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Lee MJ, Cho JY, Bae S, Jung HS, Kang CM, Kim SH, Choi HJ, Lee CK, Kim H, Jo D, Paik YK. Inhibition of the Alternative Complement Pathway May Cause Secretion of Factor B, Enabling an Early Detection of Pancreatic Cancer. J Proteome Res 2024; 23:985-998. [PMID: 38306169 DOI: 10.1021/acs.jproteome.3c00695] [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] [Indexed: 02/03/2024]
Abstract
This study aims to elucidate the cellular mechanisms behind the secretion of complement factor B (CFB), known for its dual roles as an early biomarker for pancreatic ductal adenocarcinoma (PDAC) and as the initial substrate for the alternative complement pathway (ACP). Using parallel reaction monitoring analysis, we confirmed a consistent ∼2-fold increase in CFB expression in PDAC patients compared with that in both healthy donors (HD) and chronic pancreatitis (CP) patients. Elevated ACP activity was observed in CP and other benign conditions compared with that in HD and PDAC patients, suggesting a functional link between ACP and PDAC. Protein-protein interaction analyses involving key complement proteins and their regulatory factors were conducted using blood samples from PDAC patients and cultured cell lines. Our findings revealed a complex control system governing the ACP and its regulatory factors, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, adrenomedullin (AM), and complement factor H (CFH). Particularly, AM emerged as a crucial player in CFB secretion, activating CFH and promoting its predominant binding to C3b over CFB. Mechanistically, our data suggest that the KRAS mutation stimulates AM expression, enhancing CFH activity in the fluid phase through binding. This heightened AM-CFH interaction conferred greater affinity for C3b over CFB, potentially suppressing the ACP cascade. This sequence of events likely culminated in the preferential release of ductal CFB into plasma during the early stages of PDAC. (Data set ID PXD047043.).
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Affiliation(s)
- Min Jung Lee
- Yonsei Proteome Research Center, Yonsei University, Seoul 03722, South Korea
| | - Jin-Young Cho
- Yonsei Proteome Research Center, Yonsei University, Seoul 03722, South Korea
| | - Sumi Bae
- JW BioScience Corp., 38 Gwacheon-daero, Gwacheon-si, Gyeonggi-do 13840, South Korea
| | - Hye Soo Jung
- JW BioScience Corp., 38 Gwacheon-daero, Gwacheon-si, Gyeonggi-do 13840, South Korea
| | - Chang Moo Kang
- Department of Surgery, Division of HBP Surgery, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Sung Hyun Kim
- Department of Surgery, Division of HBP Surgery, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Hye Jin Choi
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Choong-Kun Lee
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Hoguen Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Daewoong Jo
- Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul 03929, Korea
| | - Young-Ki Paik
- Yonsei Proteome Research Center, Yonsei University, Seoul 03722, South Korea
- Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul 03929, Korea
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Sardar M, Recio-Boiles A, Mody K, Karime C, Chandana SR, Mahadevan D, Starr J, Jones J, Borad M, Babiker H. Pharmacotherapeutic options for pancreatic ductal adenocarcinoma. Expert Opin Pharmacother 2022; 23:2079-2089. [PMID: 36394449 DOI: 10.1080/14656566.2022.2149322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy projected to be the 2nd leading cause of cancer related death in the USA by 2030. This manuscript discusses current and evolving treatment approaches in patients with pancreatic cancer. AREAS COVERED PDAC is classified as: a) resectable, b) borderline resectable, c) unresectable (locally advanced and metastatic). The standard of care for patients who present with resectable pancreatic adenocarcinoma is six months of adjuvant modified (m) FOLFIRINOX, gemcitabine plus capecitabine, or single agent gemcitabine. For many reasons, there has been a paradigm shift to employing neoadjuvant chemotherapy. For resectable and borderline resectable patients, we generally start with systemic therapy and reevaluate resectability with subsequent scans specifically when the tumor is located in the head or body of the pancreas. Combined chemoradiation therapy can be employed in select patients. The standard of care for metastatic PDAC is FOLFIRINOX or gemcitabine and nab-paclitaxel. Germline and somatic genomic profiling should be obtained in all patients. Patients with a germline BRCA mutation can receive upfront gemcitabine and cisplatin. EXPERT OPINION Thorough understanding of molecular pathogenesis in PDAC has opened various therapeutic avenues. We remain optimistic that future treatment modalities such as targeted therapies, cellular therapies and immunotherapy will further improve survival in PDAC.
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Affiliation(s)
- Muhammad Sardar
- Division of Hematology-Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, Az, USA
| | - Alejandro Recio-Boiles
- Division of Hematology-Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, Az, USA
| | - Kabir Mody
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Cancer Center, Jacksonville, FL, USA
| | | | | | - Daruka Mahadevan
- Division of Hematology and Oncology, Department of Medicine, University of Texas, San Antonio, Texas, USA
| | - Jason Starr
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Cancer Center, Jacksonville, FL, USA
| | - Jeremy Jones
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Cancer Center, Jacksonville, FL, USA
| | - Mitesh Borad
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Cancer Center, Phoenix, AZ, USA
| | - Hani Babiker
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Cancer Center, Jacksonville, FL, USA
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Seshacharyulu P, Halder S, Nimmakayala R, Rachagani S, Chaudhary S, Atri P, Chirravuri-Venkata R, Ouellette MM, Carmicheal J, Gautam SK, Vengoji R, Wang S, Li S, Smith L, Talmon GA, Klute K, Ly Q, Reames BN, Grem JL, Berim L, Padussis JC, Kaur S, Kumar S, Ponnusamy MP, Jain M, Lin C, Batra SK. Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling. EBioMedicine 2021; 75:103772. [PMID: 34971971 PMCID: PMC8718746 DOI: 10.1016/j.ebiom.2021.103772] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/22/2021] [Accepted: 12/07/2021] [Indexed: 12/04/2022] Open
Abstract
Background Radiation therapy (RT) has a suboptimal effect in patients with pancreatic ductal adenocarcinoma (PDAC) due to intrinsic and acquired radioresistance (RR). Comprehensive bioinformatics and microarray analysis revealed that cholesterol biosynthesis (CBS) is involved in the RR of PDAC. We now tested the inhibition of the CBS pathway enzyme, farnesyl diphosphate synthase (FDPS), by zoledronic acid (Zol) to enhance radiation and activate immune cells. Methods We investigated the role of FDPS in PDAC RR using the following methods: in vitro cell-based assay, immunohistochemistry, immunofluorescence, immunoblot, cell-based cholesterol assay, RNA sequencing, tumouroids (KPC-murine and PDAC patient-derived), orthotopic models, and PDAC patient's clinical study. Findings FDPS overexpression in PDAC tissues and cells (P < 0.01 and P < 0.05) is associated with poor RT response and survival (P = 0.024). CRISPR/Cas9 and pharmacological inhibition (Zol) of FDPS in human and mouse syngeneic PDAC cells in conjunction with RT conferred higher PDAC radiosensitivity in vitro (P < 0.05, P < 0.01, and P < 0.001) and in vivo (P < 0.05). Interestingly, murine (P = 0.01) and human (P = 0.0159) tumouroids treated with Zol+RT showed a significant growth reduction. Mechanistically, RNA-Seq analysis of the PDAC xenografts and patients-PBMCs revealed that Zol exerts radiosensitization by affecting Rac1 and Rho prenylation, thereby modulating DNA damage and radiation response signalling along with improved systemic immune cells activation. An ongoing phase I/II trial (NCT03073785) showed improved failure-free survival (FFS), enhanced immune cell activation, and decreased microenvironment-related genes upon Zol+RT treatment. Interpretation Our findings suggest that FDPS is a novel radiosensitization target for PDAC therapy. This study also provides a rationale to utilize Zol as a potential radiosensitizer and as an immunomodulator in PDAC and other cancers. Funding National Institutes of Health (P50, P01, and R01).
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Affiliation(s)
- Parthasarathy Seshacharyulu
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Sushanta Halder
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Ramakrishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Sanjib Chaudhary
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Ramakanth Chirravuri-Venkata
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Michel M Ouellette
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffet Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Joseph Carmicheal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Shuo Wang
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68198-6861, USA
| | - Sicong Li
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68198-6861, USA
| | - Lynette Smith
- Department of Statistics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Geoffrey A Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kelsey Klute
- Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Quan Ly
- Division of Surgical Oncology, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Bradley N Reames
- Division of Surgical Oncology, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jean L Grem
- Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Lyudmyla Berim
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - James C Padussis
- Division of Surgical Oncology, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred and Pamela Buffet Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred and Pamela Buffet Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Chi Lin
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68198-6861, USA; Fred and Pamela Buffet Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffet Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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Takakusagi Y, Sugyo A, Tsuji AB, Sudo H, Yasunaga M, Matsumura Y, Sugawara F, Sakaguchi K, Higashi T. The natural sulfoglycolipid derivative SQAP improves the therapeutic efficacy of tissue factor-targeted radioimmunotherapy in the stroma-rich pancreatic cancer model BxPC-3. Transl Oncol 2021; 15:101285. [PMID: 34839108 PMCID: PMC8628266 DOI: 10.1016/j.tranon.2021.101285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/31/2021] [Accepted: 11/15/2021] [Indexed: 02/07/2023] Open
Abstract
SQAP enhanced tumor uptake and the therapeutic efficacy of radiolabeled anti-tissue factor antibody 1849. SQAP allows for a reduction of the dose of the therapeutic agent 90Y-labeled 1849 to half. SQAP did not affect hematologic parameters, or gastrointestinal and respiratory systems in mice. 90Y-labeled 1849 with SQAP potentially increases exposure of tumors to radiation. α-Sulfoquinovosylacyl-1,3-propanediol (SQAP) is a semi-synthetic derivative of natural sulfoglycolipid that sensitizes tumors to external-beam radiotherapy. How SQAP affects internal radiotherapy, however, is not known. Here, we investigated the effects of SQAP for radioimmunotherapy (RIT) targeting tissue factor (TF) in a stroma-rich refractory pancreatic cancer mouse model, BxPC-3. A low dose of SQAP (2 mg/kg) increased tumor uptake of the 111In-labeled anti-TF antibody 1849, indicating increased tumor perfusion. The addition of SQAP enhanced the growth-inhibitory effect of 90Y-labeled 1849 without leading to severe body weight changes, allowing for the dose of 90Y-labeled 1849 to be reduced to half that when used alone. Histologic analysis revealed few necrotic and apoptotic cells, but Ki-67–positive proliferating cells and increased vascular formation were detected. These results suggest that the addition of a low dose of SQAP may improve the therapeutic efficacy of TF-targeted RIT by increasing tumor perfusion, even for stroma-rich refractory pancreatic cancer.
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Affiliation(s)
- Yoichi Takakusagi
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology (QST-iQMS), 4-9-1 Inage, Chiba 263-8555, Japan; Institute for Quantum Life Science, National Institutes for Quantum and Radiological Science and Technology (QST-iQLS), 4-9-1 Inage, Chiba 263-8555, Japan
| | - Aya Sugyo
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology (QST-iQMS), 4-9-1 Inage, Chiba 263-8555, Japan
| | - Atsushi B Tsuji
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology (QST-iQMS), 4-9-1 Inage, Chiba 263-8555, Japan.
| | - Hitomi Sudo
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology (QST-iQMS), 4-9-1 Inage, Chiba 263-8555, Japan
| | - Masahiro Yasunaga
- Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
| | - Yasuhiro Matsumura
- Department of Immune Medicine, National Cancer Center Research Institute 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
| | - Fumio Sugawara
- pplied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Malignant Tumor Treatment Technologies (M.T.3) Inc., 3-20-2 Shibaura, Minato-ku, Tokyo 108-0023, Japan
| | - Kengo Sakaguchi
- pplied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Malignant Tumor Treatment Technologies (M.T.3) Inc., 3-20-2 Shibaura, Minato-ku, Tokyo 108-0023, Japan
| | - Tatsuya Higashi
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology (QST-iQMS), 4-9-1 Inage, Chiba 263-8555, Japan
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Tawfik D, Zaccagnino A, Bernt A, Szczepanowski M, Klapper W, Schwab A, Kalthoff H, Trauzold A. The A818-6 system as an in-vitro model for studying the role of the transportome in pancreatic cancer. BMC Cancer 2020; 20:264. [PMID: 32228510 PMCID: PMC7106758 DOI: 10.1186/s12885-020-06773-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 03/23/2020] [Indexed: 02/08/2023] Open
Abstract
Background The human pancreatic cancer cell line A818–6 can be grown in vitro either as a highly malignant, undifferentiated monolayer (ML) or as three-dimensional (3D) single layer hollow spheres (HS) simulating a benign, highly differentiated, duct-like pancreatic epithelial structure. This characteristic allowing A818–6 cells to switch from one phenotype to another makes these cells a unique system to characterize the cellular and molecular modifications during differentiation on one hand and malignant transformation on the other hand. Ion channels and transport proteins (transportome) have been implicated in malignant transformation. Therefore, the current study aimed to analyse the transportome gene expression profile in the A818–6 cells growing as a monolayer or as hollow spheres. Methods & Results The study identified the differentially expressed transportome genes in both cellular states of A818–6 using Agilent and Nanostring arrays and some targets were validated via immunoblotting. Additionally, these results were compared to a tissue Affymetrix microarray analysis of pancreatic adenocarcinoma patients’ tissues. The overall transcriptional profile of the ML and HS cells confirmed the formerly described mesenchymal features of ML and epithelial nature of HS which was further verified via high expression of E-cadherin and low expression of vimentin found in HS in comparison to ML. Among the predicted features between HS and ML was the involvement of miRNA-9 in this switch. Importantly, the bioinformatics analysis also revealed substantial number (n = 126) of altered transportome genes. Interestingly, three genes upregulated in PDAC tissue samples (GJB2, GJB5 and SLC38A6) were found to be also upregulated in ML and 3 down-regulated transportome genes (KCNQ1, TRPV6 and SLC4A) were also reduced in ML. Conclusion This reversible HS/ML in vitro system might help in understanding the pathophysiological impact of the transportome in the dedifferentiation process in pancreatic carcinogenesis. Furthermore, the HS/ML model represents a novel system for studying the role of the transportome during the switch from a more benign, differentiated (HS) to a highly malignant, undifferentiated (ML) phenotype.
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Affiliation(s)
- Doaa Tawfik
- Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Arnold-Heller Str. 3, 24105, Kiel, Germany
| | - Angela Zaccagnino
- Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Arnold-Heller Str. 3, 24105, Kiel, Germany
| | - Alexander Bernt
- Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Arnold-Heller Str. 3, 24105, Kiel, Germany
| | - Monika Szczepanowski
- Clinic for Internal Medicine II, Christian-Albrechts-University of Kiel, UKSH, Kiel, Germany
| | - Wolfram Klapper
- Institute of Pathology, Hematopathology Section and Lymph Node Registry, Christian-Albrechts-University of Kiel, UKSH, Kiel, Germany
| | - Albrecht Schwab
- Institute of Physiology II, Westfälische Wilhelms-Universität, Münster, Germany
| | - Holger Kalthoff
- Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Arnold-Heller Str. 3, 24105, Kiel, Germany
| | - Anna Trauzold
- Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Arnold-Heller Str. 3, 24105, Kiel, Germany.
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Jin S, Lee WC, Aust D, Pilarsky C, Cordes N. β8 Integrin Mediates Pancreatic Cancer Cell Radiochemoresistance. Mol Cancer Res 2019; 17:2126-2138. [DOI: 10.1158/1541-7786.mcr-18-1352] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/26/2019] [Accepted: 07/17/2019] [Indexed: 11/16/2022]
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The significance of gene mutations across eight major cancer types. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:88-99. [PMID: 31416581 DOI: 10.1016/j.mrrev.2019.04.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 04/11/2019] [Accepted: 04/30/2019] [Indexed: 12/12/2022]
Abstract
Mutations occur spontaneously, which can be induced by either chemicals (e.g. benzene) or biological factors (e.g. virus). Not all mutations cause noticeable changes in cellular functions. However, mutation in key cellular genes leads to developmental disorders. It is one of the main ways in which proto-oncogenes can be changed into their oncogenic state. The progressive accumulation of multiple mutations throughout life leads to cancer. In the past few decades, extensive research on cancer biology has discovered many genes and pathways having role in cancer development. In this review, we tried to summarize the current knowledge of mutational effect on different cancer types and its consequences in brief for future reference and guidance of researchers in cancer biology.
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Tu MJ, Ho PY, Zhang QY, Jian C, Qiu JX, Kim EJ, Bold RJ, Gonzalez FJ, Bi H, Yu AM. Bioengineered miRNA-1291 prodrug therapy in pancreatic cancer cells and patient-derived xenograft mouse models. Cancer Lett 2019; 442:82-90. [PMID: 30389433 PMCID: PMC6311422 DOI: 10.1016/j.canlet.2018.10.038] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 09/12/2018] [Accepted: 10/25/2018] [Indexed: 02/08/2023]
Abstract
Our recent studies have revealed that microRNA-1291 (miR-1291) is downregulated in pancreatic cancer (PC) specimens and restoration of miR-1291 inhibits tumorigenesis of PC cells. This study is to assess the efficacy and underlying mechanism of our bioengineered miR-1291 prodrug monotherapy and combined treatment with chemotherapy. AT-rich interacting domain protein 3B (ARID3B) was verified as a new target for miR-1291, and miR-1291 prodrug was processed to mature miR-1291 in PC cells which surprisingly upregulated ARID3B mRNA and protein levels. Co-administration of miR-1291 with gemcitabine plus nab-paclitaxel (Gem-nP) largely increased the levels of apoptosis, DNA damage and mitotic arrest in PC cells, compared to mono-drug treatment. Consequently, miR-1291 prodrug improved cell sensitivity to Gem-nP. Furthermore, systemic administration of in vivo-jetPEI-formulated miR-1291 prodrug suppressed tumor growth in both PANC-1 xenograft and PC patients derived xenograft (PDX) mouse models to comparable degrees as Gem-nP alone, while combination treatment reduced tumor growth more ubiquitously and to the greatest degrees (70-90%), compared to monotherapy. All treatments were well tolerated in mice. In conclusion, biologic miR-1291 prodrug has therapeutic potential as a monotherapy for PC, and a sensitizing agent to chemotherapy.
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Affiliation(s)
- Mei-Juan Tu
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Pui Yan Ho
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Qian-Yu Zhang
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Chao Jian
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Jing-Xin Qiu
- Roswell Park Cancer Institute, Buffalo, NY, 14263, USA
| | - Edward J Kim
- Division of Hematology and Oncology, UC Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Richard J Bold
- Department of Surgery, UC Davis School of Medicine, Sacramento, CA, 95817, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Huichang Bi
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Ai-Ming Yu
- Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA, 95817, USA.
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Xu WY, Hu QS, Qin Y, Zhang B, Liu WS, Ni QX, Xu J, Yu XJ. Zinc finger E-box-binding homeobox 1 mediates aerobic glycolysis via suppression of sirtuin 3 in pancreatic cancer. World J Gastroenterol 2018; 24:4893-4905. [PMID: 30487699 PMCID: PMC6250915 DOI: 10.3748/wjg.v24.i43.4893] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 09/27/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To uncover the roles of tumor-promoting gene ZEB1 in aerobic glycolysis regulation and shed light on the underlying molecular mechanism. METHODS Endogenous zinc finger E-box binding homeobox-1 (ZEB1) was silenced using a lentivirus-mediated method, and the impact of ZEB1 and methyl-CpG binding domain protein 1 (MBD1) on aerobic glycolysis was measured using seahorse cellular flux analyzers, reactive oxygen species quantification, and mitochondrial membrane potential measurement. The interaction between ZEB1 and MBD1 was assessed by co-immunoprecipitation and immunofluorescence assays. The impact of ZEB1 and MBD1 interaction on sirtuin 3 (SIRT3) expression was confirmed by quantitative polymerase chain reaction, western blotting, and dual-luciferase and chromatin-immunoprecipitation assays. RESULTS ZEB1 was a positive regulator of aerobic glycolysis in pancreatic cancer. ZEB1 transcriptionally silenced expression of SIRT3, a mitochondrial-localized tumor suppressor, through interaction with MBD1. CONCLUSION ZEB1 silenced SIRT3 expression via interaction with MBD1 to promote aerobic glycolysis in pancreatic cancer.
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Affiliation(s)
- Wen-Yan Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Qiang-Sheng Hu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Yi Qin
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
| | - Wen-Sheng Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Quan-Xing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Jin Xu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
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10
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Sugyo A, Tsuji AB, Sudo H, Koizumi M, Ukai Y, Kurosawa G, Kurosawa Y, Saga T, Higashi T. Efficacy Evaluation of Combination Treatment Using Gemcitabine and Radioimmunotherapy with 90Y-Labeled Fully Human Anti-CD147 Monoclonal Antibody 059-053 in a BxPC-3 Xenograft Mouse Model of Refractory Pancreatic Cancer. Int J Mol Sci 2018; 19:ijms19102979. [PMID: 30274301 PMCID: PMC6213240 DOI: 10.3390/ijms19102979] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 09/06/2018] [Accepted: 09/28/2018] [Indexed: 02/07/2023] Open
Abstract
The poor prognosis of pancreatic cancer requires the development of more effective therapy. CD147 expresses in pancreatic cancer with high incidence and has a crucial role in invasion and metastasis. We developed a fully human monoclonal antibody (059-053) with high affinity for CD147. Here we evaluated the efficacy of combined treatment using radioimmunotherapy (RIT) with 90Y-labeled 059-053 and gemcitabine in a BxPC-3 xenograft mouse model. Expression of CD147 and matrix metalloproteinase-2 (MMP2) in BxPC-3 tumors was evaluated. In vitro and in vivo properties of 059-053 were evaluated using 111In-labeled 059-053 and a pancreatic cancer model BxPC-3. Tumor volume and body weight were periodically measured in mice receiving gemcitabine, RIT, and both RIT and gemcitabine (one cycle and two cycles). High expression of CD147 and MMP2 was observed in BxPC-3 tumors and suppressed by 059-053 injection. Radiolabeled 059-053 bound specifically to BxPC-3 cells and accumulated highly in BxPC-3 tumors but low in major organs. Combined treatment using RIT with gemcitabine (one cycle) significantly suppressed tumor growth and prolonged survival with tolerable toxicity. The two-cycle regimen had the highest anti-tumor effect, but was not tolerable. Combined treatment with 90Y-labeled 059-053 and gemcitabine is a promising therapeutic option for pancreatic cancer.
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Affiliation(s)
- Aya Sugyo
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
| | - Atsushi B Tsuji
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
| | - Hitomi Sudo
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
| | - Mitsuru Koizumi
- Department of Nuclear Medicine, Cancer Institute Hospital, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
| | - Yoshinori Ukai
- Research and Development Division, Perseus Proteomics Inc., 4-7-6 Komaba, Meguro-ku, Tokyo 153-0041, Japan.
| | - Gene Kurosawa
- Innovation Center for Advanced Medicine, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
| | - Yoshikazu Kurosawa
- Innovation Center for Advanced Medicine, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
| | - Tsuneo Saga
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
- Department of Diagnostic Radiology, Kyoto University Hospital, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
| | - Tatsuya Higashi
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
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11
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Schug C, Gupta A, Urnauer S, Steiger K, Cheung PFY, Neander C, Savvatakis K, Schmohl KA, Trajkovic-Arsic M, Schwenk N, Schwaiger M, Nelson PJ, Siveke JT, Spitzweg C. A Novel Approach for Image-Guided 131I Therapy of Pancreatic Ductal Adenocarcinoma Using Mesenchymal Stem Cell-Mediated NIS Gene Delivery. Mol Cancer Res 2018; 17:310-320. [PMID: 30224540 DOI: 10.1158/1541-7786.mcr-18-0185] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 05/28/2018] [Accepted: 08/22/2018] [Indexed: 11/16/2022]
Abstract
The sodium iodide symporter (SLC5A5/NIS) as theranostic gene would allow for non-invasive imaging of functional NIS expression and therapeutic radioiodine application. Genetically engineered mesenchymal stem cells (MSC), based on their tumor-homing abilities, show great promise as tumor-selective NIS gene delivery vehicles for non-thyroidal tumors. As a next step towards clinical application, tumor specificity and efficacy of MSCs were investigated in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC). Syngeneic murine MSCs were stably transfected with a NIS-expressing plasmid driven by the CMV-promoter (NIS-MSC). In vivo 123I-scintigraphy and 124I-PET revealed significant perchlorate-sensitive NIS-mediated radioiodide accumulation in PDAC after systemic injection of NIS-MSCs. Active MSC recruitment into the tumor stroma was confirmed using NIS immunohistochemistry (IHC). A therapeutic strategy, consisting of three cycles of systemic MSC-mediated NIS delivery, followed by 131I application, resulted in a significant delay and reduction in tumor growth as compared to controls. Furthermore, IHC analysis of α-SMA and Ki67 revealed differences in the amount and behavior of activated fibroblasts in tumors of mice injected with NIS-MSCs as compared with saline-treated mice. Taken together, MSCs as NIS gene delivery vehicles in this advanced endogenous PDAC mouse model demonstrated high stromal targeting of NIS by selective recruitment of NIS-MSCs after systemic application resulting in an impressive 131I therapeutic effect. IMPLICATIONS: These data expand the prospect of MSC-mediated radioiodine imaging-guided therapy of pancreatic cancer using the sodium iodide symporter as a theranostic gene in a clinical setting.
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Affiliation(s)
- Christina Schug
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Aayush Gupta
- Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Sarah Urnauer
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Phyllis Fung-Yi Cheung
- Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.,German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christian Neander
- Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.,German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Konstantinos Savvatakis
- Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.,German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kathrin A Schmohl
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Marija Trajkovic-Arsic
- Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.,German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nathalie Schwenk
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Markus Schwaiger
- Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Peter J Nelson
- Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jens T Siveke
- Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.,Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.,German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany.
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12
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Yadav DK, Bai X, Yadav RK, Singh A, Li G, Ma T, Chen W, Liang T. Liquid biopsy in pancreatic cancer: the beginning of a new era. Oncotarget 2018; 9:26900-26933. [PMID: 29928492 PMCID: PMC6003564 DOI: 10.18632/oncotarget.24809] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 02/25/2018] [Indexed: 12/21/2022] Open
Abstract
With dismal survival rate pancreatic cancer remains one of the most aggressive and devastating malignancy. Predominantly, due to the absence of a dependable methodology for early identification and limited therapeutic options for advanced disease. However, it takes over 17 years to develop pancreatic cancer from initiation of mutation to metastatic cancer; therefore, if diagnosed early; it may increase overall survival dramatically, thus, providing a window of opportunity for early detection. Recently, genomic expression analysis defined 4 subtypes of pancreatic cancer based on mutated genes. Hence, we need simple and standard, minimally invasive test that can monitor those altered genes or their associated pathways in time for the success of precision medicine, and liquid biopsy seems to be one answer to all these questions. Again, liquid biopsy has an ability to pair with genomic tests. Additionally, liquid biopsy based development of circulating tumor cells derived xenografts, 3D organoids system, real-time monitoring of genetic mutations by circulating tumor DNA and exosome as the targeted drug delivery vehicle holds lots of potential for the treatment and cure of pancreatic cancer. At present, diagnosis of pancreatic cancer is frantically done on the premise of CA19-9 and radiological features only, which doesn't give a picture of genetic mutations and epigenetic alteration involved. In this manner, the current diagnostic paradigm for pancreatic cancer diagnosis experiences low diagnostic accuracy. This review article discusses the current state of liquid biopsy in pancreatic cancer as diagnostic and therapeutic tools and future perspectives of research in the light of circulating tumor cells, circulating tumor DNA and exosomes.
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Affiliation(s)
- Dipesh Kumar Yadav
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Rajesh Kumar Yadav
- Department of Pharmacology, Gandaki Medical College, Tribhuwan University, Institute of Medicine, Pokhara 33700, Nepal
| | - Alina Singh
- Department of Surgery, Bir Hospital, National Academy of Medical Science, Kanti Path, Kathmandu 44600, Nepal
| | - Guogang Li
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Tao Ma
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
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13
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Biondani G, Zeeberg K, Greco MR, Cannone S, Dando I, Dalla Pozza E, Mastrodonato M, Forciniti S, Casavola V, Palmieri M, Reshkin SJ, Cardone RA. Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome. FEBS J 2018; 285:2104-2124. [PMID: 29660229 DOI: 10.1111/febs.14471] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 03/05/2018] [Accepted: 04/06/2018] [Indexed: 12/17/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Its aggressiveness is driven by an intense fibrotic desmoplastic reaction in which the increasingly collagen I-rich extracellular matrix (ECM) and several cell types, including cancer stem cells (CSCs), create a tumor-supportive environment. However, how ECM composition regulates CSC dynamics and their relationship with the principle parenchymal tumor population to promote early invasive growth is not yet characterized. For this, we utilized a platform of 3D organotypic cultures composed of laminin-rich Matrigel, representative of an early tumor, plus increasing concentrations of collagen I to simulate malignant stroma progression. As ECM collagen I increases, CSCs progress from a rapidly growing, vascular phenotype to a slower growing, avascular phase, while maintaining their endothelial-like gene signatures. This transition is supported autocrinically by the CSCs and paracrinically by the parenchymal cells via their ECM-dependent secretomes. Indeed, when growing on an early tumor ECM, the CSCs are dedicated toward the preparation of a vascular niche by (a) activating their growth program, (b) secreting high levels of proangiogenic factors which stimulate both angiogenesis and vasculogenic mimicry, and (c) overexpressing VEGFR-2, which is activated by VEGF secreted by both the CSC and parenchymal cells. On Matrigel, the more differentiated parenchymal tumor cell population had reduced growth but a high invasive capacity. This concerted high local invasion of parenchymal cells into the CSC-derived vascular network suggests that a symbiotic relationship between the parenchymal cells and the CSCs underlies the initiation and maintenance of early PDAC infiltration and metastasis.
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Affiliation(s)
- Giulia Biondani
- Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Italy
| | - Katrine Zeeberg
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Italy
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Italy
| | - Stefania Cannone
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Italy
| | - Ilaria Dando
- Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Italy
| | - Elisa Dalla Pozza
- Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Italy
| | | | - Stefania Forciniti
- Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Italy
| | - Valeria Casavola
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Italy
| | - Marta Palmieri
- Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Italy
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Italy
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Italy
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14
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Lu C, Yang D, Sabbatini ME, Colby AH, Grinstaff MW, Oberlies NH, Pearce C, Liu K. Contrasting roles of H3K4me3 and H3K9me3 in regulation of apoptosis and gemcitabine resistance in human pancreatic cancer cells. BMC Cancer 2018; 18:149. [PMID: 29409480 PMCID: PMC5801751 DOI: 10.1186/s12885-018-4061-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 01/29/2018] [Indexed: 01/18/2023] Open
Abstract
Background Pancreas ductal adenocarcinoma (PDAC) has the most dismal prognosis among all human cancers since it is highly resistant to chemotherapy, radiotherapy and immunotherapy. The anticipated consequence of all therapies is induction of tumor apoptosis. The highly resistance nature of PDACs to all therapies suggests that the intrinsic tumor cell factors, likely the deregulated apoptosis pathway, are key mechanisms underlying PDAC non-response to these therapies, rather than the therapeutic agents themselves. The aim of this study is to test the hypothesis that epigenetic dysregulation of apoptosis mediators underlies PDAC resistance to gemcitabine, the standard chemotherapy for human PDAC. Methods PDAC cells were analyzed for apoptosis sensitivity in the presence of a selective epigenetic inhibitor. The epigenetic regulation of apoptosis regulators was determined by Western Blotting and quantitative PCR. The specific epigenetic modification of apoptosis regulator promoter chromatin was determined by chromatin immunoprecipitation in PDAC cells. Results Inhibition of histone methyltransferase (HMTase) by a selective HMTase inhibitor, verticillin A, significantly increased human PDAC cell sensitivity to gemcitabine-induced growth suppression. Verticillin A treatment decreased FLIP, Mcl-1, Bcl-x and increased Bak, Bax and Bim protein level in the tumor cells, resulting in activation of caspases, elevated cytochrome C release and increased apoptosis as determined by upregulated PARP cleavage in tumor cells. Analysis of human PDAC specimens indicated that the expression levels of anti-apoptotic mediators Bcl-x, Mcl-1, and FLIP were significantly higher, whereas the expression levels of pro-apoptotic mediators Bim, Bak and Bax were dramatically lower in human PDAC tissues as compared to normal pancreas. Verticillin A downregulated H3K4me3 levels at the BCL2L1, CFLAR and MCL-1 promoter to decrease Bcl-x, FLIP and Mcl-1 expression level, and inhibited H3K9me3 levels at the BAK1, BAX and BCL2L11 promoter to upregulate Bak, Bax and Bim expression level. Conclusion We determined that PDAC cells use H3K4me3 to activate Bcl-x, FLIP and Mcl-1, and H3K9me3 to silence Bak, Bax and Bim to acquire an apoptosis-resistant phenotype. Therefore, selective inhibition of H3K4me3 and H3K9me3 is potentially an effective approach to overcome PDAC cells resistance to gemcitabine.
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Affiliation(s)
- Chunwan Lu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, 1410 Laney Walker Blvd, Augusta, GA, 30912, USA. .,Georgia Cancer Center, Medical College of Georgia, Augusta, GA, 30912, USA. .,Charlie Norwood VA Medical Center, Augusta, GA, 30904, USA.
| | - Dafeng Yang
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, 1410 Laney Walker Blvd, Augusta, GA, 30912, USA.,Georgia Cancer Center, Medical College of Georgia, Augusta, GA, 30912, USA.,Charlie Norwood VA Medical Center, Augusta, GA, 30904, USA
| | - Maria E Sabbatini
- Department of Biological Sciences, Augusta University, Augusta, GA, 30904, USA
| | - Aaron H Colby
- Ionic Pharmaceuticals, Brookline, MA, 02445, USA.,Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA
| | - Mark W Grinstaff
- Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA
| | - Nicholas H Oberlies
- Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, 27402, USA
| | | | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, 1410 Laney Walker Blvd, Augusta, GA, 30912, USA.,Georgia Cancer Center, Medical College of Georgia, Augusta, GA, 30912, USA.,Charlie Norwood VA Medical Center, Augusta, GA, 30904, USA
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15
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Fabbri C, Gibiino G, Fornelli A, Cennamo V, Grifoni D, Visani M, Acquaviva G, Fassan M, Fiorino S, Giovanelli S, Bassi M, Ghersi S, Tallini G, Jovine E, Gasbarrini A, de Biase D. Team work and cytopathology molecular diagnosis of solid pancreatic lesions. Dig Endosc 2017; 29:657-666. [PMID: 28190274 DOI: 10.1111/den.12845] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 02/08/2017] [Indexed: 02/05/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer-associated death in the next decade or so. It is widely accepted that tumorigenesis is linked to specific alterations in key genes and pancreatic neoplasms are some of the best characterized at the genomic level. Recent whole-exome and whole-genome sequencing analyses confirmed that PDAC is frequently characterized by mutations in a set of four genes among others: KRAS, TP53, CDKN2A/p16, and SMAD4. Sequencing, for example, is the preferable technique available for detecting KRAS mutations, whereas in situ immunochemistry is the main approach for detecting TP53 gene alteration. Nevertheless, the diagnosis of PDAC is still a clinical challenge, involving adequate acquisition of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) and specific pathological assessment from tissue architecture to specific biomolecular tests. The aim of the present review is to provide a complete overview of the current knowledge of the biology of pancreatic cancer as detected by the latest biomolecular techniques and, moreover, to propose a paradigm for strict teamwork collaboration in order to improve the correct use of diagnostic sources.
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Affiliation(s)
- Carlo Fabbri
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Giulia Gibiino
- Medical Pathology, Department of Internal Medicine, Gastroenterology Division, Policlinico Universitario A. Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Adele Fornelli
- Anatomic Pathology Unit, AUSL of Bologna, Maggiore Hospital, Italy
| | - Vincenzo Cennamo
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Daniela Grifoni
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy
| | - Michela Visani
- Department of Medicine (DIMES), Molecular Diagnostic Unit AUSL of Bologna, University of Bologna School of Medicine, Italy
| | - Giorgia Acquaviva
- Department of Medicine (DIMES), Molecular Diagnostic Unit AUSL of Bologna, University of Bologna School of Medicine, Italy
| | - Matteo Fassan
- Department of Medicine, Anatomic Pathology, University of Padua, Padova, Italy
| | - Sirio Fiorino
- Internal Medicine Unit, Maggiore Hospital, Bologna, Italy
| | - Silvia Giovanelli
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Marco Bassi
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Stefania Ghersi
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Giovanni Tallini
- Department of Medicine (DIMES), Molecular Diagnostic Unit AUSL of Bologna, University of Bologna School of Medicine, Italy
| | - Elio Jovine
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Antonio Gasbarrini
- Medical Pathology, Department of Internal Medicine, Gastroenterology Division, Policlinico Universitario A. Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy
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16
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Schmohl KA, Gupta A, Grünwald GK, Trajkovic-Arsic M, Klutz K, Braren R, Schwaiger M, Nelson PJ, Ogris M, Wagner E, Siveke JT, Spitzweg C. Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene. Oncotarget 2017; 8:33393-33404. [PMID: 28380420 PMCID: PMC5464876 DOI: 10.18632/oncotarget.16499] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/27/2017] [Indexed: 12/18/2022] Open
Abstract
The theranostic sodium iodide symporter (NIS) gene allows detailed molecular imaging of transgene expression and application of therapeutic radionuclides. As a crucial step towards clinical application, we investigated tumor specificity and transfection efficiency of epidermal growth factor receptor (EGFR)-targeted polyplexes as systemic NIS gene delivery vehicles in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) that closely reflects human disease. PDAC was induced in mice by pancreas-specific activation of constitutively active KrasG12D and deletion of Trp53. We used tumor-targeted polyplexes (LPEI-PEG-GE11/NIS) based on linear polyethylenimine, shielded by polyethylene glycol and coupled with the EGFR-specific peptide ligand GE11, to target a NIS-expressing plasmid to high EGFR-expressing PDAC. In vitro iodide uptake studies in cell explants from murine EGFR-positive and EGFR-ablated PDAC lesions demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS. In vivo 123I gamma camera imaging and three-dimensional high-resolution 124I PET showed significant tumor-specific accumulation of radioiodide after systemic LPEI-PEG-GE11/NIS injection. Administration of 131I in LPEI-PEG-GE11/NIS-treated mice resulted in significantly reduced tumor growth compared to controls as determined by magnetic resonance imaging, though survival was not significantly prolonged. This study opens the exciting prospect of NIS-mediated radionuclide imaging and therapy of PDAC after systemic non-viral NIS gene delivery.
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Affiliation(s)
- Kathrin A. Schmohl
- Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Aayush Gupta
- Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Geoffrey K. Grünwald
- Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Marija Trajkovic-Arsic
- Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kathrin Klutz
- Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Rickmer Braren
- Department of Radiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Markus Schwaiger
- Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Peter J. Nelson
- Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Manfred Ogris
- Department of Pharmaceutical Chemistry, Laboratory of MacroMolecular Cancer Therapeutics (MMCT), University of Vienna, Vienna, Austria
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Department of Pharmacy, Center for System-Based Drug Research and Center for Nanoscience, LMU Munich, Munich, Germany
| | - Jens T. Siveke
- Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
- Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christine Spitzweg
- Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany
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17
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Khalafalla FG, Khan MW. Inflammation and Epithelial-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma: Fighting Against Multiple Opponents. CANCER GROWTH AND METASTASIS 2017; 10:1179064417709287. [PMID: 28579826 PMCID: PMC5436837 DOI: 10.1177/1179064417709287] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 04/06/2017] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and one of the most lethal human cancers. Inflammation is a critical component in PDAC initiation and progression. Inflammation also contributes to the aggressiveness of PDAC indirectly via induction of epithelial-mesenchymal transition (EMT), altogether leading to enhanced resistance to chemotherapy and poor survival rates. This review gives an overview of the key pro-inflammatory signaling pathways involved in PDAC pathogenesis and discusses the role of inflammation in induction of EMT and development of chemoresistance in patients with PDAC.
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18
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Träger MM, Dhayat SA. Epigenetics of epithelial-to-mesenchymal transition in pancreatic carcinoma. Int J Cancer 2017; 141:24-32. [DOI: 10.1002/ijc.30626] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 01/09/2017] [Accepted: 01/25/2017] [Indexed: 12/14/2022]
Affiliation(s)
- Max M. Träger
- Department of General and Visceral Surgery; University Hospital of Muenster; Muenster Germany
| | - Sameer A. Dhayat
- Department of General and Visceral Surgery; University Hospital of Muenster; Muenster Germany
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