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Xu H, Wu D, Xiao M, Lei Y, Lei Y, Yu X, Shi S. PP2A complex disruptor SET prompts widespread hypertranscription of growth-essential genes in the pancreatic cancer cells. SCIENCE ADVANCES 2024; 10:eadk6633. [PMID: 38277454 PMCID: PMC10816699 DOI: 10.1126/sciadv.adk6633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 12/26/2023] [Indexed: 01/28/2024]
Abstract
Hyperactivation of the oncogenic transcription reflects the epigenetic plasticity of the cancer cells. Su(var)3-9, enhancer of zeste, Trithorax (SET) was described as a nuclear factor that stimulated transcription from the chromatin template. However, the mechanisms of SET-dependent transcription are unknown. Here, we found that overexpression of SET and CDK9 induced very similar transcriptome signatures in multiple cancer cell lines. SET localized in the transcription start site (TSS)-proximal regions and supported the RNA transcription. SET specifically bound the PP2A-C subunit and induced PP2A-A subunit repulsion from the C subunit, which indicated the role of SET as a PP2A-A/C complex disruptor in the TSS-proximal regions. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Our findings position SET as a key factor that modulates chromatin PP2A activity, promoting the oncogenic transcription in the pancreatic cancer.
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Affiliation(s)
- He Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Di Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Mingming Xiao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Yubin Lei
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou, Zhejiang Province 310024, China
| | - Yalan Lei
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
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2
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Al-Hassan JM, Wei D, Chakraborty S, Conway T, Rhea P, Wei B, Tran M, Gagea M, Afzal M, Oommen S, Nair D, Paul BM, Yang P. Fraction B From Catfish Epidermal Secretions Kills Pancreatic Cancer Cells, Inhibits CD44 Expression and Stemness, and Alters Cancer Cell Metabolism. Front Pharmacol 2021; 12:659590. [PMID: 34349642 PMCID: PMC8326461 DOI: 10.3389/fphar.2021.659590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 06/10/2021] [Indexed: 01/02/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in western countries. The successful treatment of PDAC remains limited. We investigated the effect of Fraction B, which is a fraction purified from catfish (Arius bilineatus, Val.) skin secretions containing proteins and lipids, on PDAC biology both in-vivo and in-vitro. We report here that Fraction B potently suppressed the proliferation of both human and mouse pancreatic cancer cells in vitro and significantly reduced the growth of their relevant xenograft (Panc02) and orthotopic tumors (human Panc-1 cells) (p < 0.05). The Reverse Phase Protein Array (RPPA) data obtained from the tumor tissues derived from orthotopic tumor bearing mice treated with Fraction B showed that Fraction B altered the cancer stem cells related pathways and regulated glucose and glutamine metabolism. The down-regulation of the cancer stem cell marker CD44 expression was further confirmed in Panc-1 cells. CBC and blood chemistry analyses showed no systemic toxicity in Fraction B treated Panc-1 tumor bearing mice compared to that of control group. Our data support that Fraction B is a potential candidate for PDAC treatment.
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Affiliation(s)
- Jassim M Al-Hassan
- Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City, Kuwait
| | - Daoyan Wei
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sharmistha Chakraborty
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Tara Conway
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Patrea Rhea
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Bo Wei
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Megan Tran
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mihai Gagea
- Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mohammad Afzal
- Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City, Kuwait
| | - Sosamma Oommen
- Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City, Kuwait
| | - Divya Nair
- Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City, Kuwait
| | - Bincy M Paul
- Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City, Kuwait
| | - Peiying Yang
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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3
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Barman S, Fatima I, Singh AB, Dhawan P. Pancreatic Cancer and Therapy: Role and Regulation of Cancer Stem Cells. Int J Mol Sci 2021; 22:ijms22094765. [PMID: 33946266 PMCID: PMC8124621 DOI: 10.3390/ijms22094765] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 12/21/2022] Open
Abstract
Despite significant improvements in clinical management, pancreatic cancer (PC) remains one of the deadliest cancer types, as it is prone to late detection with extreme metastatic properties. The recent findings that pancreatic cancer stem cells (PaCSCs) contribute to the tumorigenesis, progression, and chemoresistance have offered significant insight into the cancer malignancy and development of precise therapies. However, the heterogeneity of cancer and signaling pathways that regulate PC have posed limitations in the effective targeting of the PaCSCs. In this regard, the role for K-RAS, TP53, Transforming Growth Factor-β, hedgehog, Wnt and Notch and other signaling pathways in PC progression is well documented. In this review, we discuss the role of PaCSCs, the underlying molecular and signaling pathways that help promote pancreatic cancer development and metastasis with a specific focus on the regulation of PaCSCs. We also discuss the therapeutic approaches that target different PaCSCs, intricate mechanisms, and therapeutic opportunities to eliminate heterogeneous PaCSCs populations in pancreatic cancer.
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Affiliation(s)
- Susmita Barman
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
| | - Iram Fatima
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
- Correspondence:
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4
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Crawford HC, Pasca di Magliano M, Banerjee S. Signaling Networks That Control Cellular Plasticity in Pancreatic Tumorigenesis, Progression, and Metastasis. Gastroenterology 2019; 156:2073-2084. [PMID: 30716326 PMCID: PMC6545585 DOI: 10.1053/j.gastro.2018.12.042] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 11/29/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma is one of the deadliest cancers, and its incidence on the rise. The major challenges in overcoming the poor prognosis with this disease include late detection and the aggressive biology of the disease. Intratumoral heterogeneity; presence of a robust, reactive, and desmoplastic stroma; and the crosstalk between the different tumor components require complete understanding of the pancreatic tumor biology to better understand the therapeutic challenges posed by this disease. In this review, we discuss the processes involved during tumorigenesis encompassing the inherent plasticity of the transformed cells, development of tumor stroma crosstalk, and enrichment of cancer stem cell population during tumorigenesis.
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Affiliation(s)
- Howard C Crawford
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - Marina Pasca di Magliano
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan; Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Sulagna Banerjee
- Department of Surgery, University of Miami School of Medicine, Miami, Florida; Sylvester Cancer Center, University of Miami, Miami, Florida.
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5
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Boothello RS, Patel NJ, Sharon C, Abdelfadiel EI, Morla S, Brophy DF, Lippman HR, Desai UR, Patel BB. A Unique Nonsaccharide Mimetic of Heparin Hexasaccharide Inhibits Colon Cancer Stem Cells via p38 MAP Kinase Activation. Mol Cancer Ther 2019; 18:51-61. [PMID: 30337351 PMCID: PMC6332501 DOI: 10.1158/1535-7163.mct-18-0104] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 07/23/2018] [Accepted: 10/12/2018] [Indexed: 12/13/2022]
Abstract
Targeting of cancer stem cells (CSC) is expected to be a paradigm-shifting approach for the treatment of cancers. Cell surface proteoglycans bearing sulfated glycosaminoglycan (GAG) chains are known to play a critical role in the regulation of stem cell fate. Here, we show for the first time that G2.2, a sulfated nonsaccharide GAG mimetic (NSGM) of heparin hexasaccharide, selectively inhibits colonic CSCs in vivo G2.2-reduced CSCs (CD133+/CXCR4+, Dual hi) induced HT-29 and HCT 116 colon xenografts' growth in a dose-dependent fashion. G2.2 also significantly delayed the growth of colon xenograft further enriched in CSCs following oxaliplatin and 5-fluorouracil treatment compared with vehicle-treated xenograft controls. In fact, G2.2 robustly inhibited CSCs' abundance (measured by levels of CSC markers, e.g., CD133, DCMLK1, LGR5, and LRIG1) and self-renewal (quaternary spheroids) in colon cancer xenografts. Intriguingly, G2.2 selectively induced apoptosis in the Dual hi CSCs in vivo eluding to its CSC targeting effects. More importantly, G2.2 displayed none to minimal toxicity as observed through morphologic and biochemical studies of vital organ functions, blood coagulation profile, and ex vivo analyses of normal intestinal (and bone marrow) progenitor cell growth. Through extensive in vitro, in vivo, and ex vivo mechanistic studies, we showed that G2.2's inhibition of CSC self-renewal was mediated through activation of p38α, uncovering important signaling that can be targeted to deplete CSCs selectively while minimizing host toxicity. Hence, G2.2 represents a first-in-class (NSGM) anticancer agent to reduce colorectal CSCs.
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Affiliation(s)
- Rio S Boothello
- Division of Hematology and Oncology, Department of Internal Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia
- McGuire VA Medical Center, Richmond, Virginia
| | - Nirmita J Patel
- McGuire VA Medical Center, Richmond, Virginia
- Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia
| | | | - Elsamani I Abdelfadiel
- Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia
| | - Shravan Morla
- Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia
| | - Donald F Brophy
- Department of Pharmacotherapy and Outcomes Sciences, Virginia Commonwealth University, Richmond, Virginia
| | | | - Umesh R Desai
- Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia.
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia
| | - Bhaumik B Patel
- Division of Hematology and Oncology, Department of Internal Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
- McGuire VA Medical Center, Richmond, Virginia
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6
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Gupta VK, Sharma NS, Kesh K, Dauer P, Nomura A, Giri B, Dudeja V, Banerjee S, Bhattacharya S, Saluja A, Banerjee S. Metastasis and chemoresistance in CD133 expressing pancreatic cancer cells are dependent on their lipid raft integrity. Cancer Lett 2018; 439:101-112. [PMID: 30290209 DOI: 10.1016/j.canlet.2018.09.028] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 08/25/2018] [Accepted: 09/21/2018] [Indexed: 02/01/2023]
Abstract
Metabolic rewiring is an integral part of tumor growth. Among metabolic pathways, the Mevalonic-Acid-Pathway (MVAP) plays a key role in maintaining membrane architecture through cholesterol synthesis, thereby affecting invasiveness. In the current study, we show for the first time that CD133Hi pancreatic tumor initiating cells (TIC) have increased expression of MVAP enzymes, cholesterol-content and Caveolin expression. Further, we show that CD133 in these cells is localized in the lipid-rafts (characterized by Cav-1-cholesterol association). Disruption of lipid-rafts by either depleting Cav-1 or by inhibiting MVAP by lovastatin decreased metastatic-potential and chemoresistance in CD133Hi cells while not affecting the CD133lo cells. Additionally, disruption of lipid-raft results in deregulation of FAK-signaling, decreasing invasiveness in pancreatic-TICs. Furthermore, this also inhibits ABC-transporter activity resulting in sensitizing TICs to standard chemotherapeutic agents. Repurposing existing drugs for new clinical applications is one of the safest and least resource intensive approaches to improve therapeutic options. In this context, our study is extremely timely as it shows that targeting lipid-rafts with statins can sensitize the normally resistant pancreatic TICHi-cells to standard chemotherapy and decrease metastasis, thereby defining a novel strategy for targeting the TICHi-PDAC.
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Affiliation(s)
| | - Nikita S Sharma
- Department of Surgery, University of Miami, Miami, FL, 33136, USA
| | - Kousik Kesh
- Department of Surgery, University of Miami, Miami, FL, 33136, USA
| | - Patricia Dauer
- Department of Surgery, University of Miami, Miami, FL, 33136, USA; Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Alice Nomura
- Department of Surgery, University of Miami, Miami, FL, 33136, USA
| | - Bhuwan Giri
- Department of Surgery, University of Miami, Miami, FL, 33136, USA
| | - Vikas Dudeja
- Department of Surgery, University of Miami, Miami, FL, 33136, USA
| | - Santanu Banerjee
- Department of Surgery, University of Miami, Miami, FL, 33136, USA
| | | | - Ashok Saluja
- Department of Surgery, University of Miami, Miami, FL, 33136, USA
| | - Sulagna Banerjee
- Department of Surgery, University of Miami, Miami, FL, 33136, USA.
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7
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Noguchi K, Konno M, Eguchi H, Kawamoto K, Mukai R, Nishida N, Koseki J, Wada H, Akita H, Satoh T, Marubashi S, Nagano H, Doki Y, Mori M, Ishii H. c-Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer. Oncol Lett 2018; 16:1892-1898. [PMID: 30008881 DOI: 10.3892/ol.2018.8793] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/28/2018] [Indexed: 12/11/2022] Open
Abstract
Pancreatic adenocarcinoma is thought to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs), which exhibit similar morphological and genetic features to pancreatic ductal adenocarcinoma (PDAC). Therefore, a better understanding of the biological features underlying the progression of PanIN is essential to development more effective therapeutic interventions for PDAC. In recent years, numerous studies have reported that MET proto-oncogene receptor tyrosine kinase (c-MET) is a potential marker of pancreatic cancer stem cells (CSCs). CSCs have been revealed to initiate and propagate tumors in vitro and in vivo, and are associated with a chemoresistant phenotype. However, in vivo models using a xenograft approach are limited. In the present study, the morphological phenotype, molecular alteration and biological behavior of neoplasia in Pdx-1Cre/+, KrasLSL-G12D/+ and Metflox/flox and wild-type mice was analyzed. The results demonstrated that while oncogenic KrasLSL-G12D/+ increased PanIN initiation and significantly decreased survival rate compared with wild-type mice, no additive effect of c-Met receptor signaling on PanIN progression or prognosis was observed. Following gemcitabine administration, c-Met inhibition in Kras LSL-G12D/+ mice significantly decreased the total surface area of PanIN lesions and the number of anti-proliferation marker protein Ki-67 positive cells occupying PanIN lesions compared with Met+/+ mice. In conclusion, complete inhibition of the c-Met signaling pathway with chemotherapy may be useful for the treatment of pancreatic cancer.
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Affiliation(s)
- Kozo Noguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.,Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Ryouta Mukai
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Naohiro Nishida
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Jun Koseki
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Shigeru Marubashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.,Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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8
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Khandia R, Pattnaik B, Rajukumar K, Pateriya A, Bhatia S, Murugkar H, Prakash A, Pradhan HK, Dhama K, Munjal A, Joshi SK. Anti-proliferative role of recombinant lethal toxin of Bacillus anthracis on primary mammary ductal carcinoma cells revealing its therapeutic potential. Oncotarget 2018; 8:35835-35847. [PMID: 28415766 PMCID: PMC5482621 DOI: 10.18632/oncotarget.16214] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 03/07/2017] [Indexed: 12/11/2022] Open
Abstract
Bacillus anthracis secretes three secretary proteins; lethal factor (LF), protective antigen (PA) and edema factor (EF). The LF has ability to check proliferation of mammary tumors, chiefly depending on mitogen activated protein kinase (MAPK) signaling pathway. Evaluation of therapeutic potential of recombinant LF (rLF), recombinant PA (rPA) and lethal toxin (rLF + rPA = LeTx) on the primary mammary ductal carcinoma cells revealed significant (p < 0.01) reduction in proliferation of tumor cells with mean inhibition indices of 28.0 ± 1.37% and 19.6 ± 1.47% respectively. However, treatment with rPA alone had no significant anti-proliferative effect as evident by low mean inhibition index of 3.4 ± 3.87%. The higher inhibition index observed for rLF alone as compared to LeTx is contrary to the existing knowledge on LF, which explains the requirement of PA dependent endocytosis for its enzymatic activity. Therefore, the plausible existence of PA independent mode of action of LF including direct receptor mediated endocytosis or modulation of signal transduction cascade via unknown means is hypothesized. In silico protein docking analysis of other cellular receptors for any plausibility to play the role of receptor for LF revealed c-Met receptor showing strongest affinity for LF (H bond = 19; Free energy = −773.96), followed by nerve growth factor receptor (NGFR) and human epidermal growth factor receptor (HER)-1. The study summarizes the use of rLF or LeTx as therapeutic molecule against primary mammary ductal carcinoma cells and also the c-Met as potential alternative receptor for LF to mediate and modulate PA independent signal transduction.
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Affiliation(s)
- Rekha Khandia
- ICAR-National Institute of High Security Animal Diseases, Bhopal, Madhya Pradesh, India.,Department of Biochemistry and Genetics, Barkatullah University, Bhopal, Madhya Pradesh, India
| | - Bramhadev Pattnaik
- Project Directorate on Foot and Mouth Disease, Mukteswar, Uttarakhand, India
| | | | - Atul Pateriya
- ICAR-National Institute of High Security Animal Diseases, Bhopal, Madhya Pradesh, India
| | - Sandeep Bhatia
- ICAR-National Institute of High Security Animal Diseases, Bhopal, Madhya Pradesh, India
| | - Harshad Murugkar
- ICAR-National Institute of High Security Animal Diseases, Bhopal, Madhya Pradesh, India
| | - Anil Prakash
- Department of Microbiology, Barkatullah University, Bhopal, Madhya Pradesh, India
| | - Hare Krishna Pradhan
- Ex-Avian Influenza National Consultant, Indian Office of WHO Consultant, Bhartiya Kala Kendra, New Delhi, India
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly Uttar Pradesh, India
| | - Ashok Munjal
- Department of Biochemistry and Genetics, Barkatullah University, Bhopal, Madhya Pradesh, India
| | - Sunil K Joshi
- Cellular Immunology Laboratory, Frank Reidy Research Center of Bioelectrics, College of Health Sciences, Old Dominion University Norfolk, VA USA
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9
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Liu L, Zhi Q, Shen M, Gong FR, Zhou BP, Lian L, Shen B, Chen K, Duan W, Wu MY, Tao M, Li W. FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis. Oncotarget 2018; 7:47145-47162. [PMID: 27323403 PMCID: PMC5216931 DOI: 10.18632/oncotarget.9975] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 05/17/2016] [Indexed: 12/30/2022] Open
Abstract
The WNT/β-catenin pathway plays an important role in pancreatic cancer carcinogenesis. We evaluated the correlation between aberrant β-catenin pathway activation and the prognosis pancreatic cancer, and the potential of applying the β-catenin pathway inhibitor FH535 to pancreatic cancer treatment. Meta-analysis and immunohistochemistry showed that abnormal β-catenin pathway activation was associated with unfavorable outcome. FH535 repressed pancreatic cancer xenograft growth in vivo. Gene Ontology (GO) analysis of microarray data indicated that target genes responding to FH535 participated in stemness maintenance. Real-time PCR and flow cytometry confirmed that FH535 downregulated CD24 and CD44, pancreatic cancer stem cell (CSC) markers, suggesting FH535 impairs pancreatic CSC stemness. GO analysis of β-catenin chromatin immunoprecipitation sequencing data identified angiogenesis-related gene regulation. Immunohistochemistry showed that higher microvessel density correlated with elevated nuclear β-catenin expression and unfavorable outcome. FH535 repressed the secretion of the proangiogenic cytokines vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, and tumor necrosis factor-α, and also inhibited angiogenesis in vitro and in vivo. Protein and mRNA microarrays revealed that FH535 downregulated the proangiogenic genes ANGPT2, VEGFR3, IFN-γ, PLAUR, THPO, TIMP1, and VEGF. FH535 not only represses pancreatic CSC stemness in vitro, but also remodels the tumor microenvironment by repressing angiogenesis, warranting further clinical investigation.
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Affiliation(s)
- Lu Liu
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Qiaoming Zhi
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Meng Shen
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fei-Ran Gong
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Binhua P Zhou
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA.,Departments of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Lian Lian
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Oncology, Suzhou Xiangcheng People's Hospital, Suzhou, China.,Department of Pathology, Suzhou Xiangcheng People's Hospital, Suzhou, China
| | - Bairong Shen
- Center for Systems Biology, Soochow University, Suzhou, China
| | - Kai Chen
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Weiming Duan
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Meng-Yao Wu
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Min Tao
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.,PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, China.,Jiangsu Institute of Clinical Immunology, Suzhou, China.,Institute of Medical Biotechnology, Soochow University, Suzhou, China
| | - Wei Li
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Markey Cancer Center, University of Kentucky, Lexington, KY, USA.,Center for Systems Biology, Soochow University, Suzhou, China.,PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, China.,Jiangsu Institute of Clinical Immunology, Suzhou, China
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10
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Patel NJ, Sharon C, Baranwal S, Boothello RS, Desai UR, Patel BB. Heparan sulfate hexasaccharide selectively inhibits cancer stem cells self-renewal by activating p38 MAP kinase. Oncotarget 2018; 7:84608-84622. [PMID: 27705927 PMCID: PMC5356685 DOI: 10.18632/oncotarget.12358] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 09/05/2016] [Indexed: 12/02/2022] Open
Abstract
Heparan sulfate (HS) plays a role in the majority of essential hallmarks of cancer, yet its ability to modulate self-renewal, especially of cancer stem cells (CSCs), remains unknown. We have discovered that a non-anticoagulant HS hexasaccharide (HS06) sequence, but not other shorter or longer sequences, selectively inhibited CSC self-renewal and induced apoptosis in colorectal, pancreatic, and breast CSCs suggesting a very general phenomenon. HS06 inhibition of CSCs relied upon early and sustained activation of p38α/β mitogen activated protein kinase (MAPK) but not other MAPKs family members i.e. ERK and JNK. In contrast, polymeric HS induced exactly opposite changes in MAPK activation and failed to inhibit CSCs. In fact, TCF4 signaling, a critical regulator of CSC self-renewal, was inhibited by HS06 in a p38 activation dependent fashion. In conclusion, HS06 selectively inhibits CSCs self-renewal by causing isoform specific activation of p38MAPK to inhibit TCF4 signaling. These observations on chain length-induced specificity carry major mechanistic implications with regard to HS in cancer biology, while also presenting a novel paradigm for developing novel anti-CSC hexasaccharides that prevent cancer relapse.
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Affiliation(s)
- Nirmita J Patel
- Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA.,Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA
| | - Chetna Sharon
- Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA
| | - Somesh Baranwal
- Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA.,Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Rio S Boothello
- Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA.,Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Umesh R Desai
- Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA
| | - Bhaumik B Patel
- Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA.,Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
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11
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Tchio Mantho CI, Harbuzariu A, Gonzalez-Perez RR. Histone deacetylases, microRNA and leptin crosstalk in pancreatic cancer. World J Clin Oncol 2017; 8:178-189. [PMID: 28638788 PMCID: PMC5465008 DOI: 10.5306/wjco.v8.i3.178] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 03/06/2017] [Accepted: 04/20/2017] [Indexed: 02/06/2023] Open
Abstract
Because pancreatic cancer (PC) historically has had poor prognosis and five year survival rates, it has been intensely investigated. Analysis of PC incidence and biology has shown a link between different risk factors such as smoking, alcoholism, and obesity and disease progression. Important factors affecting PC include the epigenomic changes driven by DNA methylation and histone acetylation, and actions of microRNA inducing oncogenic or tumor suppressor effects. Studies have identified markers whose dysregulation seem to play important roles in PC progression. PC markers involve classical histone deacetylases (HDAC), PC stem cell (PCSC), and leptin. In this review, we discuss the role of several PC biomarkers, and the potential crosstalk between HDAC, microRNA, and leptin in PC progression. Dysregulated expression of these molecules can increase proliferation, survival, PCSC, resistance to chemotherapy and tumor angiogenesis. The potential relationships between these molecules are further analyzed using data from The Cancer Genome Atlas and crosstalk pathways generated by the Pathway Studio Platform (Ariadne Genomics, Inc.). Oncogenic miRNA21 and tumor suppressor miRNA200 have been previously linked to leptin signaling. Preliminary analysis of PC biopsies and signaling crosstalk suggests that the main adipokine leptin could affect the expression of microRNA and HDAC in PC. Data analysis suggests that HDAC-microRNA-leptin signaling crosstalk may be a new target for PC therapy.
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12
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Giovannetti E, van der Borden CL, Frampton AE, Ali A, Firuzi O, Peters GJ. Never let it go: Stopping key mechanisms underlying metastasis to fight pancreatic cancer. Semin Cancer Biol 2017; 44:43-59. [PMID: 28438662 DOI: 10.1016/j.semcancer.2017.04.006] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/12/2017] [Accepted: 04/18/2017] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive neoplasm, predicted to become the second leading cause of cancer-related deaths before 2030. This dismal trend is mainly due to lack of effective treatments against its metastatic behavior. Therefore, a better understanding of the key mechanisms underlying metastasis should provide new opportunities for therapeutic purposes. Genomic analyses revealed that aberrations that fuel PDAC tumorigenesis and progression, such as SMAD4 loss, are also implicated in metastasis. Recently, microRNAs have been shown to play a regulatory role in the metastatic behavior of many tumors, including PDAC. In particular, miR-10 and miR-21 have appeared as master regulators of the metastatic program, while members of the miR-200 family are involved in the epithelial-to-mesenchymal switch, favoring cell migration and invasiveness. Several studies have also found a close relationship between cancer stem cells (CSCs) and biological features of metastasis, and the CSC markers ALDH1, ABCG2 and c-Met are expressed at high levels in metastatic PDAC cells. Emerging evidence reveals that exosomes are involved in the modulation of the tumor microenvironment and can initiate PDAC pre-metastatic niche formation in the liver and lungs. In this review, we provide an overview of the role of all these pivotal factors in the metastatic behavior of PDAC, and discuss their potential exploitation in the clinic to improve current therapeutics and identify new drug targets.
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Affiliation(s)
- E Giovannetti
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands; Cancer Pharmacology Lab, AIRC Start Up Unit, University of Pisa, Pisa, Italy
| | - C L van der Borden
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - A E Frampton
- HPB Surgical Unit, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, London, UK
| | - A Ali
- Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, KP, Pakistan; Institute of Cancer Sciences, University of Glasgow, UK
| | - O Firuzi
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - G J Peters
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
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13
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Yu J, Liu SH, Sanchez R, Nemunaitis J, Rozengurt E, Brunicardi FC. Pancreatic cancer actionable genes in precision medicine and personalized surgery. Surgeon 2017; 15:24-29. [PMID: 27374183 PMCID: PMC5195911 DOI: 10.1016/j.surge.2016.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 05/02/2016] [Accepted: 05/22/2016] [Indexed: 12/17/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with an overall 5-year survival rate less than 5% due to the poor early diagnosis and lack of effective therapeutic options. The most effective therapy remains surgery, however post-operative survival could be enhanced with effective adjuvant therapy. The massive information gained from Omics techniques on PDAC at the beginning of the 21st century is a remarkable accomplishment. However, the information gained from the omics data, including next generation sequencing data, has yet to successfully affect care of patients suffering with PDAC. Therefore, we propose the development of an actionable genomic platform that matches a patient's PDAC clinically actionable genes with potential targeted adjuvant therapies. Using this platform, PDX1 has been identified as a potential actionable gene for PDAC, therefore, RNAi therapy, gene therapy and small inhibitory drugs, all targeting PDX1, serve as potential targeted adjuvant therapies. Preclinical studies support the hypothesis that identification of PDAC actionable genes could permit translation of a patient's genomic information into precision targeted adjuvant therapy for PDAC.
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Affiliation(s)
- Juehua Yu
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | - Shi-He Liu
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | - Robbi Sanchez
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | | | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | - F Charles Brunicardi
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
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14
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Stella GM, Gentile A, Baderacchi A, Meloni F, Milan M, Benvenuti S. Ockham's razor for the MET-driven invasive growth linking idiopathic pulmonary fibrosis and cancer. J Transl Med 2016; 14:256. [PMID: 27590450 PMCID: PMC5010719 DOI: 10.1186/s12967-016-1008-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 08/16/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) identifies a specific lung disorder characterized by chronic, progressive fibrosing interstitial pneumonia of unknown etiology, which lacks effective treatment. According to the current pathogenic perspective, the aberrant proliferative events in IPF resemble those occurring during malignant transformation. MAIN BODY Receptor tyrosine kinases (RTK) are known to be key players in cancer onset and progression. It has been demonstrated that RTK expression is sometimes also altered and even druggable in IPF. One example of an RTK-the MET proto-oncogene-is a key regulator of invasive growth. This physiological genetic program supports embryonic development and post-natal organ regeneration, as well as cooperating in the evolution of cancer metastasis when aberrantly activated. Growing evidence sustains that MET activation may collaborate in maintaining tissue plasticity and the regenerative potential that characterizes IPF. CONCLUSION The present work aims to elucidate-by applying the logic of simplicity-the bio-molecular mechanisms involved in MET activation in IPF. This clarification is crucial to accurately design MET blockade strategies within a fully personalized approach to IPF.
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Affiliation(s)
- Giulia M. Stella
- Pneumology Unit, Cardiothoracic and Vascular Department, IRCCS Policlinico San Matteo Foundation and University of Pavia Medical School, Piazzale Golgi 19, 27100 Pavia, Italy
- Investigational Clinical Oncology (INCO), IRCCS Candiolo Cancer Institute-FPO, Candiolo, 20060 Turin, Italy
| | - Alessandra Gentile
- Experimental Clinical Molecular Oncology (ECMO), IRCCS Candiolo Cancer Institute-FPO, Candiolo, 20060 Turin, Italy
| | - Alice Baderacchi
- Investigational Clinical Oncology (INCO), IRCCS Candiolo Cancer Institute-FPO, Candiolo, 20060 Turin, Italy
| | - Federica Meloni
- Pneumology Unit, Cardiothoracic and Vascular Department, IRCCS Policlinico San Matteo Foundation and University of Pavia Medical School, Piazzale Golgi 19, 27100 Pavia, Italy
| | - Melissa Milan
- Experimental Clinical Molecular Oncology (ECMO), IRCCS Candiolo Cancer Institute-FPO, Candiolo, 20060 Turin, Italy
| | - Silvia Benvenuti
- Experimental Clinical Molecular Oncology (ECMO), IRCCS Candiolo Cancer Institute-FPO, Candiolo, 20060 Turin, Italy
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15
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Pore N, Jalla S, Liu Z, Higgs B, Sorio C, Scarpa A, Hollingsworth R, Tice DA, Michelotti E. In Vivo Loss of Function Screening Reveals Carbonic Anhydrase IX as a Key Modulator of Tumor Initiating Potential in Primary Pancreatic Tumors. Neoplasia 2016; 17:473-80. [PMID: 26152355 PMCID: PMC4719001 DOI: 10.1016/j.neo.2015.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 05/02/2015] [Accepted: 05/05/2015] [Indexed: 02/06/2023] Open
Abstract
Reprogramming of energy metabolism is one of the emerging hallmarks of cancer. Up-regulation of energy metabolism pathways fuels cell growth and division, a key characteristic of neoplastic disease, and can lead to dependency on specific metabolic pathways. Thus, targeting energy metabolism pathways might offer the opportunity for novel therapeutics. Here, we describe the application of a novel in vivo screening approach for the identification of genes involved in cancer metabolism using a patient-derived pancreatic xenograft model. Lentiviruses expressing short hairpin RNAs (shRNAs) targeting 12 different cell surface protein transporters were separately transduced into the primary pancreatic tumor cells. Transduced cells were pooled and implanted into mice. Tumors were harvested at different times, and the frequency of each shRNA was determined as a measure of which ones prevented tumor growth. Several targets including carbonic anhydrase IX (CAIX), monocarboxylate transporter 4, and anionic amino acid transporter light chain, xc- system (xCT) were identified in these studies and shown to be required for tumor initiation and growth. Interestingly, CAIX was overexpressed in the tumor initiating cell population. CAIX expression alone correlated with a highly tumorigenic subpopulation of cells. Furthermore, CAIX expression was essential for tumor initiation because shRNA knockdown eliminated the ability of cells to grow in vivo. To the best of our knowledge, this is the first parallel in vivo assessment of multiple novel oncology target genes using a patient-derived pancreatic tumor model.
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Affiliation(s)
| | | | - Zheng Liu
- MedImmune, LLC, Gaithersburg, MD, USA
| | | | - Claudio Sorio
- ARC-NET Research Centre and Department of Pathology and Diagnostics, University of Verona Medical School, Verona, Italy
| | - Aldo Scarpa
- ARC-NET Research Centre and Department of Pathology and Diagnostics, University of Verona Medical School, Verona, Italy
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16
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The Role of miRNAs in the Regulation of Pancreatic Cancer Stem Cells. Stem Cells Int 2016; 2016:8352684. [PMID: 27006664 PMCID: PMC4783541 DOI: 10.1155/2016/8352684] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 12/24/2015] [Accepted: 01/27/2016] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.
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17
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Chang K, Karnad A, Zhao S, Freeman JW. Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets. Oncotarget 2016; 6:3507-18. [PMID: 25784650 PMCID: PMC4414132 DOI: 10.18632/oncotarget.3420] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 01/21/2015] [Indexed: 02/06/2023] Open
Abstract
c-Met and receptor originated from nantes (RON) are structurally related transmembrane phosphotyrosine kinase receptors. c-Met and RON show increased expression or activity in a variety of tumors leading to tumor progression and may play a role in acquired resistance to therapy. Although often co-expressed, the distinct functional roles of c-Met and RON are not fully understood. c-Met and RON form both activated homodimers and heterodimers with themselves and other families of phosphotyrosine kinase receptors. Inhibitors for c-Met and RON including small molecular weigh kinase inhibitors and neutralizing antibodies are in pre-clinical investigation and clinical trials. Several of the tyrosine kinase inhibitors have activity against both c-Met and RON kinases whereas the antibodies generally are target specific. As with many targeted agents used to treat solid tumors, it is likely that c-Met/RON inhibitors will have greater benefit when used in combination with chemotherapy or other targeted agents. A careful analysis of c-Met/RON expression or activity and a better elucidation of how they influence cell signaling will be useful in predicting which tumors respond best to these inhibitors as well as determining which agents can be used with these inhibitors for combined therapy.
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Affiliation(s)
- Katherine Chang
- Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.,Cancer Therapy and Research Center, Experimental and Developmental Therapeutics Program, San Antonio, TX, USA
| | - Anand Karnad
- Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.,Cancer Therapy and Research Center, Experimental and Developmental Therapeutics Program, San Antonio, TX, USA
| | - Shujie Zhao
- Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - James W Freeman
- Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.,Cancer Therapy and Research Center, Experimental and Developmental Therapeutics Program, San Antonio, TX, USA.,Research and Development, Audie Murphy Veterans Administration Hospital, San Antonio, TX, USA
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18
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WANG WENJIE, WU MENGYAO, SHEN MENG, ZHI QIAOMING, LIU ZEYI, GONG FEIRAN, TAO MIN, LI WEI. Cantharidin and norcantharidin impair stemness of pancreatic cancer cells by repressing the β-catenin pathway and strengthen the cytotoxicity of gemcitabine and erlotinib. Int J Oncol 2015; 47:1912-22. [DOI: 10.3892/ijo.2015.3156] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 08/20/2015] [Indexed: 11/06/2022] Open
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19
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Yan HH, Jung KH, Son MK, Fang Z, Kim SJ, Ryu YL, Kim J, Kim MH, Hong SS. Crizotinib exhibits antitumor activity by targeting ALK signaling not c-MET in pancreatic cancer. Oncotarget 2015; 5:9150-68. [PMID: 25193856 PMCID: PMC4253425 DOI: 10.18632/oncotarget.2363] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Crizotinib, a c-MET/ALK inhibitor, has exhibited antitumor efficacy in different types of cancers. However, studies regarding Crizotinib in pancreatic cancer have been limited. Thus, we investigated the effect of Crizotinib on pancreatic cancer and its mechanism of action. Crizotinib strongly suppressed the growth and proliferation of pancreatic cancer cells in a dose-dependent manner. Also, it induced apoptosis by modulating its related factors. In the study, with regard to the mechanism of action, Crizotinib did not inhibit c-MET expression on pancreatic cancer cells; instead, it specifically inhibited the activity of ALK, which was identified to be highly expressed on various pancreatic cancer cells and tissues in our study. In 42 different receptor tyrosine kinase (RTKs) array, Crizotinib also strongly inhibited the expression of activated ALK in pancreatic cancer cells, modulating its downstream mediators such as STAT3, AKT, and ERK. Furthermore, Crizotinib inhibited angiogenesis in a mouse Matrigel plug assay as well as the progression of tumor growth in a mouse xenograft model. Taken together, our investigation shows that Crizotinib inhibits the ALK signaling pathway in pancreatic cancer, resulting in cell growth/angiogenesis inhibition and apoptosis induction. We suggest that Crizotinib might be used as a novel therapeutic drug for treating pancreatic cancer.
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Affiliation(s)
- Hong Hua Yan
- College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea; These authors equally contributed to this work
| | - Kyung Hee Jung
- College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea; These authors equally contributed to this work
| | - Mi Kwon Son
- College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea
| | - Zhenghuan Fang
- College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea
| | - Soo Jung Kim
- College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea
| | - Ye-Lim Ryu
- College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea
| | - Juyoung Kim
- College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea
| | - Mi-Hyun Kim
- School of Biological & Chemical Engineering, Yanbian University of Science & Technology, Beishan St., Yanji City, Jilin Prov., 133000, China
| | - Soon-Sun Hong
- College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea
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20
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Singh D, Upadhyay G, Srivastava RK, Shankar S. Recent advances in pancreatic cancer: biology, treatment, and prevention. Biochim Biophys Acta Rev Cancer 2015; 1856:13-27. [PMID: 25977074 DOI: 10.1016/j.bbcan.2015.04.003] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 04/28/2015] [Accepted: 04/30/2015] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer (PC) is the fourth leading cause of cancer-related death in United States. Efforts have been made towards the development of the viable solution for its treatment with constrained accomplishment because of its complex biology. It is well established that pancreatic cancer stem cells (CSCs), albeit present in a little count, contribute incredibly to PC initiation, progression, and metastasis. Customary chemo and radiotherapeutic alternatives, however, expands general survival, the related side effects are the significant concern. Amid the most recent decade, our insight about molecular and cellular pathways involved in PC and role of CSCs in its progression has increased enormously. Presently the focus is to target CSCs. The herbal products have gained much consideration recently as they, usually, sensitize CSCs to chemotherapy and target molecular signaling involved in various tumors including PC. Some planned studies have indicated promising results proposing that examinations in this course have a lot to offer for the treatment of PC. Although preclinical studies uncovered the importance of herbal products in attenuating pancreatic carcinoma, limited studies have been conducted to evaluate their role in clinics. The present review provides a new insight to recent advances in pancreatic cancer biology, treatment and current status of herbal products in its anticipation.
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Affiliation(s)
- Divya Singh
- Department of Biology, City College of New York, 160 Convent Avenue, New York, NY 10031, USA.
| | - Ghanshyam Upadhyay
- Department of Biology, City College of New York, 160 Convent Avenue, New York, NY 10031, USA.
| | - Rakesh K Srivastava
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, USA.
| | - Sharmila Shankar
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, USA; Department of Pathology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
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21
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Zhan HX, Xu JW, Wu D, Zhang TP, Hu SY. Pancreatic cancer stem cells: new insight into a stubborn disease. Cancer Lett 2015; 357:429-37. [PMID: 25499079 DOI: 10.1016/j.canlet.2014.12.004] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 11/30/2014] [Accepted: 12/02/2014] [Indexed: 02/07/2023]
Abstract
Resistance to conventional therapy and early distant metastasis contribute to the unsatisfactory prognosis of patients with pancreatic cancer. The concept of cancer stem cells (CSCs) brings new insights into cancer biology and therapy. Many studies have confirmed the important role of these stem cells in carcinogenesis and the development of hematopoietic and solid cancers. Recent studies have shown that CSCs regulate aggressive behavior, recurrence, and drug resistance in pancreatic cancer. Here, we review recent advances in pancreatic cancer stem cells (PCSCs) research. Particular attention is paid to the regulation mechanisms of pancreatic cancer stem cell functions, such as stemness-related signaling pathways, microRNAs, the epithelial-mesenchymal transition (EMT), and the tumor microenvironment, and the development of novel PCSCs targeted therapy. We seek to further understand PCSCs and explore potential therapeutic targets for pancreatic cancer.
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Affiliation(s)
- Han-xiang Zhan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Jian-wei Xu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Dong Wu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Tai-ping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - San-yuan Hu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China.
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22
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Noble M, Mayer-Pröschel M, Li Z, Dong T, Cui W, Pröschel C, Ambeskovic I, Dietrich J, Han R, Yang YM, Folts C, Stripay J, Chen HY, Stevens BM. Redox biology in normal cells and cancer: restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment. Free Radic Biol Med 2015; 79:300-23. [PMID: 25481740 PMCID: PMC10173888 DOI: 10.1016/j.freeradbiomed.2014.10.860] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 10/29/2014] [Accepted: 10/30/2014] [Indexed: 12/12/2022]
Abstract
This review discusses a unique discovery path starting with novel findings on redox regulation of precursor cell and signaling pathway function and identification of a new mechanism by which relatively small changes in redox status can control entire signaling networks that regulate self-renewal, differentiation, and survival. The pathway central to this work, the redox/Fyn/c-Cbl (RFC) pathway, converts small increases in oxidative status to pan-activation of the c-Cbl ubiquitin ligase, which controls multiple receptors and other proteins of central importance in precursor cell and cancer cell function. Integration of work on the RFC pathway with attempts to understand how treatment with systemic chemotherapy causes neurological problems led to the discovery that glioblastomas (GBMs) and basal-like breast cancers (BLBCs) inhibit c-Cbl function through altered utilization of the cytoskeletal regulators Cool-1/βpix and Cdc42, respectively. Inhibition of these proteins to restore normal c-Cbl function suppresses cancer cell division, increases sensitivity to chemotherapy, disrupts tumor-initiating cell (TIC) activity in GBMs and BLBCs, controls multiple critical TIC regulators, and also allows targeting of non-TICs. Moreover, these manipulations do not increase chemosensitivity or suppress division of nontransformed cells. Restoration of normal c-Cbl function also allows more effective harnessing of estrogen receptor-α (ERα)-independent activities of tamoxifen to activate the RFC pathway and target ERα-negative cancer cells. Our work thus provides a discovery strategy that reveals mechanisms and therapeutic targets that cannot be deduced by standard genetics analyses, which fail to reveal the metabolic information, isoform shifts, protein activation, protein complexes, and protein degradation critical to our discoveries.
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Affiliation(s)
- Mark Noble
- Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
| | - Margot Mayer-Pröschel
- Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
| | - Zaibo Li
- Department of Pathology, Ohio State University Wexner Medical Center, 410W 10th Avenue, E403 Doan Hall, Columbus, OH 43210-1240, USA.
| | - Tiefei Dong
- University of Michigan Tech Transfer, 1600 Huron Pkwy, 2nd Floor, Building 520, Ann Arbor, MI 48109-2590, USA.
| | - Wanchang Cui
- Department of Radiation Oncology, University of Maryland School of Medicine,10 South Pine Street, MSTF Room 600, Baltimore, MD 21201, USA.
| | - Christoph Pröschel
- Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
| | - Ibro Ambeskovic
- Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
| | - Joerg Dietrich
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Yawkey 9E, Boston, MA 02114, USA.
| | - Ruolan Han
- Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
| | - Yin Miranda Yang
- Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
| | - Christopher Folts
- Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
| | - Jennifer Stripay
- Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
| | - Hsing-Yu Chen
- Harvard Medical School, Department of Cell Biology 240 Longwood Avenue Building C1, Room 513B Boston, MA 02115, USA.
| | - Brett M Stevens
- University of Colorado School of Medicine, Division of Hematology, 12700 E. 19th Avenue, Campus Box F754-AMCA, Aurora, CO 80045, USA.
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23
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Kim IG, Lee JH, Kim SY, Kim JY, Cho EW. Fibulin-3 negatively regulates ALDH1 via c-MET suppression and increases γ-radiation-induced sensitivity in some pancreatic cancer cell lines. Biochem Biophys Res Commun 2014; 454:369-75. [PMID: 25451256 DOI: 10.1016/j.bbrc.2014.10.084] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 10/18/2014] [Indexed: 01/16/2023]
Abstract
Fibulin-3 (FBLN-3) has been postulated to be either a tumor suppressor or promoter depending on the cell type, and hypermethylation of the FBLN-3 promoter is often associated with human disease, especially cancer. We report that the promoter region of the FBLN-3 was significantly methylated (>95%) in some pancreatic cancer cell lines and thus FBLN-3 was poorly expressed in pancreatic cancer cell lines such as AsPC-1 and MiaPaCa-2. FBLN-3 overexpression significantly down-regulated the cellular level of c-MET and inhibited hepatocyte growth factor-induced c-MET activation, which were closely associated with γ-radiation resistance of cancer cells. Moreover, we also showed that c-MET suppression or inactivation decreased the cellular level of ALDH1 isozymes (ALDH1A1 or ALDH1A3), which serve as cancer stem cell markers, and subsequently induced inhibition of cell growth in pancreatic cancer cells. Therefore, forced overexpression of FBLN-3 sensitized cells to cytotoxic agents such as γ-radiation and strongly inhibited the stemness and epithelial to mesenchymal transition (EMT) property of pancreatic cancer cells. On the other hand, if FBLN3 was suppressed in FBLN-3-expressing BxPC3 cells, the results were opposite. This study provides the first demonstration that the FBLN-3/c-MET/ALDH1 axis in pancreatic cancer cells partially modulates stemness and EMT as well as sensitization of cells to the detrimental effects of γ-radiation.
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Affiliation(s)
- In-Gyu Kim
- Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353, Republic of Korea; Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-daero, Yusong-gu, Daejeon 305-353, Republic of Korea.
| | - Jae-Ha Lee
- Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353, Republic of Korea; Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-daero, Yusong-gu, Daejeon 305-353, Republic of Korea
| | - Seo-Yoen Kim
- Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353, Republic of Korea
| | - Jeong-Yul Kim
- Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 989-111 Daedeok-daero, Yuseong-gu, Daejeon 305-353, Republic of Korea
| | - Eun-Wie Cho
- Epigenomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea
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24
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Sinha A, Cherba D, Bartlam H, Lenkiewicz E, Evers L, Barrett MT, Haab BB. Mesenchymal-like pancreatic cancer cells harbor specific genomic alterations more frequently than their epithelial-like counterparts. Mol Oncol 2014; 8:1253-65. [PMID: 24837184 PMCID: PMC4198499 DOI: 10.1016/j.molonc.2014.04.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 04/24/2014] [Accepted: 04/25/2014] [Indexed: 01/06/2023] Open
Abstract
The aggressiveness of pancreatic cancer is associated with the acquisition of mesenchymal characteristics by a subset of pancreatic cancer cells. The factors driving the development of this subset are not well understood. In this study, we tested the hypothesis that acquisition of a mesenchymal phenotype occurs selectively in tumor cells that harbor specific enabling genetic alterations. We obtained whole-genome comparative genomic hybridization (CGH) measurements on pancreatic cancer cell lines that have either an epithelial-like (17 cell lines) or a mesenchymal-like (9 cell lines) phenotype in vitro. The total amounts of amplifications and deletions were equivalent between the epithelial and mesenchymal groups, but 20 genes showed a major difference between the groups in prevalence of alterations. All 20 alterations (18 deletions and 2 amplifications) were more prevalent in the mesenchymal group, confirming the advanced nature of this cellular subtype. CDKN2A was altered in more than 50% of both groups, but co-deletions in neighboring genes, and concomitant loss of gene expression, were more prevalent in the mesenchymal group, suggesting that the size of the loss around CDKN2A affects cell phenotype. Whole-genome CGH on 11 primary cancer tissues revealed that the 20 genes were altered at a higher prevalence (up to 55% of the cases for certain genes) than randomly selected sets of 20 genes, with the same direction of alteration as in the cell lines. These findings support the concept that specific genetic alterations enable phenotype plasticity and provide promising candidate genes for further research.
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Affiliation(s)
- Arkadeep Sinha
- Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA; Genetics Program, Michigan State University, East Lansing, MI, USA
| | - David Cherba
- Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA
| | - Heather Bartlam
- Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA
| | - Elizabeth Lenkiewicz
- Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ, USA
| | - Lisa Evers
- Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ, USA
| | - Michael T Barrett
- Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ, USA
| | - Brian B Haab
- Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI 49503, USA; Genetics Program, Michigan State University, East Lansing, MI, USA.
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25
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Tanase CP, Neagu AI, Necula LG, Mambet C, Enciu AM, Calenic B, Cruceru ML, Albulescu R. Cancer stem cells: involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics. World J Gastroenterol 2014; 20:10790-10801. [PMID: 25152582 PMCID: PMC4138459 DOI: 10.3748/wjg.v20.i31.10790] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/07/2014] [Accepted: 04/05/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells (CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.
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26
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Delitto D, Vertes-George E, Hughes SJ, Behrns KE, Trevino JG. c-Met signaling in the development of tumorigenesis and chemoresistance: Potential applications in pancreatic cancer. World J Gastroenterol 2014; 20:8458-8470. [PMID: 25024602 PMCID: PMC4093697 DOI: 10.3748/wjg.v20.i26.8458] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 12/18/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer deaths in the United States. The majority of patients are candidates only for palliative chemotherapy, which has proven largely ineffective in halting tumor progression. One proposed mechanism of chemoresistance involves signaling via the mesenchymal-epithelial transition factor protein (MET), a previously established pathway critical to cell proliferation and migration. Here, we review the literature to characterize the role of MET in the development of tumorigenesis, metastasis and chemoresistance, highlighting the potential of MET as a therapeutic target in pancreatic cancer. In this review, we characterize the role of c-Met in the development of tumorigenesis, metastasis and chemoresistance, highlighting the potential of c-Met as a therapeutic target in pancreatic cancer.
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MESH Headings
- Animals
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/enzymology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/secondary
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Drug Design
- Drug Resistance, Neoplasm/genetics
- Humans
- Molecular Targeted Therapy
- Neoplastic Stem Cells/enzymology
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/enzymology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Protein Kinase Inhibitors/therapeutic use
- Proto-Oncogene Proteins c-met/antagonists & inhibitors
- Proto-Oncogene Proteins c-met/genetics
- Proto-Oncogene Proteins c-met/metabolism
- Signal Transduction/drug effects
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27
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Schiavone M, Rampazzo E, Casari A, Battilana G, Persano L, Moro E, Liu S, Leach SD, Tiso N, Argenton F. Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer. Dis Model Mech 2014; 7:883-94. [PMID: 24878567 PMCID: PMC4073277 DOI: 10.1242/dmm.014969] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Pancreatic adenocarcinoma, one of the worst malignancies of the exocrine pancreas, is a solid tumor with increasing incidence and mortality in industrialized countries. This condition is usually driven by oncogenic KRAS point mutations and evolves into a highly aggressive metastatic carcinoma due to secondary gene mutations and unbalanced expression of genes involved in the specific signaling pathways. To examine in vivo the effects of KRASG12D during pancreatic cancer progression and time correlation with cancer signaling pathway activities, we have generated a zebrafish model of pancreatic adenocarcinoma in which eGFP-KRASG12D expression was specifically driven to the pancreatic tissue by using the GAL4/UAS conditional expression system. Outcrossing the inducible oncogenic KRASG12D line with transgenic zebrafish reporters, harboring specific signaling responsive elements of transcriptional effectors, we were able to follow TGFβ, Notch, Bmp and Shh activities during tumor development. Zebrafish transgenic lines expressing eGFP-KRASG12D showed normal exocrine pancreas development until 3 weeks post fertilization (wpf). From 4 to 24 wpf we observed several degrees of acinar lesions, characterized by an increase in mesenchymal cells and mixed acinar/ductal features, followed by progressive bowel and liver infiltrations and, finally, highly aggressive carcinoma. Moreover, live imaging analysis of the exocrine pancreatic tissue revealed an increasing number of KRAS-positive cells and progressive activation of TGFβ and Notch pathways. Increase in TGFβ, following KRASG12D activation, was confirmed in a concomitant model of medulloblastoma (MDB). Notch and Shh signaling activities during tumor onset were different between MDB and pancreatic adenocarcinoma, indicating a tissue-specific regulation of cell signaling pathways. Moreover, our results show that a living model of pancreatic adenocarcinoma joined with cell signaling reporters is a suitable tool for describing in vivo the signaling cascades and molecular mechanisms involved in tumor development and a potential platform to screen for novel oncostatic drugs.
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Affiliation(s)
- Marco Schiavone
- Department of Biology, University of Padua, 35131 Padua, Italy
| | - Elena Rampazzo
- Department of Molecular Medicine, University of Padua, 35131 Padua, Italy
| | | | - Giusy Battilana
- Department of Molecular Medicine, University of Padua, 35131 Padua, Italy
| | - Luca Persano
- Department of Woman and Child Health, University of Padua, 35131 Padua, Italy
| | - Enrico Moro
- Department of Molecular Medicine, University of Padua, 35131 Padua, Italy
| | - Shu Liu
- Department of Surgery and The McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Steve D Leach
- Department of Surgery and The McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Natascia Tiso
- Department of Biology, University of Padua, 35131 Padua, Italy
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28
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Current World Literature. Curr Opin Oncol 2013; 25:325-30. [DOI: 10.1097/cco.0b013e328360f591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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