer development and are largely mirrored by cancer cells in culture conditions.
Collapse
|
|
10
|
Mörchen B, Shkura O, Stoll R, Helfrich I. Targeting the "undruggable" RAS - new strategies - new hope? CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:813-826. [PMID: 35582595 PMCID: PMC8992515 DOI: 10.20517/cdr.2019.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/25/2019] [Accepted: 06/04/2019] [Indexed: 06/15/2023]
Abstract
K-RAS is the most frequently mutated oncogene in solid tumors, such as pancreatic, colon or lung cancer. The GTPase K-RAS can either be in an active (GTP-loaded) or inactive (GDP-loaded) form. In its active form K-RAS forwards signals from growth factors, cytokines or hormones to the nucleus, regulating essential pathways, such as cell proliferation and differentiation. In turn, activating somatic mutations of this proto-oncogene deregulate the complex interplay between GAP (GTPase-activating) - and GEF (Guanine nucleotide exchange factor) - proteins, driving neoplastic transformation. Due to a rather shallow surface, K-RAS lacks proper binding pockets for small molecules, hindering drug development over the past thirty years. This review summarizes recent progress in the development of low molecular antagonists and further shows insights of a newly described interaction between mutant K-RAS signaling and PD-L1 induced immunosuppression, giving new hope for future treatments of K-RAS mutated cancer.
Collapse
Affiliation(s)
- Britta Mörchen
- Skin Cancer Unit of the Dermatology Department, Medical Faculty, University Duisburg-Essen, West German Cancer Center, Essen 45147, Germany
- German Cancer Consortium (DKTK) partner site Düsseldorf/Essen, Essen 45147, Germany
| | - Oleksandr Shkura
- Biomolecular NMR, Faculty of Chemistry and Biochemistry, Ruhr University of Bochum, Bochum D-44780, Germany
| | - Raphael Stoll
- Biomolecular NMR, Faculty of Chemistry and Biochemistry, Ruhr University of Bochum, Bochum D-44780, Germany
- Both authors contribute equally
| | - Iris Helfrich
- Skin Cancer Unit of the Dermatology Department, Medical Faculty, University Duisburg-Essen, West German Cancer Center, Essen 45147, Germany
- German Cancer Consortium (DKTK) partner site Düsseldorf/Essen, Essen 45147, Germany
- Both authors contribute equally
| |
Collapse
|
|
11
|
Fendiline Enhances the Cytotoxic Effects of Therapeutic Agents on PDAC Cells by Inhibiting Tumor-Promoting Signaling Events: A Potential Strategy to Combat PDAC. Int J Mol Sci 2019; 20:ijms20102423. [PMID: 31100813 PMCID: PMC6567171 DOI: 10.3390/ijms20102423] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 05/10/2019] [Accepted: 05/12/2019] [Indexed: 02/07/2023] Open
Abstract
The L-type calcium channel blocker fendiline has been shown to interfere with Ras-dependent signaling in K-Ras mutant cancer cells. Earlier studies from our lab had shown that treatment of pancreatic cancer cells with fendiline causes significant cytotoxicity and interferes with proliferation, survival, migration, invasion and anchorage independent growth. Currently there are no effective therapies to manage PDACs. As fendiline has been approved for treatment of patients with angina, we hypothesized that, if proven effective, combinatorial therapies using this agent would be easily translatable to clinic for testing in PDAC patients. Here we tested combinations of fendiline with gemcitabine, visudyne (a YAP1 inhibitor) or tivantinib (ARQ197, a c-Met inhibitor) for their effectiveness in overcoming growth and oncogenic characteristics of PDAC cells. The Hippo pathway component YAP1 has been shown to bypass K-Ras addiction, and allow tumor growth, in a Ras-null mouse model. Similarly, c-Met expression has been associated with poor prognosis and metastasis in PDAC patients. Our results presented here show that combinations of fendiline with these inhibitors show enhanced anti-tumor activity in Panc1, MiaPaCa2 and CD18/HPAF PDAC cells, as evident from the reduced viability, migration, anchorage-independent growth and self-renewal. Biochemical analysis shows that these agents interfere with various signaling cascades such as the activation of Akt and ERK, as well as the expression of c-Myc and CD44 that are altered in PDACs. These results imply that inclusion of fendiline may improve the efficacy of various chemotherapeutic agents that could potentially benefit PDAC patients.
Collapse
|
|
12
|
Abstract
OBJECTIVE The incidence of pancreatic adenocarcinoma (PA) approximates its prevalence, as the malignancy is almost consistently fatal within a year. Although the currently available adjuvant therapy seems to provide survival benefit, it is only moderate, and the standard regimen has not yet been established. Therefore, more biological resources to investigate the PA are needed. METHODS Here, we established and characterized 10 human pancreatic cancer cell lines derived from primary tumor mass. Whole exome sequencing technique was used to identify driver mutations and aberrant pathways in each cell line. RESULTS Five anticancer drugs were treated to find half maximal effective concentration (EC50), and the response was analyzed in reference to mutational status. Frame shift mutations in ARID1A gene and HER2 amplification were mutually related to better response to the anticancer drugs. In contrast, frame shift mutation in MSH6 gene was associated with resistance to anticancer drugs. CONCLUSIONS In summary, we established 10 pancreatic cancer cell lines and integrated various molecular aberrations and features of pancreatic cancer cells. Our biological resources are expected to contribute to facilitating research on PA.
Collapse
|
|
13
|
Masetti M, Acquaviva G, Visani M, Tallini G, Fornelli A, Ragazzi M, Vasuri F, Grifoni D, Di Giacomo S, Fiorino S, Lombardi R, Tuminati D, Ravaioli M, Fabbri C, Bacchi-Reggiani ML, Pession A, Jovine E, de Biase D. Long-term survivors of pancreatic adenocarcinoma show low rates of genetic alterations in KRAS, TP53 and SMAD4. Cancer Biomark 2018; 21:323-334. [PMID: 29103024 DOI: 10.3233/cbm-170464] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Pancreatic adenocarcinoma (PDAC) is one of the deadliest human malignancies. Although surgery is currently the only effective treatment for PDAC, most patients survive less than 20 months after tumor resection. OBJECTIVE The primary goal was to investigate alterations in KRAS, TP53, SMAD4 and CDKN2A/p16 in tumors from patients with exceptionally long survival after surgery. METHODS Tumors from 15 patients with PDAC that survived more than 55 months after surgery ("LS") were analyzed for KRAS, TP53, IDH1, NRAS and BRAF using next-generation sequencing. SMAD4 and CDKN2A/p16 was tested using immunohistochemistry. MGMT promoter methylation was investigated. RESULTS Tumors from "LS" have a lower prevalence of KRAS and TP53 mutations and had more frequently SMAD4 retained expression, if compared with that of patients died within 24 months from surgery. The survival of patients with wild-type KRAS and TP53 tumors was more than twice longer than that of patients bearing KRAS and TP53 mutations (90.2 vs. 41.1 months). Patients with KRAS wild-type tumors and that retained SMAD4 expression had a survival twice longer than cases with alterations in both genes (83.8 vs. 36.7 months). Eleven tumors (39.3%) showed MGMT methylation. CONCLUSIONS Our data indicate that absence of KRAS, TP53 and SMAD4 genetic alterations may identify a subset of pancreatic carcinomas with better outcome.
Collapse
Affiliation(s)
- Michele Masetti
- Surgery Unit, Azienda USL-Maggiore Hospital, Bologna, Italy
- Surgery Unit, Azienda USL-Maggiore Hospital, Bologna, Italy
| | - Giorgia Acquaviva
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
- Surgery Unit, Azienda USL-Maggiore Hospital, Bologna, Italy
| | - Michela Visani
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
| | - Giovanni Tallini
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
| | - Adele Fornelli
- Anatomic Pathology Unit, Azienda USL-Maggiore Hospital, Bologna, Italy
| | - Moira Ragazzi
- Anatomic Pathology Unit, Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italy
| | - Francesco Vasuri
- Anatomic Pathology Unit, "F. Addarii" Institute of Oncology and Transplantation Pathology, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Daniela Grifoni
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna, Italy
| | - Simone Di Giacomo
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna, Italy
| | - Sirio Fiorino
- Internal Medicine Unit, Maggiore Hospital, Bologna, Italy
| | | | - David Tuminati
- Surgery Unit, Azienda USL-Maggiore Hospital, Bologna, Italy
| | - Matteo Ravaioli
- Department of General Surgery and Transplantation, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Carlo Fabbri
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Bologna, Italy
| | - Maria Letizia Bacchi-Reggiani
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Cardiology Unit, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy
| | - Annalisa Pession
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna, Italy
| | - Elio Jovine
- Surgery Unit, Azienda USL-Maggiore Hospital, Bologna, Italy
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna, Italy
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
| |
Collapse
|
|
14
|
Imperial R, Toor OM, Hussain A, Subramanian J, Masood A. Comprehensive pancancer genomic analysis reveals (RTK)-RAS-RAF-MEK as a key dysregulated pathway in cancer: Its clinical implications. Semin Cancer Biol 2017; 54:14-28. [PMID: 29175106 DOI: 10.1016/j.semcancer.2017.11.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 11/19/2017] [Indexed: 02/07/2023]
Abstract
Recent advances in Next Generation Sequencing (NGS) have provided remarkable insights into the genomic characteristics of human cancers that have spurred a revolution in the field of oncology. The mitogen-activated protein kinase pathway (MAPK) and its activating cell receptor, the receptor tyrosine kinases (RTKs), which together encompass the (RTK)-RAS-RAF-MEK-ERK axis, are central to oncogenesis. A pan-cancer genomics analysis presented in this review is made possible by large collaborative projects, including The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and others. Landmark studies contributing to these projects have revealed alterations in cell signaling cascades that vary between cancer types and within tumors themselves. We review several of these studies in major tumor types to highlight recent advances in our understanding of the role of (RTK)-RAS-RAF alterations in cancer. Further studies are needed to increase the statistical power to detect clinically relevant low-frequency mutations, in addition to the known (RTK)-RAS-RAF pathway alterations, and to refine the resolution of the genomic landscape that defines these cancer mutations. The (RTK)-RAS-RAF-MEK-ERK mutation status, and their prognostic value, are also examined and correlated with clinical phenotypes. Treatments targeting various components of this pathway are ongoing, and are often effective initially in defined subgroups of patients. However, resistance to these agents can develop through adaptive mechanisms. With our steady increase in understanding the molecular biology of cancer, ongoing evaluation and monitoring through genomic analysis will continue to provide important information to the clinician in the context of treatment selection, response, resistance and outcomes.
Collapse
Affiliation(s)
- Robin Imperial
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Omer M Toor
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA; Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA; Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA
| | - Arif Hussain
- Division of Oncology, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA; The Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA
| | - Janakiraman Subramanian
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA; Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA; Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA
| | - Ashiq Masood
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA; Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA; Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA.
| |
Collapse
|
|
15
|
Zhu Q, Pan X, Sun Y, Wang Z, Liu F, Li A, Zhao Z, Wang Y, Li K, Mi L. Biological nanoparticles carrying the Hmda-7 gene are effective in inhibiting pancreatic cancer in vitro and in vivo. PLoS One 2017; 12:e0185507. [PMID: 28985230 PMCID: PMC5630125 DOI: 10.1371/journal.pone.0185507] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 09/06/2017] [Indexed: 12/13/2022] Open
Abstract
Objectives Pancreatic cancer is one of the most common malignancies of the digestive system, and remains a clinical challenge. This study aimed to assess the effects of bovine serum albumin (BSA) nanoparticles carrying the hMDA-7 gene (BSA-NP-hMDA-7) in the treatment of pancreatic cancer. Methods BSA-NP-hMDA-7 was generated by nanotechnology and gene recombination technology. A total of 5 BXPC-3 or PANC-1 pancreatic cancer cell groups were examined, including Control, BSA-NPs, Empty vector, hMDA-7 plasmid, and hMDA-7 BSA-NPs groups, respectively. Proliferation and apoptosis of cultured cells were assessed by the MTT method and flow-cytometry, respectively. In addition, pancreatic cancer models were established with both cell lines in nude mice, and the expression profiles of hMDA-7 and VEGF in cancer tissues were measured by Western blot and immunohistochemistry. Results BSA-NP-hMDA-7 nanoparticles were successfully generated, and significantly inhibited the proliferation of BXPC-3 and PANC-1 cells; in addition, apoptosis rates were higher in both cell lines after treatment with BSA-NP-hMDA-7 (P<0.05). Nude mouse xenograft studies indicated that treatment with BSA-NP-hMDA-7 nanoparticles resulted in decreased tumor size. Moreover, the hMDA-7 protein was found in tumor tissues after hMDA-7 gene transfection, while BSA-NP-hMDA-7 significantly suppressed VEGF expression in tumor tissues. Similar results were obtained for both BXPC-3 and PANC-1 xenograft models. Conclusion BSA nanoparticles carrying the hMDA-7 gene effectively transfected BXPC-3 and PANC-1 pancreatic cancer cells, causing reduced cell proliferation and enhanced apoptosis in vitro. In mouse xenografts, BSA-NP-hMDA-7 treatment decreased tumor size and reduced VEGF expression. These findings indicated that BSA-NP-hMDA-7 might exert anticancer effects via VEGF suppression.
Collapse
Affiliation(s)
- Qingyun Zhu
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xinting Pan
- The Affiliated Hospital of Qingdao University, Qingdao, China
- * E-mail:
| | - Yunbo Sun
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhengbin Wang
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Fuguo Liu
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Aiqin Li
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhihui Zhao
- Nano New Material Key Laboratories of Qingdao University, Qingdao, China
| | - Yunlong Wang
- Nano New Material Key Laboratories of Qingdao University, Qingdao, China
| | - Kun Li
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liangyu Mi
- Department of ICU, the Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
|
16
|
Matera R, Saif MW. New therapeutic directions for advanced pancreatic cancer: cell cycle inhibitors, stromal modifiers and conjugated therapies. Expert Opin Emerg Drugs 2017; 22:223-233. [PMID: 28783977 DOI: 10.1080/14728214.2017.1362388] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Pancreatic adenocarcinoma is a devastating malignancy with an extremely poor prognosis. These tumors progress rapidly and somewhat silently with few specific symptoms and are relatively resistant to chemotherapeutic agents. Many agents, including cell cycle inhibitors, are under development for the treatment of this cancer for which there are disappointingly few treatment options. Areas covered: Here we outline the existing approved treatments for advanced pancreatic disease and discuss a range of novel therapies currently under development including cell cycle inhibitors, stromal modifiers and conjugated therapies. We also describe the current state of the pancreatic cancer therapeutics market both past and future. Expert opinion: Despite the recent explosion of novel therapies with an array of unique targets, the core treatment of pancreatic cancer still with traditional cytotoxic agents with a few exceptions. However, as these novel treatments move through the pipeline, we are hopeful that there will soon be a number of effective options for patients with advanced pancreatic cancer.
Collapse
Affiliation(s)
- Robert Matera
- a Department of Hematology and Oncology , Tufts University School of Medicine , Boston , MA , USA
| | - Muhammad Wasif Saif
- a Department of Hematology and Oncology , Tufts University School of Medicine , Boston , MA , USA
| |
Collapse
|
|
17
|
Moravec R, Divi R, Verma M. Detecting circulating tumor material and digital pathology imaging during pancreatic cancer progression. World J Gastrointest Oncol 2017; 9:235-250. [PMID: 28656074 PMCID: PMC5472554 DOI: 10.4251/wjgo.v9.i6.235] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 03/04/2017] [Accepted: 03/24/2017] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer (PC) is a leading cause of cancer-related death worldwide. Clinical symptoms typically present late when treatment options are limited and survival expectancy is very short. Metastatic mutations are heterogeneous and can accumulate up to twenty years before PC diagnosis. Given such genetic diversity, detecting and managing the complex states of disease progression may be limited to imaging modalities and markers present in circulation. Recent developments in digital pathology imaging show potential for early PC detection, making a differential diagnosis, and predicting treatment sensitivity leading to long-term survival in advanced stage patients. Despite large research efforts, the only serum marker currently approved for clinical use is CA 19-9. Utility of CA 19-9 has been shown to improve when it is used in combination with PC-specific markers. Efforts are being made to develop early-screening assays that can detect tumor-derived material, present in circulation, before metastasis takes a significant course. Detection of markers that identify circulating tumor cells and tumor-derived extracellular vesicles (EVs) in biofluid samples offers a promising non-invasive method for this purpose. Circulating tumor cells exhibit varying expression of epithelial and mesenchymal markers depending on the state of tumor differentiation. This offers a possibility for monitoring disease progression using minimally invasive procedures. EVs also offer the benefit of detecting molecular cargo of tumor origin and add the potential to detect circulating vesicle markers from tumors that lack invasive properties. This review integrates recent genetic insights of PC progression with developments in digital pathology and early detection of tumor-derived circulating material.
Collapse
|
|
18
|
Genomic Variations in Pancreatic Cancer and Potential Opportunities for Development of New Approaches for Diagnosis and Treatment. Int J Mol Sci 2017; 18:ijms18061201. [PMID: 28587243 PMCID: PMC5486024 DOI: 10.3390/ijms18061201] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 04/30/2017] [Accepted: 05/26/2017] [Indexed: 02/07/2023] Open
Abstract
Human pancreatic cancer has a very poor prognosis with an overall five-year survival rate of less than 5% and an average median survival time of six months. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Although our understanding of the molecular events underlying multi-step carcinogenesis in pancreatic cancer has steadily increased, translation into more effective therapeutic approaches has been inefficient in recent decades. Therefore, it is imperative that novel and targeted approaches are designed to facilitate the early detection and treatment of pancreatic cancer. Presently, there are numerous ongoing studies investigating the types of genomic variations in pancreatic cancer and their impact on tumor initiation and growth, as well as prognosis. This has led to the development of therapeutics to target these genetic variations for clinical benefit. Thus far, there have been minimal clinical successes directly targeting these genomic alterations; however research is ongoing to ultimately discover an innovative approach to tackle this devastating disease. This review will discuss the genomic variations in pancreatic cancer, and the resulting potential diagnostic and therapeutic implications.
Collapse
|
|
19
|
Grasso C, Jansen G, Giovannetti E. Drug resistance in pancreatic cancer: Impact of altered energy metabolism. Crit Rev Oncol Hematol 2017; 114:139-152. [PMID: 28477742 DOI: 10.1016/j.critrevonc.2017.03.026] [Citation(s) in RCA: 180] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 03/21/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this tumor is poorly responsive, largely due to drug resistance. Accumulating evidence suggest that this chemoresistance is intimately linked to specific metabolic aberrations of pancreatic cancer cells, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome chemoresistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for pancreatic cancer in preclinical studies. These results warrant confirmation in clinical trials. Thus, this review summarizes the impact of metabolic aberrations from the perspective of drug resistance and discusses possible novel applications of metabolic inhibition for the development of more effective drugs against pancreatic cancer.
Collapse
Affiliation(s)
- Cristoforo Grasso
- Laboratory Medical Oncology, Department of Medical Oncology VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - Gerrit Jansen
- Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VUmc, Amsterdam, The Netherlands
| | - Elisa Giovannetti
- Laboratory Medical Oncology, Department of Medical Oncology VU University Medical Center (VUmc), Amsterdam, The Netherlands; Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, Italy.
| |
Collapse
|
|
20
|
Usul Afsar Ç, Karabulut M, Karabulut S, Alis H, Gonenc M, Dagoglu N, Serilmez M, Tas F. Circulating interleukin-18 (IL-18) is a predictor of response to gemcitabine based chemotherapy in patients with pancreatic adenocarcinoma. J Infect Chemother 2017; 23:196-200. [PMID: 28087305 DOI: 10.1016/j.jiac.2016.12.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 11/22/2016] [Accepted: 12/08/2016] [Indexed: 12/21/2022]
Abstract
BACKGROUND This study was conducted to investigate the serum levels of interleukin-18 (IL-18) in patients with pancreatic adenocarcinoma (PA) and the relationship with tumor progression and known prognostic parameters. METHODS Thirty-three patients with PA were studied. Serum samples were obtained on first admission before any treatment. Serum IL-18 levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Age- and sex-matched 30 healthy controls were included in the analysis. RESULTS The median age at diagnosis was 59 years, range 32-84 years; 20 (61%) patients were men and the remaining were women. The median follow-up time was 26.0 weeks (range: 1.0-184.0 weeks). The median overall survival of the whole group was 41.3 ± 8.3 weeks [95% confidence interval (CI) = 25-58 weeks]. The baseline serum IL-18 levels were significantly higher in patients with PA than in the control group (p < 0.001). Serum IL-18 levels were significantly higher in the patients with high erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) (p = 0.01 and p = 0.05). Moreover, the chemotherapy-(CTx) unresponsive patients had higher serum IL-18 levels compared to CTx-responsive (p = 0.04) subjects. Conversely, serum IL-18 concentration was found to have no prognostic role on survival (p = 0.45). CONCLUSION Serum levels of IL-18 can be a good diagnostic and predictive marker; especially for predicting the response to gemcitabine based CTx in patients with PA but it has no prognostic role.
Collapse
Affiliation(s)
- Çiğdem Usul Afsar
- Clinic of Medical Oncology, Istanbul Education and Research Hospital, Istanbul, Turkey.
| | - Mehmet Karabulut
- Clinic of General Surgery, Istanbul Bakırköy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
| | - Senem Karabulut
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Halil Alis
- Clinic of General Surgery, Istanbul Bakırköy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
| | - Murat Gonenc
- Clinic of General Surgery, Istanbul Bakırköy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
| | - Nergiz Dagoglu
- Department of Radiation Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Murat Serilmez
- Department of Basic Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Faruk Tas
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| |
Collapse
|
|
21
|
Abstract
Pancreatic cancer represents the seventh leading cause of cancer death in the world, responsible for more than 300,000 deaths per year. The most common tumor type among pancreatic cancers is pancreatic ductal adenocarcinoma, an infiltrating neoplasm with glandular differentiation that is derived from pancreatic ductal tree. Here we present and discuss the most important macroscopic, microscopic, and immunohistochemical characteristics of this tumor, highlighting its key diagnostic features. Furthermore, we present the classic features of the most common variants of pancreatic ductal adenocarcinoma. Last, we summarize the prognostic landscape of this highly malignant tumor and its variants.
Collapse
Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy; ARC-Net Research Center, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy; Surgical Pathology Unit, Santa Chiara Hospital, Largo Medaglie D'oro, Trento 38122, Italy.
| | - Paola Capelli
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy; ARC-Net Research Center, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy
| |
Collapse
|
|
22
|
Chang JM, Katariya NN, Lam-Himlin DM, Haakinson DJ, Ramanathan RK, Halfdanarson TR, Borad MJ, Pannala R, Faigel D, Moss AA, Mathur AK. Hepatoid Carcinoma of the Pancreas: Case Report, Next-Generation Tumor Profiling, and Literature Review. Case Rep Gastroenterol 2016; 10:605-612. [PMID: 27920649 PMCID: PMC5121547 DOI: 10.1159/000448064] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 06/28/2016] [Indexed: 12/12/2022] Open
Abstract
Fewer than 25 cases of hepatoid carcinoma of the pancreas have been reported in the literature. We present a case in a 61-year-old male with a remote history of Hodgkin's lymphoma and gastric neuroendocrine cell hyperplasia. On surveillance endoscopic ultrasound, an 8 × 5 mm cystic lesion was seen in the tail of the pancreas. MRI showed a focal pancreatic duct cut-off with mild ductal dilation. Fine needle aspiration was performed, which was concerning for acinar cell carcinoma. The patient underwent distal pancreatectomy and recovered uneventfully. Final pathology demonstrated a 1.3-cm hepatoid carcinoma of the pancreas, with a final clinicopathological stage of T1N0M0. Next-generation nucleic acid sequencing of the tumor did not suggest a viable adjuvant chemotherapeutic agent, and no adjuvant therapy was administered. The patient has no evidence of disease 6 months following resection. A further characterization and description of the outcomes of these rare tumors is warranted to help guide providers and counsel patients.
Collapse
Affiliation(s)
- James M Chang
- Division of Transplant and Hepatopancreatobiliary Surgery, Mayo Clinic Arizona, Phoenix, Ariz., USA
| | - Nitin N Katariya
- Division of Transplant and Hepatopancreatobiliary Surgery, Mayo Clinic Arizona, Phoenix, Ariz., USA
| | - Dora M Lam-Himlin
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Phoenix, Ariz., USA
| | - Danielle J Haakinson
- Division of Transplant and Hepatopancreatobiliary Surgery, Mayo Clinic Arizona, Phoenix, Ariz., USA
| | | | | | - Mitesh J Borad
- Division of Hematology/Oncology, Mayo Clinic Arizona, Phoenix, Ariz., USA
| | - Rahul Pannala
- Division of Gastroenterology/Hepatology, Mayo Clinic Arizona, Phoenix, Ariz., USA
| | - Douglas Faigel
- Division of Gastroenterology/Hepatology, Mayo Clinic Arizona, Phoenix, Ariz., USA
| | - Adyr A Moss
- Division of Transplant and Hepatopancreatobiliary Surgery, Mayo Clinic Arizona, Phoenix, Ariz., USA
| | - Amit K Mathur
- Division of Transplant and Hepatopancreatobiliary Surgery, Mayo Clinic Arizona, Phoenix, Ariz., USA
| |
Collapse
|
|
23
|
Weighted gene co-expression network analysis reveals key genes involved in pancreatic ductal adenocarcinoma development. Cell Oncol (Dordr) 2016; 39:379-88. [PMID: 27240826 DOI: 10.1007/s13402-016-0283-7] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2016] [Indexed: 12/29/2022] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Up till now, the patient's prognosis remains poor which, among others, is due to the paucity of reliable early diagnostic biomarkers. In the past, candidate diagnostic biomarkers and therapeutic targets have been delineated from genes that were found to be differentially expressed in normal versus tumour samples. Recently, new systems biology approaches have been developed to analyse gene expression data, which may yield new biomarkers. As of yet, the weighted gene co-expression network analysis (WGCNA) tool has not been applied to PDAC microarray-based gene expression data. METHODS PDAC microarray-based gene expression datasets, listed in the Gene Expression Omnibus (GEO) database, were analysed. After pre-processing of the data, we built two final datasets, Normal and PDAC, encompassing 104 and 129 patient samples, respectively. Next, we constructed a weighted gene co-expression network and identified modules of co-expressed genes distinguishing normal from disease conditions. Functional annotations of the genes in these modules were carried out to highlight PDAC-associated molecular pathways and common regulatory mechanisms. Finally, overall survival analyses were carried out to assess the suitability of the genes identified as prognostic biomarkers. RESULTS Using WGCNA, we identified several key genes that may play important roles in PDAC. These genes are mainly related to either endoplasmic reticulum, mitochondrion or membrane functions, exhibit transferase or hydrolase activities and are involved in biological processes such as lipid metabolism or transmembrane transport. As a validation of the applied method, we found that some of the identified key genes (CEACAM1, MCU, VDAC1, CYCS, C15ORF52, TMEM51, LARP1 and ERLIN2) have previously been reported by others as potential PDAC biomarkers. Using overall survival analyses, we found that several of the newly identified genes may serve as biomarkers to stratify PDAC patients into low- and high-risk groups. CONCLUSIONS Using this new systems biology approach, we identified several genes that appear to be critical to PDAC development. As such, they may represent potential diagnostic biomarkers as well as therapeutic targets with clinical utility.
Collapse
|