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Ail DA, Paulose RR. A relook at gastroenteropancreatic neuroendocrine tumours as per 2019 WHO classification-A tertiary centre experience. Ir J Med Sci 2023; 192:2065-2070. [PMID: 36409421 DOI: 10.1007/s11845-022-03217-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 11/08/2022] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Neuroendocrine neoplasm of GIT (gastrointestinal tract) and pancreas is heterogenous with variable clinical features and disease outcomes. Despite multiple attempts of risk stratification by grading and staging, some have unpredictable clinical courses. Well-differentiated grade 3 neuroendocrine tumour (G3NET) is a recent subcategory introduced in the 2019 WHO classification based on morphology, molecular profile and prognosis distinguishing it from neuroendocrine carcinoma(NEC). This study aimed at describing the spectrum of NENs encountered in a tertiary centre with focus on reclassifying previously reported G3 tumours into G3 NET and NEC and comparing the survival between them. METHODOLOGY This is an 8-year retrospective study of all gastro-entero-pancreatic neuroendocrine neoplasms reclassified according to the 2019 WHO classification based on morphology and Ki-67 index with analysis of the survival rates between the categories. Minimum follow-up period was 20 months. RESULTS Eighty-six patients with NENs of gastro-entero-pancreas were included, with median age group of 40-60 years (age range 9 to 79 years) and male:female ratio of 1.7:1. The tumour grade correlated with the TNM staging and most of the syndromic NETs were low grade. Eleven percent of the tumours were reclassified as well-differentiated G3NETs. The survival of G3 NETs was higher than NEC. CONCLUSION Grading of NEN is vital for therapeutic decisions and for prognostication. Currently, morphology is the key to recognise the well-differentiated G3 NETs, but can be subject to interobserver variability. Molecular surrogates may play a role in accurately identifying these entities, the validity of which is warranted.
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Affiliation(s)
- Divya Achutha Ail
- GI and Liver Pathology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
- Department of Pathology, Yenepoya Medical College, Mangalore, India
| | - Roopa Rachel Paulose
- Department of Pathology, Amrita Institute of Medical Sciences, Kochi, Kerala, India.
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Lee NR, Kim DY, Jin H, Meng R, Chai OH, Kim SH, Park BH, Kim SM. Inactivation of the Akt/FOXM1 Signaling Pathway by Panobinostat Suppresses the Proliferation and Metastasis of Gastric Cancer Cells. Int J Mol Sci 2021; 22:5955. [PMID: 34073071 PMCID: PMC8199011 DOI: 10.3390/ijms22115955] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/28/2021] [Accepted: 05/28/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Histone deacetylase (HDAC) inhibitors are a new class of cytostatic agents available for the treatment of various cancers and diseases. Although numerous clinical and pre-clinical trials on the anticancer effects of panobinostat have been conducted, only a few reports have investigated its efficacy in gastric cancer. The present study aimed to investigate the effects of panobinostat in gastric cancer cells. Panobinostat significantly inhibited the cell viability and proliferation of the gastric cancer cell lines SNU484 and SNU638 in a dose-dependent manner; it reduced the colony-forming ability of these cells. Moreover, it induced apoptosis as indicated by increased protein levels of cleaved poly ADP-ribose polymerase and cleaved caspase-3. Panobinostat induced the G2/M cell cycle arrest in SNU484 and SNU638 cells and subsequently decreased the G2/M phase regulatory-associated protein expression of p-Wee1, Myt1, and Cdc2. Furthermore, panobinostat significantly inhibited the metastasis of SNU484 and SNU638 cells by regulating the expression of MMP-9 and E-cadherin. Further, it decreased the protein levels of p-Akt and forkhead box protein M1 (FOXM1). These effects were reversed by the Akt agonist SC79 and were accelerated by the Akt inhibitor LY2940002. Moreover, tumor growth in xenograft animal experiments was suppressed by panobinostat. These results indicated that panobinostat inhibits the proliferation, metastasis, and cell cycle progression of gastric cancer cells by promoting apoptosis and inactivating Akt/FOXM1 signaling. Cumulatively, our present study suggests that panobinostat is a potential drug for the treatment of gastric cancer.
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Affiliation(s)
- Na-Ri Lee
- Division of Hematology/Oncology, Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju 54907, Korea;
- Research Institute of Clinical Medicine, Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea
| | - Da-Yeah Kim
- Department of Physiology, Institute of Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea; (D.-Y.K.); (R.M.)
| | - Hua Jin
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China;
| | - Ruoyu Meng
- Department of Physiology, Institute of Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea; (D.-Y.K.); (R.M.)
| | - Ok Hee Chai
- Department of Anatomy, Institute of Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea;
| | - Seong-Hun Kim
- Research Institute of Clinical Medicine, Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea
- Department of Internal Medicine, Division of Gastroentrology, Jeonbuk National University Medical School, Jeonbuk National University Hospital, Jeonju 54907, Korea;
| | - Byung-Hyun Park
- Department of Biochemistry, Jeonbuk National University Medical School, Jeonju 54907, Korea;
| | - Soo Mi Kim
- Department of Physiology, Institute of Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea; (D.-Y.K.); (R.M.)
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Briest F, Koziolek EJ, Albrecht J, Schmidt F, Bernsen MR, Haeck J, Kühl AA, Sedding D, Hartung T, Exner S, Welzel M, Fischer C, Grötzinger C, Brenner W, Baum RP, Grabowski P. Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? - A preclinical assessment in vitro and in vivo. Neoplasia 2020; 23:80-98. [PMID: 33246310 PMCID: PMC7701025 DOI: 10.1016/j.neo.2020.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib. METHODS AND RESULTS In this study, we assessed several combined treatment modalities in vitro and in vivo. By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo, however with no significant additional benefit related to PRRT alone. CONCLUSIONS We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo. Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model.
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Affiliation(s)
- Franziska Briest
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Department of Biology, Chemistry, and Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität (FU) Berlin, Berlin, Germany.
| | - Eva J Koziolek
- German Cancer Consortium (DKTK), Germany; Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jakob Albrecht
- Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany
| | - Fränze Schmidt
- German Cancer Consortium (DKTK), Germany; Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute for Biochemistry and Biotechnology, Martin-Luther-University (MLU) Halle-Wittenberg, Halle (Saale), Germany
| | | | - Joost Haeck
- Department of Radiology, Erasmus MC, Rotterdam, The Netherlands
| | - Anja A Kühl
- iPATH.Berlin, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
| | - Dagmar Sedding
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Institute of Biology, Humboldt-Universität (HU) Berlin, Berlin, Germany
| | - Teresa Hartung
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Samantha Exner
- Department of Hepatology and Gastroenterology and Molecular Cancer Research Center, Tumor Targeting Laboratory, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Martina Welzel
- Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany
| | - Christian Fischer
- Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany
| | - Carsten Grötzinger
- German Cancer Consortium (DKTK), Germany; Department of Hepatology and Gastroenterology and Molecular Cancer Research Center, Tumor Targeting Laboratory, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Winfried Brenner
- German Cancer Consortium (DKTK), Germany; Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin Germany; Berlin Experimental Radionuclide Imaging Center (BERIC), Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Richard P Baum
- Department of Nuclear Medicine, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; CURANOSTICUM Wiesbaden-Frankfurt, DKD Helios Clinic, Wiesbaden, Germany
| | - Patricia Grabowski
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany; Department of Gastroenterology and Endocrinology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; Department of Medical Immunology, Charité Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
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Busse A, Mochmann LH, Spenke C, Arsenic R, Briest F, Jöhrens K, Lammert H, Sipos B, Kühl AA, Wirtz R, Pavel M, Hummel M, Kaemmerer D, Baum RP, Grabowski P. Immunoprofiling in Neuroendocrine Neoplasms Unveil Immunosuppressive Microenvironment. Cancers (Basel) 2020; 12:E3448. [PMID: 33228231 PMCID: PMC7699546 DOI: 10.3390/cancers12113448] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023] Open
Abstract
Checkpoint inhibitors have shown promising results in a variety of tumors; however, in neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), low response rates were reported. We aimed herein to investigate the tumor immune microenvironment in NET/NEC to determine whether checkpoint pathways like programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) might play a role in immune escape and whether other escape mechanisms might need to be targeted to enable a functional antitumor response. Forty-eight NET and thirty NEC samples were analyzed by immunohistochemistry (IHC) and mRNA immunoprofiling including digital spatial profiling. Through IHC, both NET/NEC showed stromal, but less intratumoral CD3+ T cell infiltration, although this was significantly higher in NEC compared to NET. Expression of PD1, PD-L1, and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on immune cells was low or nearly absent. mRNA immunoprofiling revealed low expression of IFNγ inducible genes in NET and NEC without any spatial heterogeneity. However, we observed an increased mRNA expression of chemokines, which attract myeloid cells in NET and NEC, and a high abundance of genes related to immunosuppressive myeloid cells and genes with immunosuppressive functions like CD47 and CD74. In conclusion, NET and NEC lack signs of an activation of the adaptive immune system, but rather show abundance of several immunosuppressive genes that represent potential targets for immunomodulation.
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Affiliation(s)
- Antonia Busse
- Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany; (L.H.M.); (C.S.); (F.B.); (P.G.)
- German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Liliana H. Mochmann
- Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany; (L.H.M.); (C.S.); (F.B.); (P.G.)
| | - Christiane Spenke
- Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany; (L.H.M.); (C.S.); (F.B.); (P.G.)
| | - Ruza Arsenic
- Institute of Pathology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany; (R.A.); (K.J.); (H.L.); (M.H.)
- Institute für histologische und zytologische Diagnostik AG Aarau, 5000 Aarau, Switzerland
| | - Franziska Briest
- Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany; (L.H.M.); (C.S.); (F.B.); (P.G.)
| | - Korinna Jöhrens
- Institute of Pathology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany; (R.A.); (K.J.); (H.L.); (M.H.)
- Institute of Pathology, Carl Gustav Carus University Hospital Dresden, 01307 Dresden, Germany
| | - Hedwig Lammert
- Institute of Pathology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany; (R.A.); (K.J.); (H.L.); (M.H.)
| | - Bence Sipos
- Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, 72076 Tübingen, Germany;
- Private Practice of Pathology and Molecular Pathology, 70176 Stuttgart, Germany
| | - Anja A. Kühl
- iPATH Berlin—Immunopathology for Experimental Models, Core Unit of the Charité, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 12203 Berlin, Germany;
| | - Ralph Wirtz
- Stratifyer Molecular Oncology GmbH, 50935 Cologne, Germany;
| | - Marianne Pavel
- Department of Endocrinology, Universitatsklinikum Erlangen, 91054 Erlangen, Germany;
| | - Michael Hummel
- Institute of Pathology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany; (R.A.); (K.J.); (H.L.); (M.H.)
- Central Biobank, Berlin Institute of Health, 10178 Berlin, Germany
| | - Daniel Kaemmerer
- Department of General and Visceral Surgery, Zentralklinik Bad Berka, 99437 Bad Berka, Germany;
| | - Richard P. Baum
- CURANOSTICUM Wiesbaden-Frankfurt in der DKD HELIOS Klinik, 65191 Wiesbaden, Germany;
| | - Patricia Grabowski
- Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany; (L.H.M.); (C.S.); (F.B.); (P.G.)
- Institute of Medical Immunology, Campus Virchow Klinikum, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
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In Reply. Oncologist 2020; 25:e1259. [DOI: 10.1634/theoncologist.2020-0336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 04/20/2020] [Indexed: 11/17/2022] Open
Abstract
This letter to the editor responds to commentary on the recently reported PALBONET trial results, which focused on the role of Palbociclib in patients with low-grade pancreatic neuroendocrine tumors.
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Mpilla GB, Philip PA, El-Rayes B, Azmi AS. Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations. World J Gastroenterol 2020; 26:4036-4054. [PMID: 32821069 PMCID: PMC7403797 DOI: 10.3748/wjg.v26.i28.4036] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/10/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are known to be the second most common epithelial malignancy of the pancreas. PNETs can be listed among the slowest growing as well as the fastest growing human cancers. The prevalence of PNETs is deceptively low; however, its incidence has significantly increased over the past decades. According to the American Cancer Society's estimate, about 4032 (> 7% of all pancreatic malignancies) individuals will be diagnosed with PNETs in 2020. PNETs often cause severe morbidity due to excessive secretion of hormones (such as serotonin) and/or overall tumor mass. Patients can live for many years (except for those patients with poorly differentiated G3 neuroendocrine tumors); thus, the prevalence of the tumors that is the number of patients actually dealing with the disease at any given time is fairly high because the survival is much longer than pancreatic ductal adenocarcinoma. Due to significant heterogeneity, the management of PNETs is very complex and remains an unmet clinical challenge. In terms of research studies, modest improvements have been made over the past decades in the identification of potential oncogenic drivers in order to enhance the quality of life and increase survival for this growing population of patients. Unfortunately, the majority of systematic therapies approved for the management of advanced stage PNETs lack objective response or at most result in modest benefits in survival. In this review, we aim to discuss the broad challenges associated with the management and the study of PNETs.
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Affiliation(s)
- Gabriel Benyomo Mpilla
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
| | - Philip Agop Philip
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
| | - Bassel El-Rayes
- Department of Hematology Oncology, Emory Winship Institute, Atlanta, GA 30322, United States
| | - Asfar Sohail Azmi
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
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Forkhead box M1 transcription factor: a novel target for pulmonary arterial hypertension therapy. World J Pediatr 2020; 16:113-119. [PMID: 31190319 DOI: 10.1007/s12519-019-00271-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 05/23/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Forkhead box M1 (FoxM1), a member of forkhead family, plays a key role in carcinogenesis, progression, invasion, metastasis and drug resistance. Based on the similarities between cancer and pulmonary arterial hypertension, studies on the roles and mechanisms of FoxM1 in pulmonary arterial hypertension have been increasing. This article aims to review recent advances in the mechanisms of signal transduction associated with FoxM1 in pulmonary arterial hypertension. DATA SOURCES Articles were retrieved from PubMed and MEDLINE published after 1990, including-but not limited to-FoxM1 and pulmonary arterial hypertension. RESULTS FoxM1 is overexpressed in pulmonary artery smooth muscle cells in both pulmonary arterial hypertension patients and animal models, and promotes pulmonary artery smooth muscle cell proliferation and inhibits cell apoptosis via regulating cell cycle progression. Multiple signaling molecules and pathways, including hypoxia-inducible factors, transforming growth factor-β/Smad, SET domain-containing 3/vascular endothelial growth factor, survivin, cell cycle regulatory genes and DNA damage response network, are reported to cross talk with FoxM1 in pulmonary arterial hypertension. Proteasome inhibitors are effective in the prevention and treatment of pulmonary arterial hypertension by inhibiting the expression and transcriptional activity of FoxM1. CONCLUSIONS FoxM1 has a crucial role in the pathogenesis of pulmonary arterial hypertension and may represent a novel therapeutic target. But more details of interaction between FoxM1 and other signaling pathways need to be clarified in the future.
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Ai C, Zhang J, Lian S, Ma J, Győrffy B, Qian Z, Han Y, Feng Q. FOXM1 functions collaboratively with PLAU to promote gastric cancer progression. J Cancer 2020; 11:788-794. [PMID: 31949481 PMCID: PMC6959008 DOI: 10.7150/jca.37323] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/04/2019] [Indexed: 12/24/2022] Open
Abstract
Background: Gastric cancer (GC) is one of the main mortality cause worldwide. Previously, we found Forkhead box protein (FOXM1) or Urokinase-type plasminogen activator (PLAU) are independent prognostic markers of GC. This study aims to explore the combining prognostic efficacy and the potential insights underlying additive effect of FOXM1 to PLAU in GC progression through in-silico analyses. Method: The expression of FOXM1 and PLAU were profiled in 33 cancer types using public data. A merged GC expression dataset containing 598 samples was used for evaluating prognostic significance of FOXM1/PLAU. Gene Set Enrichment Analysis (GSEA) was performed to elucidate the mechanisms underlying FOXM1/PLAU promoted GC progression. The Cancer Genome Atlas (TCGA) was used for analyzing the association between FOXM1/PLAU and tumor immune infiltration. Genomic and proteomic differences between FOXM1+PLAU+ and FOXM1-PLAU- groups were also computed using TCGA GC data. Drugs targeting FOXM1/PLAU associated gene expression pattern was analyzed using LINCs database. Results: FOXM1 and PLAU are overexpressed in 17/33 cancer types including GC. Kaplan-Meier analyses indicate that the FOXM1+PLAU+ subgroup have the worst prognosis, while FOXM1-PLAU- subgroup have the best survival. Bioinformatics analysis indicated that FOXM1+PLAU+ associated genes are enriched in TGF-beta, DNA repair and drug resistance signaling pathways; FOXM1 and PLAU expression are negatively correlated with tumor immune infiltration. Genomic and proteomic differences between FOXM1+PLAU+ and FOXM1-PLAU- groups were presented. Data mining from LINCs suggested several chemicals or drugs that could target the gene expression pattern of FOXM1+PLAU+ patients. Conclusion: FOXM1+PLAU+ can serve as effective prognostic biomarkers and potential therapeutic targets for GC. Due to the additive effect of these two genes, screening for drugs or chemicals that targeting the expression patterns PLAU+FOXM1+ subgroup may exert important clinical impact on GC management.
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Affiliation(s)
- Chao Ai
- Department of Pharmacy, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, P. R. China
| | - Jixin Zhang
- Department of Pathology, Peking University First Hospital, Beijing, China
| | - Shenyi Lian
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital &Institute, Beijing, China
| | - Jie Ma
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
| | - Balázs Győrffy
- Momentum Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Budapest, H-1117, Hungary; Second Department of Pediatrics, Semmelweis University, Budapest, H-1094, Hungary
| | - Zhenyuan Qian
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
| | - Yong Han
- Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
| | - Qin Feng
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital &Institute, Beijing, China
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Gastroenteropancreatic neuroendocrine neoplasms and inflammation: A complex cross-talk with relevant clinical implications. Crit Rev Oncol Hematol 2019; 146:102840. [PMID: 31918344 DOI: 10.1016/j.critrevonc.2019.102840] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 11/21/2019] [Accepted: 11/23/2019] [Indexed: 02/07/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are a group of tumors originating from the neuroendocrine system. They mainly occur in the digestive system and the respiratory tract. It is well-know a strict interaction between neuroendocrine system and inflammation, which can play an important role in NEN carcinogenesis. Inflammatory mediators, which are produced by the tumor microenvironment, can favor cancer induction and progression, and can promote immune editing. On the other hand, a balanced immune system represents a relevant step in cancer prevention through the elimination of dysplastic and cancer cells. Therefore, an inflammatory response may be both pro- and anti-tumorigenic. In this review, we provide an overview concerning the complex interplay between inflammation and gastroenteropancreatic NENs, focusing on the tumorigenesis and clinical implications in these tumors.
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Chen P, Wang Q, Xie J, Kwok HF. Signaling networks and the feasibility of computational analysis in gastroenteropancreatic neuroendocrine tumors. Semin Cancer Biol 2019; 58:80-89. [DOI: 10.1016/j.semcancer.2019.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/25/2019] [Accepted: 04/29/2019] [Indexed: 12/22/2022]
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Pereira SS, Pereira R, Santos AP, Costa MM, Morais T, Sampaio P, Machado B, Afonso LP, Henrique R, Monteiro MP. Higher IL-6 peri-tumoural expression is associated with gastro-intestinal neuroendocrine tumour progression. Pathology 2019; 51:593-599. [DOI: 10.1016/j.pathol.2019.07.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 07/05/2019] [Accepted: 07/11/2019] [Indexed: 12/28/2022]
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12
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FoxM1 promotes epithelial-mesenchymal transition, invasion, and migration of tongue squamous cell carcinoma cells through a c-Met/AKT-dependent positive feedback loop. Anticancer Drugs 2018; 29:216-226. [PMID: 29360662 PMCID: PMC5821477 DOI: 10.1097/cad.0000000000000585] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Supplemental Digital Content is available in the text. Forkhead box protein M1 (FoxM1) has been associated with cancer progression and metastasis. However, the function of FoxM1 in tongue squamous cell carcinoma (TSCC) remains largely unknown. The purpose of this study was to determine the role of FoxM1 in regulation of epithelial–mesenchymal transition (EMT) and migration of TSCC cells. We found that FoxM1 induced EMT and increased invasion/migration capacity in SCC9 and SCC25 cells. FoxM1 stimulation increased c-Met, pAKT, and vimentin levels but decreased E-cadherin level. Chromatin immunoprecipitation assay established that FoxM1 is bound to the promoter of c-Met to activate its transcription. In turn, c-Met promoted the expression of FoxM1 and pAKT. Blocking AKT signaling attenuated the invasion and migration of SCC9 and SCC25 cells stimulated by FoxM1 or c-Met. These results indicate that a positive feedback loop controls the EMT and migration of TSCC cells induced by FoxM1 and c-Met through AKT. Furthermore, the expression levels of FoxM1, pAKT, and c-Met were found to significantly increase in TSCC tissues compared with normal tissues, and these three biomarkers were concomitantly expressed in TSCC tissues. Clinical association analyses indicated that the expression of FoxM1, c-Met, and pAKT was associated with clinicopathological characteristics of patients with TSCC including tumor stage, tumor size, and lymph node metastasis. Taken together, our findings suggest that FoxM1 promotes the EMT, invasion and migration of TSCC cells, and cross-talks with c-Met/AKT signaling to form a positive feedback loop to promote TSCC development.
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13
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Han S, Ma X, Zhao Y, Zhao H, Batista A, Zhou S, Zhou X, Yang Y, Wang T, Bi J, Xia Z, Bai Z, Garkavtsev I, Zhang Z. Identification of Glypican-3 as a potential metastasis suppressor gene in gastric cancer. Oncotarget 2018; 7:44406-44416. [PMID: 27259271 PMCID: PMC5190106 DOI: 10.18632/oncotarget.9763] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 05/23/2016] [Indexed: 01/07/2023] Open
Abstract
Gastric cancer is a prevalent tumor that is usually detected at an advanced metastatic stage. Currently, standard therapies are mostly ineffective. Here, we report that Glypican-3 (GPC3) is absent in invasive tumors and metastatic lymph nodes, in particular in aggressive and highly disseminated signet ring cell carcinomas. We demonstrate that loss of GPC3 correlates with poor overall survival in patients. Moreover, we show that absence of GPC3 causes up-regulation of MAPK/FoxM1 signaling and that blockade of this pathway alters cellular invasion. An inverse correlation between GPC3 and FoxM1 is also shown in patient samples. These data identify GPC3 as a potential metastasis suppressor gene and suggest its value as a prognostic marker in gastric cancer. Development of therapies targeting signaling downstream of GPC3 are warranted.
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Affiliation(s)
- Shiwei Han
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Xuemei Ma
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yanxia Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongying Zhao
- Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Ana Batista
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Sheng Zhou
- Institute of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaona Zhou
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yao Yang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Tingting Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Jingtao Bi
- Department of General Surgery, Beijing Jishuitan Hospital, The Fourth Medical College of Peking University, Beijing, China
| | - Zheng Xia
- Department of Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Zhigang Bai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Igor Garkavtsev
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China
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14
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Wang Y, Zhang W, Wen L, Yang H, Wen M, Yun Y, Zhao L, Zhu X, Tian L, Luo E, Li Y, Liu W, Wen N. FOXM1 confers resistance to gefitinib in lung adenocarcinoma via a MET/AKT-dependent positive feedback loop. Oncotarget 2018; 7:59245-59259. [PMID: 27494877 PMCID: PMC5312309 DOI: 10.18632/oncotarget.11043] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 07/18/2016] [Indexed: 12/15/2022] Open
Abstract
Gefitinib resistance remains a major problem in the treatment of lung adenocarcinoma. However, the molecular mechanisms of gefitinib resistance are not fully understood. In this study, we characterized the critical role of transcription factor Forkhead box protein M1 (FOXM1) in gefitinib resistance of lung adenocarcinoma cells. In vitro drug sensitivity assays demonstrated that FOXM1 inhibition sensitized PC9/GR and HCC827/GR cells to gefitinib, whereas FOXM1 overexpression enhanced PC9 and HCC827 cell resistance to gefitinib. Increased FOXM1 resulted in the upregulation of hepatocyte growth factor receptor (MET), which led to activation of the protein kinase B (AKT) pathway, whereas knockdown of FOXM1 did the opposite. FOXM1 bound directly to the MET promoter regions and regulated the promoter activities and the expression of MET at the transcriptional level. Moreover, MET/AKT pathway upregulated the expression of FOXM1 in lung adenocarcinoma cells. Inhibition of pAKT by LY294002 or inhibition of pMET by PHA-665752 significantly inhibited the expression of FOXM1 in lung adenocarcinoma cells. Importantly, we further demonstrated that the expression levels of FOXM1, pAKT and MET were significantly increased in lung adenocarcinoma tissues relative to normal lung tissues, and these three biomarkers were concomitantly overexpressed in lung adenocarcinoma tissues. Taken together, our results indicate that FOXM1 promotes acquired resistance to gefitinib of lung adenocarcinoma cells, and FOXM1 crosstalks with MET/AKT signaling to form a positive feedback loop to promote lung adenocarcinoma development.
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Affiliation(s)
- Yu Wang
- Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.,Institute of Stomatology, Chinese PLA General Hospital, Beijing, China
| | - Weiwei Zhang
- Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Li Wen
- Institute of Stomatology, Chinese PLA General Hospital, Beijing, China
| | - Huiling Yang
- Institute of Stomatology, Chinese PLA General Hospital, Beijing, China
| | - Mingling Wen
- Department of Pharmacy, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
| | - Yuyu Yun
- State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lisheng Zhao
- Institute of Stomatology, Chinese PLA General Hospital, Beijing, China
| | - Xiaofei Zhu
- Department of Neurology, Kunming General Hospital, Chinese People's Liberation Army, Kunming, Yunnan, China
| | - Li Tian
- Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Erping Luo
- Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yu Li
- State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wenchao Liu
- Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ning Wen
- Institute of Stomatology, Chinese PLA General Hospital, Beijing, China
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15
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Luo X, Yao J, Nie P, Yang Z, Feng H, Chen P, Shi X, Zou Z. FOXM1 promotes invasion and migration of colorectal cancer cells partially dependent on HSPA5 transactivation. Oncotarget 2018; 7:26480-95. [PMID: 27034162 PMCID: PMC5041994 DOI: 10.18632/oncotarget.8419] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 03/04/2016] [Indexed: 12/18/2022] Open
Abstract
In this study, to investigate whether endoplastic reticulum (ER) stress correlated with FOXM1 in colorectal cancer, we analysed the mRNA levels of FOXM1 and ER stress markers HSPA5 and spliced XBP1 by qRT-PCR. FOXM1 mRNA levels were found to positively correlate with HSPA5 in colorectal cancer. However, no significant correlation between FOXM1 and spliced XBP1 mRNA levels was found. Theses results suggested the positive correlation between FOXM1 and HSPA5 in colorectal cancer was not associated with ER stress. Next, we provided evidences that FOXM1 promoted HSPA5 transcription by directly binding to and stimulating HSPA5 promoter. Moreover, a FOXM1-binding site mapped between -1019 and -1012 bp of the proximal HSPA5 promoter was identified. In addition, we found that enhancement of cell migration and invasion by FOXM1 was significantly attenuated by depletion of HSPA5 in colorectal cancer cell. Furthermore, FOXM1 triggered colorectal cancer cell migration and invasion was involved in activities of cell-surface HSPA5. Lastly, our results suggested FOXM1 facilitated the activities and expressions of MMP2 and 9 associated with cell-surface HSPA5 in colorectal cancer cells. Moreover, statistically significant positive correlations between FOXM1 and MMP2 mRNA expression, between HSPA5 and MMP2 were found in colorectal cancer tissue specimens. Together, our results suggested that FOXM1-HSPA5 signaling might be considered as a novel molecular target for designing novel therapeutic regimen to control colorectal cancer metastasis and progression.
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Affiliation(s)
- Xiaoyong Luo
- Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Jinke Yao
- Department of General Surgery, Boji-Affiliated Hospital (Zengcheng People's Hospital), Sun Yat-Sen University, Guangzhou, China
| | - Peipei Nie
- KingMed Diagnostics and KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China
| | - Zhiyuan Yang
- Department of Medcine, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Hongbo Feng
- Department of Medcine, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Pinjia Chen
- Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Xinpeng Shi
- Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Zhengzhi Zou
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, College of Biophotonics, South China Normal University, Guangzhou, China
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16
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Abdeljaoued S, Bettaieb L, Nasri M, Adouni O, Goucha A, Bouzaiene H, Boussen H, Rahal K, Gamoudi A. Forkhead box M1 (FOXM1) expression predicts disease free survival and may mediate resistance to chemotherapy and hormonotherapy in male breast cancer. Breast Dis 2018; 37:109-114. [PMID: 29504520 DOI: 10.3233/bd-170315] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
BACKGROUND Male breast cancer (MBC) is a rare and neglected disease. Prognostic and predictive factors in MBC are extrapoled from trials conducted on its female counterpart. OBJECTIVE Since the relationship between the transcription factor Forkhead box M1 (FOXM1) expression and the clinical response to chemotherapy and hormonotherapy in MBC remains unknown, we sought to investigate the predictive value of FOXM1 in MBC. METHODS FOXM1 expression was assessed in 130 MBC cases. Clinical significance was analyzed by Kaplan Meier curves, log-rank test and multivariate Cox regression analyses. RESULTS Patients with high FOXM1 expression had a significantly lower response rate to chemotherapy (P = 0.045) and hormonotherapy (P = 0.029) than those with low FOXM1 expression. Multivariate analyses indicated that FOXM1 was an independent prognostic factor for disease free survival in MBC patients (P < 0.001). CONCLUSIONS FOXM1 may have a reliable predictive significance in male breast cancer and thus may become an important target for male breast cancer therapy in the near future.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents/therapeutic use
- Antineoplastic Agents, Hormonal/therapeutic use
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Breast Neoplasms, Male/drug therapy
- Breast Neoplasms, Male/genetics
- Breast Neoplasms, Male/pathology
- Breast Neoplasms, Male/surgery
- Disease-Free Survival
- Drug Resistance, Neoplasm/genetics
- Forkhead Box Protein M1/genetics
- Forkhead Box Protein M1/metabolism
- Gene Expression Regulation, Neoplastic
- Genetic Association Studies
- Humans
- Kaplan-Meier Estimate
- Male
- Middle Aged
- Prognosis
- Tamoxifen/therapeutic use
- Tunisia
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Affiliation(s)
- Syrine Abdeljaoued
- Department of Immuno-Histo-Cytology, Salah Azaïz Cancer Institute, Bab Saadoun, 1006 Tunis, Tunisia
| | - Lhem Bettaieb
- Department of Immuno-Histo-Cytology, Salah Azaïz Cancer Institute, Bab Saadoun, 1006 Tunis, Tunisia
| | - Meher Nasri
- Department of Medical Oncology, Salah Azaïz Cancer Institute, Bab Saadoun, 1006 Tunis, Tunisia
| | - Olfa Adouni
- Department of Immuno-Histo-Cytology, Salah Azaïz Cancer Institute, Bab Saadoun, 1006 Tunis, Tunisia
| | - Aida Goucha
- Department of Immuno-Histo-Cytology, Salah Azaïz Cancer Institute, Bab Saadoun, 1006 Tunis, Tunisia
| | - Hatem Bouzaiene
- Department of Surgical Oncology, Salah Azaïz Cancer Institute, Bab Saadoun, 1006 Tunis, Tunisia
| | - Hamouda Boussen
- Department of Oncology, Abderrahmen Mami Hospital, 2080 Ariana, Tunisia
| | - Khaled Rahal
- Department of Surgical Oncology, Salah Azaïz Cancer Institute, Bab Saadoun, 1006 Tunis, Tunisia
| | - Amor Gamoudi
- Department of Immuno-Histo-Cytology, Salah Azaïz Cancer Institute, Bab Saadoun, 1006 Tunis, Tunisia
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17
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Egawa M, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Furuta K, Kamada Y, Chatani N, Hamano M, Kiso S, Hikita H, Tatsumi T, Eguchi H, Nagano H, Doki Y, Mori M, Takehara T. Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma. Hepatol Res 2017; 47:1196-1205. [PMID: 28002884 DOI: 10.1111/hepr.12854] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 09/29/2016] [Accepted: 12/19/2016] [Indexed: 02/08/2023]
Abstract
AIM Forkhead Box M1 (FoxM1) is a proliferation-specific transcription factor. In this study, we aimed to elucidate the clinicopathological and prognostic values of FoxM1 expression in human hepatocellular carcinoma (HCC) and correlate FoxM1 expression with various etiologies of liver diseases. We also investigated its therapeutic value in HCC. METHODS We investigated the expression of FoxM1 in tumor tissues and adjacent non-tumor tissues of 79 Japanese HCC patients by quantitative real-time reverse transcription-polymerase chain reaction analysis. Depletion by siRNA or specific inhibition by siomycin A were also used to investigate the effect of FoxM1 inhibition on stem-like features of human HCC cells. RESULTS Quantitative real-time reverse transcription-polymerase chain reaction analysis showed that tumor tissues displayed an approximately 14-fold increase in FoxM1 expression compared with adjacent non-tumor tissues. Interestingly, the expression levels of FoxM1in tumor tissues did not depend on the etiology of liver disease. The expression of FoxM1 in tumor tissues was associated with serum α-fetoprotein level, maximum tumor size, histological grade, TNM staging, and portal involvement. Kaplan-Meier analysis indicated that the high FoxM1 expression (≥median) group had a poor prognosis compared with the low FoxM1 expression (<median) group. Using multivariate analysis, the expression of FoxM1 in tumor tissues was shown to be an independent prognostic factor that affected overall survival and disease-free survival. Furthermore, FoxM1 inhibition by siRNA or siomycin A reduced spheroid colony formation of HCC cells in vitro. CONCLUSION Our data suggest that FoxM1 might be a prognostic biomarker and a promising therapeutic target for HCC.
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Affiliation(s)
- Mayumi Egawa
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | - Satoshi Ogura
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | | | - Takashi Kizu
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | | | - Yoshihiro Kamada
- Department of Gastroenterology and Hepatology, Osaka, Japan.,Department of Molecular Biochemistry and Clinical Investigation, Osaka, Japan
| | | | - Mina Hamano
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | - Shinichi Kiso
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka, Japan
| | | | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Nagano
- Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
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18
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Taromi S, Lewens F, Arsenic R, Sedding D, Sänger J, Kunze A, Möbs M, Benecke J, Freitag H, Christen F, Kaemmerer D, Lupp A, Heilmann M, Lammert H, Schneider CP, Richter K, Hummel M, Siegmund B, Burger M, Briest F, Grabowski P. Proteasome inhibitor bortezomib enhances the effect of standard chemotherapy in small cell lung cancer. Oncotarget 2017; 8:97061-97078. [PMID: 29228593 PMCID: PMC5722545 DOI: 10.18632/oncotarget.21221] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 08/04/2017] [Indexed: 12/26/2022] Open
Abstract
Small cell lung cancer (SCLC) is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In this study we investigated the role of FOXM1 in SCLC progression and analyzed the effect of FOXM1 inhibition using two proteasome inhibitors, bortezomib and siomycin A. FOXM1 was strongly expressed in patient-derived SCLC samples (n=123) and its nuclear localization was associated with the proliferation marker Ki-67. Both proteasome inhibitors successfully inhibited FOXM1 expression leading to a significantly reduced proliferation and a decreased mitotic rate along with cell cycle arrest and apoptosis induction. These effects were further enhanced by addition of bortezomib to standard chemotherapy. Treatment of mice bearing chemoresistant SCLC xenografts with bortezomib reduced the mean bioluminescence signal of tumors by 54%. Similarly, treatment with cisplatin as a standard chemotherapy reduced the mean bioluminescence signal of tumors by 58%. However, in combination with standard chemotherapy bortezomib further reduced the mean bioluminescence signal by 93% (p=0.0258). In conclusion, we demonstrate the effect of bortezomib in inhibiting FOXM1 expression and thus in sensitizing resistant SCLC cells to standard chemotherapy. Thus, addition of bortezomib to standard chemotherapy might potently improve SCLC therapy, particularly in an extensive cancer stage.
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Affiliation(s)
- Sanaz Taromi
- Department of Medicine, Division of Hematology and Oncology, University Medical Center, Freiburg, Germany
| | - Florentine Lewens
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité-Universitätsmedizin, Berlin, Germany
| | - Ruza Arsenic
- Institute of Pathology, Charité-Universitätsmedizin, Berlin, Germany
| | - Dagmar Sedding
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité-Universitätsmedizin, Berlin, Germany
| | | | | | - Markus Möbs
- Institute of Pathology, Charité-Universitätsmedizin, Berlin, Germany
| | - Joana Benecke
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité-Universitätsmedizin, Berlin, Germany
| | - Helma Freitag
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité-Universitätsmedizin, Berlin, Germany.,Department of Medical Immunology, Charité Universitätsmedizin, Berlin, Germany
| | - Friederike Christen
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité-Universitätsmedizin, Berlin, Germany.,Institute of Biology, Humboldt-Universität, Berlin, Germany
| | - Daniel Kaemmerer
- Department of General and Visceral Surgery, Zentralklinik Bad Berka GmbH, Bad Berka, Germany
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Mareike Heilmann
- Department for Oncology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany
| | - Hedwig Lammert
- Institute of Pathology, Charité-Universitätsmedizin, Berlin, Germany
| | | | - Karen Richter
- Department for Oncology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany
| | - Michael Hummel
- Institute of Pathology, Charité-Universitätsmedizin, Berlin, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité-Universitätsmedizin, Berlin, Germany
| | - Meike Burger
- Department of Medicine, Division of Hematology and Oncology, University Medical Center, Freiburg, Germany
| | - Franziska Briest
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité-Universitätsmedizin, Berlin, Germany.,Department of Chemistry and Biochemistry, Freie Universität (FU), Berlin, Germany.,Department of Gastroenterology and Endocrinology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany
| | - Patricia Grabowski
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité-Universitätsmedizin, Berlin, Germany.,Department of Gastroenterology and Endocrinology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany.,Department of Medical Immunology, Charité Universitätsmedizin, Berlin, Germany
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19
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Freitag H, Christen F, Lewens F, Grass I, Briest F, Iwaszkiewicz S, Siegmund B, Grabowski P. Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease. Neuroendocrinology 2017; 105:90-104. [PMID: 27513674 PMCID: PMC5475233 DOI: 10.1159/000448843] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 08/02/2016] [Indexed: 01/17/2023]
Abstract
BACKGROUND The characteristic clinical heterogeneity and mostly slow-growing behavior of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) cause problems in finding appropriate treatments. Thus, the current therapy options are not satisfactory. PKI-587 is a highly potent, novel dual inhibitor of PI3K and mTORC1/C2. AIM We assessed the effects of PKI-587 in different GEP-NEN tumor models, including the poorly differentiated cell line LCC-18, and compared them with those of the established mTORC1 inhibitor everolimus. METHODS We treated BON, QGP-1, KRJ-I, and LCC-18 cell lines with increasing concentrations of the inhibitor PKI-587, and compared the results with those of everolimus and DMSO. We assessed the impact of the treatments on viability (WST-1 assay), on apoptotic processes (caspase 3/7 assay, JC-1), and on cell cycle regulation (flow cytometry). We determined alterations in signaling mediators by phosphor-specific Western blot analysis and conducted multiplexed gene expression analysis (nCounter® technology). RESULTS In all cell lines, PKI-587 dose-dependently inhibited proliferation, whereas everolimus was less effective. Treatment with PKI-587 led to cell cycle arrest and induction of apoptosis and successfully suppressed activity of the direct mTORC1 target 4E-BP1, a crucial factor for tumor genesis only partially inhibited by everolimus. Gene expression analyses revealed relevant changes of RAS, MAPK, STAT, and PI3K pathway genes after treatment. Treatment-dependent and cell line-characteristic effects on AKT/Rb/E2F signaling regarding cell cycle control and apoptosis are extensively discussed in this paper. CONCLUSION PI3K/mTOR dual targeting is a promising new therapeutic approach in neuroendocrine tumor disease that should be evaluated in further clinical trials.
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Affiliation(s)
- Helma Freitag
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité - Universitätsmedizin Berlin, Germany
| | - Friederike Christen
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité - Universitätsmedizin Berlin, Germany
- Institute of Biology, Humboldt-Universität Berlin, Berlin, Germany
| | - Florentine Lewens
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité - Universitätsmedizin Berlin, Germany
| | - Irina Grass
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité - Universitätsmedizin Berlin, Germany
- Department of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Franziska Briest
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité - Universitätsmedizin Berlin, Germany
- Department of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Sara Iwaszkiewicz
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité - Universitätsmedizin Berlin, Germany
- Institute of Biology, Humboldt-Universität Berlin, Berlin, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité - Universitätsmedizin Berlin, Germany
| | - Patricia Grabowski
- Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité - Universitätsmedizin Berlin, Germany
- Department of Gastroenterology and Endocrinology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany
- *Patricia Grabowski, Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, DE-12203 Berlin (Germany), E-Mail
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Sayanjali B, Christensen GJ, Al-Zeer MA, Mollenkopf HJ, Meyer TF, Brüggemann H. Propionibacterium acnes inhibits FOXM1 and induces cell cycle alterations in human primary prostate cells. Int J Med Microbiol 2016; 306:517-528. [DOI: 10.1016/j.ijmm.2016.06.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 06/17/2016] [Accepted: 06/27/2016] [Indexed: 12/29/2022] Open
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Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets. Mod Pathol 2016; 29:616-29. [PMID: 26965582 DOI: 10.1038/modpathol.2016.48] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 01/31/2016] [Accepted: 01/31/2016] [Indexed: 02/07/2023]
Abstract
We wanted to define the transcriptome of small intestinal neuroendocrine tumors in order to identify clinically relevant subgroups of tumors, prognostic markers and novel targets for treatment. Genome-wide expression profiling was conducted on tumor biopsies from 33 patients with well-differentiated neuroendocrine tumors of the distal ileum and metastatic disease at the time of diagnosis. Unsupervised hierarchical clustering analysis identified three groups of tumors. The largest group, comprising half of the tumors, was characterized by longer patient survival and higher expression of neuroendocrine markers, including SSTR2. Tumors with higher grade (G2/3) or gain of chromosome 14 were associated with shorter patient survival and increased expression of cell cycle-promoting genes. Pathway analysis predicted the prostaglandin E receptor 2 (PTGER2) as the most significantly activated regulator in tumors of higher grade, whereas Forkhead box M1 (FOXM1) was the most significantly activated regulator in tumors with gain of chromosome 14. Druggable genes identified from expression profiles included clinically proven SSTR2 and also novel targets, for example, receptor tyrosine kinases (RET, FGFR1/3, PDGFRB and FLT1), epigenetic regulators, molecular chaperones and signal transduction molecules. Evaluation of candidate drug targets on neuroendocrine tumors cells (GOT1) showed significant inhibition of tumor cell growth after treatment with tyrosine kinase inhibitors or inhibitors of HDAC, HSP90 and AKT. In conclusion, we have defined the transcriptome of small intestinal neuroendocrine tumors and identified novel subgroups with clinical relevance. We found specific gene expression patterns associated with tumor grade and chromosomal alterations. Our data also suggest novel prognostic biomarkers and therapies for these patients.
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Li Z. [Classification and clinicopathological characteristics of gastroenteropancreatic neuroendocrine neoplasms]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2016; 45:10-23. [PMID: 27045236 PMCID: PMC10397099 DOI: 10.3785/j.issn.1008-9292.2016.01.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 01/10/2016] [Indexed: 06/05/2023]
Abstract
Gastroenteropancreatic neuroendocrine neoplasms are a rare, heterogeneous group of neoplasms. The incidence has increased greatly during the past 40 years, partially due to the advanced endoscopic and imaging techniques. As a type of neoplasm with the specific morphology and immunophenotype, its nomenclature and classification have also been changed considerably over the past 40 years, from the past "carcinoid" to the current "neuroendocrine neoplasm". WHO currently recommends two-tiered classification, neuroendocrine tumors and neuroendocrine cancer, according to the differentiation, morphology and proliferation index. However, the neoplasms from different sites have different phenotypes, biological behaviors, and accordingly the different staging systems for the indication on prognosis and therapy selection. Recent research indicates that the tumor from different sites could express different molecular markers which are useful for the further study of molecular features, as well as the evaluation of the site of primary tumor. Along with the progress of the research on molecular mechanisms, including signal transduction, epigenetics and tumor microenviroment, the mode of diagnosis and treatment would also be changed accordingly. In this article, new advances in classification, clinical and pathological features and molecular mechanism of gastroenteropancreatic neuroendocrine neoplasms will be reviewed.
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