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Yazdani A, Lenz HJ, Pillonetto G, Mendez-Giraldez R, Yazdani A, Sanoff H, Hadi R, Samiei E, Venook AP, Ratain MJ, Rashid N, Vincent BG, Qu X, Wen Y, Kosorok M, Symmans WF, Shen JPYC, Lee MS, Kopetz S, Nixon AB, Bertagnolli MM, Perou CM, Innocenti F. Gene signatures derived from transcriptomic-causal networks stratify colorectal cancer patients for effective targeted therapy. COMMUNICATIONS MEDICINE 2025; 5:9. [PMID: 39779996 PMCID: PMC11711454 DOI: 10.1038/s43856-024-00728-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Gene signatures derived from transcriptomic-causal networks offer potential for tailoring clinical care in cancer treatment by identifying predictive and prognostic biomarkers. This study aimed to uncover such signatures in metastatic colorectal cancer (CRC) patients to aid treatment decisions. METHODS We constructed transcriptomic-causal networks and integrated gene interconnectivity into overall survival (OS) analysis to control for confounding genes. This integrative approach involved germline genotype and tumor RNA-seq data from 1165 metastatic CRC patients. The patients were enrolled in a randomized clinical trial receiving either cetuximab or bevacizumab in combination with chemotherapy. An external cohort of paired CRC normal and tumor samples, along with protein-protein interaction databases, was used for replication. RESULTS We identify promising predictive and prognostic gene signatures from pre-treatment gene expression profiles. Our study discerns sets of genes, each forming a signature that collectively contribute to define patient subgroups with different prognosis and response to the therapies. Using an external cohort, we show that the genes influencing OS within the signatures, such as FANCI and PRC1, are upregulated in CRC tumor vs. normal tissue. These signatures are highly associated with immune features, including macrophages, cytotoxicity, and wound healing. Furthermore, the corresponding proteins encoded by the genes within the signatures interact with each other and are functionally related. CONCLUSIONS This study underscores the utility of gene signatures derived from transcriptomic-causal networks in patient stratification for effective therapies. The interpretability of the findings, supported by replication, highlights the potential of these signatures to identify patients likely to benefit from cetuximab or bevacizumab.
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Affiliation(s)
- Akram Yazdani
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- University of Texas Health Science Center at Houston, Texas, TX, USA.
| | | | | | - Raul Mendez-Giraldez
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC, USA
| | - Azam Yazdani
- Center of Perioperative Genetics and Genomics, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hanna Sanoff
- Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Reza Hadi
- School of Mathematics, University of Science and Technology of Iran, Tehran, Iran
| | | | - Alan P Venook
- University of California at San Francisco, San Francisco, CA, USA
| | - Mark J Ratain
- Division of the Biological Sciences, University of Chicago, Chicago, IL, USA
| | - Naim Rashid
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, US
| | - Benjamin G Vincent
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, USA
| | - Xueping Qu
- Genentech, South San Francisco, San Francisco, CA, USA
| | - Yujia Wen
- Alliance for Clinical Trials in Oncology, Chicago, IL, USA
| | - Michael Kosorok
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, US
| | - William F Symmans
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John Paul Y C Shen
- Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael S Lee
- Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Scott Kopetz
- Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew B Nixon
- Duke Center for Cancer Immunotherapy, Duke University, Durham, NC, USA
| | | | - Charles M Perou
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Federico Innocenti
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Rodríguez-Lescure Á, Gallego J, Garcia-Alfonso P, Massuti B, Márquez R, Calvo L, Sánchez-Rovira P, Antón A, Chacón JI, Ciruelos E, Ponce JJ, Santaballa A, Valladares-Ayerbes M, Dueñas MR, Alonso V, Aparicio J, Encinas S, Robles L, Escudero MJ, Caballero R, Bezares S, de la Haba-Rodriguez J. Hypertension as predictive factor for bevacizumab-containing first-line therapy in metastatic breast and colorectal cancer in BRECOL (GEICAM/2011-04) study. Clin Transl Oncol 2024; 26:1896-1907. [PMID: 38578537 PMCID: PMC11249439 DOI: 10.1007/s12094-024-03411-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 02/16/2024] [Indexed: 04/06/2024]
Abstract
BACKGROUND Retrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT. METHODS This prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels. RESULTS From Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy. CONCLUSIONS Neither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy. CLINICAL TRIAL REGISTRY ClinicalTrials.gov Identifier: NCT01733628.
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Affiliation(s)
- Álvaro Rodríguez-Lescure
- Medical Oncology Department, Hospital General Universitario de Elche, Carrer Almazara, 11, 03203, Elche, Alicante, Spain.
- GEICAM Spanish Breast Cancer Group, Madrid, Spain.
| | - Javier Gallego
- Medical Oncology Department, Hospital General Universitario de Elche, Carrer Almazara, 11, 03203, Elche, Alicante, Spain
| | - Pilar Garcia-Alfonso
- Instituto de Investigación Sanitaria Gregorio Marañón, Facultad de Medicina de la Universidad Complutense de Madrid, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Bartomeu Massuti
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital General Universitario Dr. Balmis, Alicante, Spain
| | - Raúl Márquez
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
- MD Anderson Cancer Center Madrid, Madrid, Spain
| | - Lourdes Calvo
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
- Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain
| | - Pedro Sánchez-Rovira
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
- Hospital Universitario de Jaén, Jaén, Spain
| | - Antonio Antón
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
- Instituto de Investigación Sanitaria de Aragón (IISA), Hospital Universitario Miguel Servet, Universidad de Zaragoza, Saragossa, Spain
| | - José Ignacio Chacón
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
- Hospital Universitario de Toledo, Toledo, Spain
| | - Eva Ciruelos
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
- Hospital Universitario, 12 de Octubre, Madrid, Spain
| | - Jose Juan Ponce
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital General Universitario Dr. Balmis, Alicante, Spain
| | - Ana Santaballa
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
- Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Manuel Valladares-Ayerbes
- Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Seville, Spain
| | | | - Vicente Alonso
- Instituto de Investigación Sanitaria de Aragón (IISA), Hospital Universitario Miguel Servet, Universidad de Zaragoza, Saragossa, Spain
| | - Jorge Aparicio
- Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | | | - Luis Robles
- Hospital Universitario, 12 de Octubre, Madrid, Spain
| | | | | | | | - Juan de la Haba-Rodriguez
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
- Instituto Maimónides de Investigación Biomédica (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
- Oncology Biomedical Research National Network (CIBERONC-ISCIII), Madrid, Spain
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Yu Z, Zhang Q, Wei S, Zhang Y, Zhou T, Zhang Q, Shi R, Zinovkin D, Pranjol ZI, Zhang J, Wang H. CD146 +CAFs promote progression of endometrial cancer by inducing angiogenesis and vasculogenic mimicry via IL-10/JAK1/STAT3 pathway. Cell Commun Signal 2024; 22:170. [PMID: 38459564 PMCID: PMC10921754 DOI: 10.1186/s12964-024-01550-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 03/01/2024] [Indexed: 03/10/2024] Open
Abstract
Heterogeneous cancer-associated fibroblasts (CAFs) play important roles in cancer progression. However, the specific biological functions and regulatory mechanisms involved in endometrial cancer have yet to be elucidated. We aimed to explore the potential mechanisms of heterogeneous CAFs in promoting endometrial cancer progression. The presence of melanoma cell adhesion molecule (MCAM; CD146) positive CAFs was confirmed by tissue multi-immunofluorescence (mIF), and fluorescence activated cell sorting (FACS). The biological functions were determined by wound healing assays, tuber formation assays and cord formation assays. The effects of CD146+CAFs on endometrial cancer cells were studied in vitro and in vivo. The expression level of interleukin 10 (IL-10) was measured by quantitative real time polymerase chain reaction (qRT-PCR), western boltting and enzyme linked immunosorbent assays (ELISAs). In addition, the transcription factor STAT3 was identified by bioinformatics methods and chromatin immunoprecipitation (ChIP). A subtype of CAFs marked with CD146 was found in endometrial cancer and correlated with poor prognosis. CD146+CAFs promoted angiogenesis and vasculogenic mimicry (VM) in vitro. A xenograft tumour model also showed that CD146+CAFs can facilitate tumour progression. The expression of IL-10 was elevated in CD146+CAFs. IL-10 promoted epithelial-endothelial transformation (EET) and further VM formation in endometrial cancer cells via the janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) signalling pathway. This process could be blocked by the JAK1/STAT3 inhibitor niclosamide. Mechanically, STAT3 can bind to the promoter of cadherin5 (CDH5) to promote its transcription which may be stimulated by IL-10. We concluded that CD146+CAFs could promote angiogenesis and VM formation via the IL-10/JAK1/STAT3 signalling pathway. These findings may lead to the identification of potential targets for antiangiogenic therapeutic strategies for endometrial cancers.
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Affiliation(s)
- Zhicheng Yu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, People's Republic of China
| | - Qian Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Sitian Wei
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yang Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Ting Zhou
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Qi Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Rui Shi
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Dmitry Zinovkin
- Department of Pathology, Gomel State Medical University, Gomel, Republic of Belarus
| | - Zahidul Islam Pranjol
- Department of Biochemistry, School of Life Sciences, University of Sussex, Falmer, UK
| | - Jun Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
| | - Hongbo Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
- Clinical Research Center of Cancer Immunotherapy, Wuhan, Hubei, People's Republic of China.
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Murphy AD, Morgan RD, Clamp AR, Jayson GC. The role of vascular endothelial growth factor inhibitors in the treatment of epithelial ovarian cancer. Br J Cancer 2022; 126:851-864. [PMID: 34716396 PMCID: PMC8927157 DOI: 10.1038/s41416-021-01605-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 09/21/2021] [Accepted: 10/13/2021] [Indexed: 12/09/2022] Open
Abstract
Advanced epithelial ovarian, fallopian tube and primary peritoneal cancers (EOC) are a leading cause of gynaecological cancer-associated mortality and angiogenesis plays a key role in their growth. Vascular endothelial growth factor inhibitors (VEGFi) disrupt angiogenesis and improve the response rate, progression-free survival and in some cases, overall survival, when administered with and following cytotoxic chemotherapy, irrespective of the platinum sensitivity of EOC. Recent data have identified new indications for VEGFi in EOC: repeated exposure to VEGFi in the first- and then second-line treatment has sustained clinical efficacy; combinations of VEGFi with poly (ADP-ribose) polymerase inhibitors (PARPi) have proven effective as first-line or second-line maintenance regimens. However, recent trial data have not shown improved outcomes with combinations of VEGFi and immune checkpoint inhibitors. There remains a critical need to optimise patient selection for these effective yet somewhat toxic and expensive treatments. The search continues for validated biomarkers to optimise the use of VEGFi, of which the most promising at present is plasma Tie2. Based upon these studies, we propose a model of care incorporating VEGFi into the treatment of EOC, highlighting the need to change from the prescription of single courses of VEGFi, to allow use and re-use as clinically indicated.
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Affiliation(s)
| | - Robert D Morgan
- The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
- Division of Cancer Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - Andrew R Clamp
- The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
- Division of Cancer Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - Gordon C Jayson
- The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
- Division of Cancer Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
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The Brain Penetrating and Dual TORC1/TORC2 Inhibitor, RES529, Elicits Anti-Glioma Activity and Enhances the Therapeutic Effects of Anti-Angiogenetic Compounds in Preclinical Murine Models. Cancers (Basel) 2019; 11:cancers11101604. [PMID: 31640252 PMCID: PMC6826425 DOI: 10.3390/cancers11101604] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 10/07/2019] [Accepted: 10/17/2019] [Indexed: 12/13/2022] Open
Abstract
Background. Glioblastoma multiforme (GBM) is a devastating disease showing a very poor prognosis. New therapeutic approaches are needed to improve survival and quality of life. GBM is a highly vascularized tumor and as such, chemotherapy and anti-angiogenic drugs have been combined for treatment. However, as treatment-induced resistance often develops, our goal was to identify and treat pathways involved in resistance to treatment to optimize the treatment strategies. Anti-angiogenetic compounds tested in preclinical and clinical settings demonstrated recurrence associated to secondary activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Aims. Here, we determined the sensitizing effects of the small molecule and oral available dual TORC1/TORC2 dissociative inhibitor, RES529, alone or in combination with the anti-VEGF blocking antibody, bevacizumab, or the tyrosine kinase inhibitor, sunitinib, in human GBM models. Results. We observed that RES529 effectively inhibited dose-dependently the growth of GBM cells in vitro counteracting the insurgence of recurrence after bevacizumab or sunitinib administration in vivo. Combination strategies were associated with reduced tumor progression as indicated by the analysis of Time to Tumor Progression (TTP) and disease-free survival (DSF) as well as increased overall survival (OS) of tumor bearing mice. RES529 was able to reduce the in vitro migration of tumor cells and tubule formation from both brain-derived endothelial cells (angiogenesis) and tumor cells (vasculogenic mimicry). Conclusions. In summary, RES529, the first dual TORC1/TORC2 dissociative inhibitor, lacking affinity for ABCB1/ABCG2 and having good brain penetration, was active in GBM preclinical/murine models giving credence to its use in clinical trial for patients with GBM treated in association with anti-angiogenetic compounds.
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Sánchez Ramírez J, Bequet-Romero M, Morera Díaz Y, Hernández-Bernal F, Ayala Avila M. Does VEGF-targeted active immunotherapy induce complete abrogation of platelet VEGF levels? BMC Res Notes 2019; 12:323. [PMID: 31182141 PMCID: PMC6558718 DOI: 10.1186/s13104-019-4368-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 06/05/2019] [Indexed: 01/09/2023] Open
Abstract
OBJECTIVES Vascular endothelial growth factor (VEGF) is involved in physiological angiogenesis, but also is considered one of the key factors that promotes tumor angiogenesis. CIGB-247 is a VEGF-based vaccine that has been evaluated in phase I clinical trial patients with advanced solid tumors. This specific active immunotherapy is able to reduce platelet VEGF levels; however it is unknown whether this effect leads to a decrease in VEGF below the levels that can be observed in healthy individuals. The objective of the present study is to investigate platelet VEGF levels in cancer patients vaccinated with CIGB-247, and then compare these values with those obtained in healthy individuals. To achieve this, platelet VEGF levels of 62 cancer patients and 93 healthy individuals were compared. Cancer patients were those individuals recruited in CENTAURO and CENTAURO-2 clinical trials. RESULTS Before vaccination, platelets of cancer patients carried more VEGF than the levels seen in platelet of healthy individuals. However, after vaccination, cancer patients had platelet VEGF values within the range established by healthy individuals, indicating that the antibody response elicited by CIGB-247 is not able to induce a complete suppression of VEGF. Vaccination with CIGB-247 helps to normalize VEGF levels within platelets.
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Affiliation(s)
- Javier Sánchez Ramírez
- Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Ave 31 e/158 y 190, Playa, P.O. Box 6162, Havana, Cuba.
| | - Mónica Bequet-Romero
- Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Ave 31 e/158 y 190, Playa, P.O. Box 6162, Havana, Cuba
| | - Yanelys Morera Díaz
- Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Ave 31 e/158 y 190, Playa, P.O. Box 6162, Havana, Cuba
| | - Francisco Hernández-Bernal
- Department of Clinical Research, Center for Genetic Engineering and Biotechnology, Ave 31 e/158 y 190, Playa, P.O. Box 6162, Havana, Cuba
| | - Marta Ayala Avila
- Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Ave 31 e/158 y 190, Playa, P.O. Box 6162, Havana, Cuba
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Wang FT, Sun W, Zhang JT, Fan YZ. Cancer-associated fibroblast regulation of tumor neo-angiogenesis as a therapeutic target in cancer. Oncol Lett 2019; 17:3055-3065. [PMID: 30867734 PMCID: PMC6396119 DOI: 10.3892/ol.2019.9973] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 12/21/2018] [Indexed: 12/20/2022] Open
Abstract
Adequate blood supply is essential for tumor survival, growth and metastasis. The tumor microenvironment (TME) is dynamic and complex, comprising cancer cells, cancer-associated stromal cells and their extracellular products. The TME serves an important role in tumor progression. Cancer-associated fibroblasts (CAFs) are the principal component of stromal cells within the TME, and contribute to tumor neo-angiogenesis by altering the proteome and degradome. The present paper reviews previous studies of the molecular signaling pathways by which CAFs promote tumor neo-angiogenesis and highlights therapeutic response targets. Also discussed are potential strategies for antitumor neo-angiogenesis to improve tumor treatment efficacy.
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Affiliation(s)
- Fang-Tao Wang
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Wei Sun
- Department of Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Jing-Tao Zhang
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Yue-Zu Fan
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
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Graziani G, Ruffini F, Tentori L, Scimeca M, Dorio AS, Atzori MG, Failla CM, Morea V, Bonanno E, D'Atri S, Lacal PM. Antitumor activity of a novel anti-vascular endothelial growth factor receptor-1 monoclonal antibody that does not interfere with ligand binding. Oncotarget 2018; 7:72868-72885. [PMID: 27655684 PMCID: PMC5341950 DOI: 10.18632/oncotarget.12108] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 09/12/2016] [Indexed: 11/29/2022] Open
Abstract
Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase transmembrane receptor that has also a soluble isoform containing most of the extracellular ligand binding domain (sVEGFR-1). VEGF-A binds to both VEGFR-2 and VEGFR-1, whereas placenta growth factor (PlGF) interacts exclusively with VEGFR-1. In this study we generated an anti-VEGFR-1 mAb (D16F7) by immunizing BALB/C mice with a peptide that we had previously reported to inhibit angiogenesis and endothelial cell migration induced by PlGF. D16F7 did not affect binding of VEGF-A or PlGF to VEGFR-1, thus allowing sVEGFR-1 to act as decoy receptor for these growth factors, but it hampered receptor homodimerization and activation. D16F7 inhibited both the chemotactic response of human endothelial, myelomonocytic and melanoma cells to VEGFR-1 ligands and vasculogenic mimicry by tumor cells. Moreover, D16F7 exerted in vivo antiangiogenic effects in a matrigel plug assay. Importantly, D16F7 inhibited tumor growth and was well tolerated by B6D2F1 mice injected with syngeneic B16F10 melanoma cells. The antitumor effect was associated with melanoma cell apoptosis, vascular abnormalities and decrease of both monocyte/macrophage infiltration and myeloid progenitor mobilization. For all the above, D16F7 may be exploited in the therapy of metastatic melanoma and other tumors or pathological conditions involving VEGFR-1 activation.
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Affiliation(s)
- Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Federica Ruffini
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy
| | - Lucio Tentori
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Manuel Scimeca
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Annalisa S Dorio
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | | | - Cristina M Failla
- Laboratory of Experimental Immunology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy
| | - Veronica Morea
- National Research Council of Italy (CNR), Institute of Molecular Biology and Pathology, Rome, Italy
| | - Elena Bonanno
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Stefania D'Atri
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy
| | - Pedro M Lacal
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy
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9
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Atzori MG, Tentori L, Ruffini F, Ceci C, Bonanno E, Scimeca M, Lacal PM, Graziani G. The Anti-Vascular Endothelial Growth Factor Receptor-1 Monoclonal Antibody D16F7 Inhibits Glioma Growth and Angiogenesis In Vivo. J Pharmacol Exp Ther 2018; 364:77-86. [PMID: 29025978 DOI: 10.1124/jpet.117.244434] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 10/10/2017] [Indexed: 03/08/2025] Open
Abstract
The vascular endothelial growth factor (VEGF) receptor-1 (VEGFR-1) is a tyrosine kinase receptor that does not play a relevant role in physiologic angiogenesis in adults, whereas it is important in tumor angiogenesis. In high-grade glioma VEGFR-1 expression by tumor endothelium and neoplastic cells contributes to the aggressive phenotype. We recently generated an anti-VEGFR-1 monoclonal antibody (D16F7 mAb) characterized by a novel mechanism of action, since it hampers receptor activation without interfering with ligand binding. The mAb is able to inhibit chemotaxis and extracellular matrix invasion of glioma cells in vitro stimulated by VEGF-A and by the VEGFR-1-selective ligand placental growth factor (PlGF). In this study, we have investigated the influence of D16F7 on glioma growth and angiogenesis in vivo using C6 glioma cells transfected with the human VEGFR-1. D16F7 was able to inhibit receptor activation and migration and extracellular matrix invasion of C6 cells overexpressing the receptor in response to PlGF and VEGF-A. In nude mice, treatment with 10 and 20 mg/kg D16F7 as a single agent was well tolerated and significantly inhibited glioma growth (P < 0.001). Strikingly, in an intracranial orthotopic model, mice dosed with 20 mg/kg D16F7 demonstrated a 65% increase in median survival time compared with vehicle-treated controls (P < 0.001) with a high percentage of long-term survivors (46%). These effects were associated with glioma cell apoptosis and decreased tumor-associated vessel formation. Overall, these results highlight the therapeutic potential of D16F7 in glioma treatment, deserving further investigation after a humanization process as single agent or in combination therapies.
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Affiliation(s)
- Maria Grazia Atzori
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Lucio Tentori
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Federica Ruffini
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Claudia Ceci
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Elena Bonanno
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Manuel Scimeca
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Pedro Miguel Lacal
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Grazia Graziani
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
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Atzori MG, Tentori L, Ruffini F, Ceci C, Lisi L, Bonanno E, Scimeca M, Eskilsson E, Daubon T, Miletic H, Ricci Vitiani L, Pallini R, Navarra P, Bjerkvig R, D'Atri S, Lacal PM, Graziani G. The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:106. [PMID: 28797294 PMCID: PMC5553938 DOI: 10.1186/s13046-017-0577-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 08/02/2017] [Indexed: 01/09/2023]
Abstract
BACKGROUND Glioblastoma (GBM) is a highly migratory, invasive, and angiogenic brain tumor. Like vascular endothelial growth factor-A (VEGF-A), placental growth factor (PlGF) promotes GBM angiogenesis. VEGF-A is a ligand for both VEGF receptor-1 (VEGFR-1) and VEGFR-2, while PlGF interacts exclusively with VEGFR-1. We recently generated the novel anti-VEGFR-1 monoclonal antibody (mAb) D16F7 that diminishes VEGFR-1 homodimerization/activation without affecting VEGF-A and PlGF binding. METHODS In the present study, we evaluated the expression of VEGFR-1 in human GBM tissue samples (n = 42) by immunohistochemistry, in cell lines (n = 6) and GBM stem cells (GSCs) (n = 18) by qRT-PCR and/or western blot analysis. In VEGFR-1 positive GBM or GSCs we also analyzed the ability of D16F7 to inhibit GBM invasiveness in response to VEGF-A and PlGF. RESULTS Most of GBM specimens stained positively for VEGFR-1 and all but one GBM cell lines expressed VEGFR-1. On the other hand, in GSCs the expression of the receptor was heterogeneous. D16F7 reduced migration and invasion of VEGFR-1 positive GBM cell lines and patient-derived GSCs in response to VEGF-A and PlGF. Interestingly, this effect was also observed in VEGFR-1 positive GSCs transfected to over-express wild-type EGFR (EGFRwt+) or mutant EGFR (ligand binding domain-deficient EGFRvIII+). Furthermore, D16F7 suppressed intracellular signal transduction in VEGFR-1 over-expressing GBM cells by reducing receptor auto-phosphorylation at tyrosine 1213 and downstream Erk1/2 activation induced by receptor ligands. CONCLUSION The results from this study suggest that VEGFR-1 is a relevant target for GBM therapy and that D16F7-derived humanized mAbs warrant further investigation.
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Affiliation(s)
- Maria Grazia Atzori
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Lucio Tentori
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Federica Ruffini
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Via dei Monti di Creta, 104, 00167, Rome, Italy
| | - Claudia Ceci
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Lucia Lisi
- Istituto di Farmacologia, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italia
| | - Elena Bonanno
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Manuel Scimeca
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Eskil Eskilsson
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Thomas Daubon
- INSERM U1029, University of Bordeaux, Pessac, France.,Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Lucia Ricci Vitiani
- Department of Hematology, Oncology and Molecular Medicine, "Istituto Superiore di Sanità" (ISS), Rome, Italy
| | - Roberto Pallini
- Department of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Pierluigi Navarra
- Istituto di Farmacologia, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italia.,UOC di Farmacologia, Fondazione Policlinico Universitario Agostino Gemelli, Largo Francesco Vito 1, 00168, Roma, Italia
| | - Rolf Bjerkvig
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Stefania D'Atri
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Via dei Monti di Creta, 104, 00167, Rome, Italy
| | - Pedro Miguel Lacal
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Via dei Monti di Creta, 104, 00167, Rome, Italy.
| | - Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
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11
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Wang Z, You D, Lu M, He Y, Yan S. Inhibitory effect of norcantharidin on melanoma tumor growth and vasculogenic mimicry by suppressing MMP-2 expression. Oncol Lett 2017; 13:1660-1664. [PMID: 28454306 PMCID: PMC5403267 DOI: 10.3892/ol.2017.5622] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 09/09/2016] [Indexed: 12/18/2022] Open
Abstract
A form of microcirculation called vasculogenic mimicry (VM), which constitutes a novel approach for tumor blood supply in certain highly aggressive malignant tumors, was recently reported to contribute to tumor metastasis and poor prognosis in melanoma patients. Development of strategies to target tumor VM may be significant to reduce the recurrence and metastasis of melanoma. Norcantharidin (NCTD) has been shown to inhibit tumor growth and VM of human gallbladder carcinomas. Besides, NCTD could induce melanoma cell apoptosis. However, whether NCTD can inhibit the growth and VM formation of melanoma has not been evaluated. The present study aims to investigate the anti-VM activity of NCTD as a VM inhibitor for melanoma and its potential mechanisms. The anti-VM activity of NCTD was determined in human melanoma A375 cells and xenografts in vitro and in vivo. The findings indicate that NCTD inhibits tumor growth and VM formation of melanoma both in vitro and in vivo by suppressing matrix metalloproteinase-2 expression. The results suggest that NCTD is a potential therapeutic agent targeting VM in melanoma.
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Affiliation(s)
- Zhenyu Wang
- Biomedical Engineering Research Center, Kunming Medical University, Yunnan, Kunming 650500, P.R. China
| | - Dingyun You
- Department of Science and Technology, Kunming Medical University, Yunnan, Kunming 650500, P.R. China
| | - Minnan Lu
- Experimental Center for Medical Science Research, Kunming Medical University, Yunnan, Kunming 650500, P.R. China
| | - Yuefeng He
- School of Public Health, Kunming Medical University, Yunnan, Kunming 650500, P.R. China
| | - Shan Yan
- Institute of Molecular and Clinical Medicine, Kunming Medical University, Yunnan, Kunming 650500, P.R. China
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Abstract
Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The most commonly studied adnectin is CT-322, which is an inhibitor of vascular endothelial growth factor receptor-2. A bispecific adnectin, El-Tandem, has also been developed and binds to epidermal growth factor receptor and insulin-like growth factor-1 receptor simultaneously. Pre-clinical studies have shown promising results in relation to reducing tumor growth, decreasing microvessel density, and promoting normalization of tumor architecture. The phase I trial with CT-322 demonstrates relatively low toxicities. However, the phase II study done with CT-322 in recurrent glioblastoma does not reveal as promising results.
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Affiliation(s)
- Esha Sachdev
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA,
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Konda B, Shum H, Rajdev L. Anti-angiogenic agents in metastatic colorectal cancer. World J Gastrointest Oncol 2015; 7:71-86. [PMID: 26191351 PMCID: PMC4501927 DOI: 10.4251/wjgo.v7.i7.71] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 05/13/2015] [Accepted: 06/01/2015] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a major public health concern being the third leading cause of cancer mortality in the United States. The availability of better therapeutic options has led to a decline in cancer mortality in these patients. Surgical resection should be considered in all stages of the disease. The use of conversion therapy has made surgery a potentially curative option even in patients with initially unresectable metastatic disease. In this review we discuss the role of various anti-angiogenic agents in patients with metastatic CRC (mCRC). We describe the mechanism of action of these agents, and the rationale for their use in combination with chemotherapy. We also review important clinical studies that have evaluated the safety and efficacy of these agents in mCRC patients. Despite the discovery of several promising anti-angiogenic agents, mCRC remains an incurable disease with a median overall survival of just over 2 years in patients exposed to all available treatment regimens. Further insights into tumor biology and tumor microenvironment may help improve outcomes in these patients.
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Brandes AA, Bartolotti M, Tosoni A, Poggi R, Franceschi E. Practical management of bevacizumab-related toxicities in glioblastoma. Oncologist 2015; 20:166-75. [PMID: 25568148 DOI: 10.1634/theoncologist.2014-0330] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Bevacizumab, currently an option for treatment of different types of tumors including glioblastoma, has a peculiar toxicity profile related to its antiangiogenic effect. Because some bevacizumab-related adverse events can be life threatening, it is important to identify risk factors and to establish treatment protocols to minimize treatment-related morbidity and mortality. In glioblastoma patients, the risk of developing certain side effects, such as gastrointestinal perforation, venous thromboembolism, and intracranial hemorrhages, is slightly higher than in patients treated with bevacizumab for other tumor types. We performed a systematic review of the side effects of bevacizumab and their incidence, causal mechanisms, and available treatments. Finally, we identified risk factors and proposed preventive and therapeutic measures for these adverse events.
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Affiliation(s)
- Alba A Brandes
- Department of Medical Oncology, Bellaria Hospital, Azienda USL - IRCCS Institute of Neurological Sciences, Bologna, Italy
| | - Marco Bartolotti
- Department of Medical Oncology, Bellaria Hospital, Azienda USL - IRCCS Institute of Neurological Sciences, Bologna, Italy
| | - Alicia Tosoni
- Department of Medical Oncology, Bellaria Hospital, Azienda USL - IRCCS Institute of Neurological Sciences, Bologna, Italy
| | - Rosalba Poggi
- Department of Medical Oncology, Bellaria Hospital, Azienda USL - IRCCS Institute of Neurological Sciences, Bologna, Italy
| | - Enrico Franceschi
- Department of Medical Oncology, Bellaria Hospital, Azienda USL - IRCCS Institute of Neurological Sciences, Bologna, Italy
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ZHU WEI, SUN WEI, ZHANG JINGTAO, LIU ZHONGYAN, LI XINPING, FAN YUEZU. Norcantharidin enhances TIMP-2 anti-vasculogenic mimicry activity for human gallbladder cancers through downregulating MMP-2 and MT1-MMP. Int J Oncol 2014; 46:627-40. [DOI: 10.3892/ijo.2014.2753] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 10/24/2014] [Indexed: 11/06/2022] Open
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Røsland GV, Engelsen AST. Novel points of attack for targeted cancer therapy. Basic Clin Pharmacol Toxicol 2014; 116:9-18. [PMID: 25154903 PMCID: PMC4309509 DOI: 10.1111/bcpt.12313] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 08/11/2014] [Indexed: 12/13/2022]
Abstract
New molecular insight reveals novel points of attack for targeted cancer therapy. The recent advances in cancer genomics and novel insight into the complex biology of cancer make the promise of personalized, targeted cancer medicine closer than ever. The massive parallel sequencing endeavours performed by The Cancer Genome Atlas, the International Cancer Genome Consortium and by numerous individual investigators have provided a comprehensive genomic characterization of a wide range of cancers. The joint efforts enabled by the improved sequencing technology have demonstrated that individual cancers comprise mutational repertoires with only a few frequently recurrent driver genes. Thus, the identification of new drug targets and novel drugs have accelerated and renewed the hopes of personalized cancer therapy achieving clinical reality for a wider range of cancers. Together with cost-effective sequencing technology to perform comprehensive mutational profiling of each individual cancer, this provides the basis for a personalized cancer medicine revolution within the next few years. The aim of this MiniReview is to provide an overview of the history and evolution of targeted cancer therapy, exemplified by molecularly targeted drugs successfully implemented in the clinic. Furthermore, we aim to highlight novel molecular targets for therapeutic intervention, as well as the main present challenges including inter- and intratumor heterogeneity and cellular plasticity in addition to the importance of the tumor micro-environment. Many cancer patients already receive some form of tailored therapy, and recent evidence suggests that novel and highly innovative, targeted approaches are on their way into the clinic.
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Wang H, Sun W, Zhang WZ, Ge CY, Zhang JT, Liu ZY, Fan YZ. Inhibition of tumor vasculogenic mimicry and prolongation of host survival in highly aggressive gallbladder cancers by norcantharidin via blocking the ephrin type a receptor 2/focal adhesion kinase/paxillin signaling pathway. PLoS One 2014; 9:e96982. [PMID: 24811250 PMCID: PMC4014585 DOI: 10.1371/journal.pone.0096982] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 04/14/2014] [Indexed: 01/15/2023] Open
Abstract
Vasculogenic mimicry (VM) is a newly-defined tumor microcirculation pattern in highly aggressive malignant tumors. We recently reported tumor growth and VM formation of gallbladder cancers through the contribution of the ephrin type a receptor 2 (EphA2)/focal adhesion kinase (FAK)/Paxillin signaling pathways. In this study, we further investigated the anti-VM activity of norcantharidin (NCTD) as a VM inhibitor for gallbladder cancers and the underlying mechanisms. In vivo and in vitro experiments to determine the effects of NCTD on tumor growth, host survival, VM formation of GBC-SD nude mouse xenografts, and vasculogenic-like networks, malignant phenotypes i.e., proliferation, apoptosis, invasion and migration of GBC-SD cells. Expression of VM signaling-related markers EphA2, FAK and Paxillin in vivo and in vitro were examined by immunofluorescence, western blotting and real-time polymerase chain reaction (RT-PCR), respectively. The results showed that after treatment with NCTD, GBC-SD cells were unable to form VM structures when injecting into nude mouse, growth of the xenograft was inhibited and these observations were confirmed by facts that VM formation by three-dimensional (3-D) matrix, proliferation, apoptosis, invasion, migration of GBC-SD cells were affected; and survival time of the xenograft mice was prolonged. Furthermore, expression of EphA2, FAK and Paxillin proteins/mRNAs of the xenografts was downregulated. Thus, we concluded that NCTD has potential anti-VM activity against human gallbladder cancers; one of the underlying mechanisms may be via blocking the EphA2/FAK/Paxillin signaling pathway.
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Affiliation(s)
- Hui Wang
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, P.R. China
| | - Wei Sun
- Department of Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Tongji University, Shanghai, P.R. China
| | - Wen-Zhong Zhang
- Department of Surgery, Shanghai Pudong New Area People's Hospital, Shanghai, P.R. China
| | - Chun-Yan Ge
- Department of Oncology, Shanghai Yangpu Geriatric Hospital, Shanghai, P.R. China
| | - Jing-Tao Zhang
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, P.R. China
| | - Zhong-Yan Liu
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, P.R. China
| | - Yue-Zu Fan
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, P.R. China
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Zhang JT, Sun W, Zhang WZ, Ge CY, Liu ZY, Zhao ZM, Lu XS, Fan YZ. Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway. BMC Cancer 2014; 14:193. [PMID: 24628713 PMCID: PMC3985599 DOI: 10.1186/1471-2407-14-193] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Accepted: 03/10/2014] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Vasculogenic mimicry (VM) is a novel tumor blood supply in some highly aggressive malignant tumors. Recently, we reported VM existed in gallbladder carcinomas (GBCs) and the formation of the special passage through the activation of the PI3K/MMPs/Ln-5γ2 signaling pathway. GBC is a highly aggressive malignant tumor with disappointing treatments and a poor prognosis. Norcantharidin (NCTD) has shown to have multiple antitumor activities against GBCs, etc; however the exact mechanism is not thoroughly elucidated. In this study, we firstly investigated the anti-VM activity of NCTD as a VM inhibitor for GBCs and its underlying mechanisms. METHODS In vitro and in vivo experiments to determine the effects of NCTD on proliferation, invasion, migration, VM formation, hemodynamic and tumor growth of GBC-SD cells and xenografts were respectively done by proliferation, invasion, migration assays, H&E staining and CD31-PAS double stainings, optic/electron microscopy, tumor assay, and dynamic micro-MRA. Further, immunohistochemistry, immunofluorescence, Western blotting and RT-PCR were respectively used to examine expression of VM signaling-related markers PI3-K, MMP-2, MT1-MMP and Ln-5γ2 in GBC-SD cells and xenografts in vitro and in vivo. RESULTS After treatment with NCTD, proliferation, invasion, migration of GBC-SD cells were inhibited; GBC-SD cells and xenografts were unable to form VM-like structures; tumor center-VM region of the xenografts exhibited a decreased signal in intensity; then cell or xenograft growth was inhibited. Whereas all of untreated GBC-SD cells and xenografts formed VM-like structures with the same conditions; the xenograft center-VM region exhibited a gradually increased signal; and facilitated cell or xenograft growth. Furthermore, expression of MMP-2 and MT1-MMP products from sections/supernates of 3-D matrices and the xenografts, and expression of PI3-K, MMP-2, MM1-MMP and Ln-5γ2 proteins/mRNAs of the xenografts were all decreased in NCTD or TIMP-2 group; (all P < 0.01, vs. control group); NCTD down-regulated expression of these VM signaling-related markers in vitro and in vivo. CONCLUSIONS NCTD inhibited tumor growth and VM of human GBCs in vitro and in vivo by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway. It is firstly concluded that NCTD may be a potential anti-VM agent for human GBCs.
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Affiliation(s)
| | | | | | | | | | | | | | - Yue-Zu Fan
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200065, P,R, China.
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Speyer CL, Hachem AH, Assi AA, Johnson JS, DeVries JA, Gorski DH. Metabotropic glutamate receptor-1 as a novel target for the antiangiogenic treatment of breast cancer. PLoS One 2014; 9:e88830. [PMID: 24633367 PMCID: PMC3954556 DOI: 10.1371/journal.pone.0088830] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 01/13/2014] [Indexed: 02/07/2023] Open
Abstract
Metabotropic glutamate receptors (mGluRs) are normally expressed in the central nervous system, where they mediate neuronal excitability and neurotransmitter release. Certain cancers, including melanoma and gliomas, express various mGluR subtypes that have been implicated as playing a role in disease progression. Recently, we detected metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in breast cancer and found that it plays a role in the regulation of cell proliferation and tumor growth. In addition to cancer cells, brain endothelial cells express mGluR1. In light of these studies, and because angiogenesis is both a prognostic indicator in cancer correlating with a poorer prognosis and a potential therapeutic target, we explored a potential role for mGluR1 in mediating endothelial cell (EC) proliferation and tumor-induced angiogenesis. GRM1 and mGluR1 were detected in various types of human ECs and, using mGluR1-specific inhibitors or shRNA silencing, we demonstrated that EC growth and Matrigel tube formation are dependent on mGluR1 signaling. In addition, loss of mGluR1 activity leads to reduced angiogenesis in a murine Matrigel sponge implant model as well as a murine tumor model. These results suggest a role for mGluR1 in breast cancer as a pro-angiogenic factor as well as a mediator of tumor progression. They also suggest mGluR1 as a potential new molecular target for the anti-angiogenic therapy of breast cancer.
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Affiliation(s)
- Cecilia L. Speyer
- Tumor Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America
- Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan, United States of America
| | - Ali H. Hachem
- University of Michigan, Dearborn, Michigan, United States of America
| | - Ali A. Assi
- University of Michigan, Dearborn, Michigan, United States of America
| | - Jennifer S. Johnson
- Van Andel Research Institute, Grand Rapids, Michigan, United States of America
| | - John A. DeVries
- Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan, United States of America
| | - David H. Gorski
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America
- Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan, United States of America
- * E-mail:
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Lin J, Chen Y, Wei L, Hong Z, Sferra TJ, Peng J. Ursolic acid inhibits colorectal cancer angiogenesis through suppression of multiple signaling pathways. Int J Oncol 2013; 43:1666-1674. [PMID: 24042330 DOI: 10.3892/ijo.2013.2101] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 09/02/2013] [Indexed: 11/05/2022] Open
Abstract
Angiogenesis plays a critical role in the development of solid tumors by supplying nutrients and oxygen to support continuous growth of tumor as well as providing an avenue for hematogenous metastasis. Tumor angiogenesis is highly regulated by multiple intracellular signaling transduction cascades such as Hedgehog, STAT3, Akt and p70S6K pathways that are known to malfunction in many types of cancer including colorectal cancer (CRC). Therefore, suppression of tumor angiogenesis through targeting these signaling pathways has become a promising strategy for cancer chemotherapy. Ursolic acid (UA) is a major active compound present in many medicinal herbs that have long been used in China for the clinical treatment of various types of cancer. Although previous studies have demonstrated an antitumor effect for UA, the precise mechanisms of its anti-angiogenic activity are not well understood. To further elucidate the mechanism(s) of the tumorcidal activity of UA, using a CRC mouse xenograft model, chick embryo chorioallantoic membrane (CAM) model, the human colon carcinoma cell line HT-29 and human umbilical vein endothelial cells (HUVECs), in the present study we evaluated the efficacy of UA against tumor growth and angiogenesis in vivo and in vitro and investigated the underlying molecular mechanisms. We found that administration of UA significantly inhibited tumor volume but had no effect on body weight changes in CRC mice, suggesting that UA can suppress colon cancer growth in vivo without noticeable signs of toxicity. In addition, UA treatment reduced intratumoral microvessel density (MVD) in CRC mice, decreased the total number of blood vessels in the CAM model, and dose and time-dependently inhibited the proliferation, migration and tube formation of HUVECs, demonstrating UA's antitumor angiogenesis in vivo and in vitro. Moreover, UA treatment inhibited the expression of critical angiogenic factors, such as VEGF-A and bFGF. Furthermore, UA suppressed the activation of sonic hedgehog (SHH), STAT3, Akt and p70S6K pathways. Collectively, our findings suggest that inhibition of tumor angiogenesis via suppression of multiple signaling pathways might be one of the mechanisms whereby UA can be effective in cancer treatment.
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Affiliation(s)
- Jiumao Lin
- Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Minhou Shangjie, Fuzhou, Fujian 350122, P.R. China
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Islam R, Chyou PH, Burmester JK. Modeling efficacy of bevacizumab treatment for metastatic colon cancer. J Cancer 2013; 4:330-5. [PMID: 23678369 PMCID: PMC3654489 DOI: 10.7150/jca.6083] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2013] [Accepted: 04/23/2013] [Indexed: 01/21/2023] Open
Abstract
Purpose: Bevacizumab, an FDA-approved adjuvant treatment for metastatic colon cancer, has extended survival for many patients. However, factors predicting response to treatment remain undefined. Patients and Methods: Relevant clinical and environmental data were abstracted from medical records of 149 evaluable patients treated with bevacizumab for metastatic colon cancer at a multi-specialty clinic. Tumor response was calculated from radiologic reports using Response Evaluation Criteria in Solid Tumors (RECIST) criteria and verified by oncologist review. Patients with at least one occurrence of complete or partial response or stable disease were classified as responders; those exhibiting progressive disease were classified as non-responders. Results: Univariate analysis demonstrated that blood in stool (P<0.05), unexplained weight loss (P<0.05), primary colon cancer site (P<0.05), chemotherapy treatment of primary tumor site (P<0.05), and adenocarcinoma versus adenoma subtype (P<0.05) was associated with tumor responsiveness. Factors remaining statistically significant following multivariate modeling included adenocarcinoma as tumor cell type versus other adenocarcinoma subtypes (OR=6.35, 95% CI: 1.08-37.18), chemotherapy treatment applied to primary tumor (OR= 0.07, 95% CI: 0.0-0.76,), tumor localization to cecal/ascending colon (OR=0.061, 95% CI: 0.006-0.588,), and unexplained weight loss (OR=0.1, 95% CI: 0.02-0.56,). Chemotherapy treatment of primary tumor, unexplained weight loss, and cecal/ascending localization of the tumor were associated with poorer outcomes. Adenocarcinoma as cell type compared to other adenocarcinoma subtypes was associated with better response to bevacizumab treatment. Conclusion: Results suggest that response to bevacizumab therapy may be predicted by modeling clinical factors including symptomology on presentation, tumor location and type, and initial response to chemotherapy.
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Affiliation(s)
- Rezwan Islam
- 1. Department of Oncology/Hematology, Marshfield Clinic Weston Center, Marshfield, WI, USA
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22
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ZHAO RENPING, SUN LI, LIN SENSEN, BAI XIANSHU, YU BOYANG, YUAN SHENGTAO, ZHANG LUYONG. The saponin monomer of dwarf lilyturf tuber, DT-13, inhibits angiogenesis under hypoxia and normoxia via multi-targeting activity. Oncol Rep 2013; 29:1379-86. [DOI: 10.3892/or.2013.2272] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 11/26/2012] [Indexed: 11/05/2022] Open
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Lin J, Wei L, Shen A, Cai Q, Xu W, Li H, Zhan Y, Hong Z, Peng J. Hedyotis diffusa Willd extract suppresses Sonic hedgehog signaling leading to the inhibition of colorectal cancer angiogenesis. Int J Oncol 2013; 42:651-656. [PMID: 23291612 DOI: 10.3892/ijo.2012.1753] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2012] [Accepted: 12/07/2012] [Indexed: 11/06/2022] Open
Abstract
Sonic hedgehog (SHH) signaling pathway promotes the process of angiogenesis, contributing to the growth and progression of many human malignancies including colorectal cancer (CRC), which therefore has become a promising target for cancer chemotherapy. Hedyotis diffusa Willd (HDW), as a well-known traditional Chinese herbal medicine, has long been used in China for the clinic treatment of various cancers. Recently, we reported that HDW can inhibit colorectal cancer growth in vivo and in vitro via suppression of the STAT3 pathway. In addition, we demonstrated the anti-angiogenic activity of HDW in vitro. To further elucidate the mechanism of the tumoricidal activity of HDW, by using a CRC mouse xenograft model we evaluated the in vivo effect of the ethanol extract of HDW (EEHDW) on tumor angiogenesis, and investigated the underlying molecular mechanisms. We found that EEHDW could significantly reduce intratumoral microvessel density (MVD), indicating its activity of antitumor angiogenesis in vivo. EEHDW suppressed the activation of SHH signaling in CRC xenograft tumors since it significantly decreased the expression of key mediators of SHH pathway. EEHDW treatment inhibited the expression of the critical SHH signaling target gene VEGF-A as well as its specific receptor VEGFR2. Taken together, we propose for the first time that Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of SHH-mediated tumor angiogenesis.
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Affiliation(s)
- Jiumao Lin
- Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Minhou Shangjie, Fuzhou, Fujian 350122, P.R. China
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Eveno C, Contreres JO, Hainaud P, Nemeth J, Dupuy E, Pocard M. Netrin-4 overexpression suppresses primary and metastatic colorectal tumor progression. Oncol Rep 2012; 29:73-8. [PMID: 23124703 DOI: 10.3892/or.2012.2104] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 06/28/2012] [Indexed: 11/06/2022] Open
Abstract
Tumor angiogenesis is closely associated with clinical staging and has been proposed to correlate with clinical response in terms of subsequent metastases following primary resection. Netrin-4 (NT-4) regulates angiogenic responses. Therefore, we sought to examine the effects of NT-4 on the primary tumor growth of colon cancer cells, liver and lung metastases of colon cancer cells, and responses following primary tumor resection. We used 3 different mouse models of orthotopic primary tumor and liver and lung metastases, comparing 2 human colon cancer cells lines: wild-type (low expression of NT-4) and NT-4 (overexpression of NT-4) LS174 cells. NT-4 overexpression inhibited the primary tumor growth of colorectal LS174 xenografts in nude mice (144.3±12.9 vs. 62.4±4.5 mm3; p<0.0001) as well as its related local and systemic recurrence (38 vs. 0%; p<0.01). NT-4 overexpression also markedly decreased colorectal cancer progression in terms of tumor number and volume of liver metastases in the NT-4 group of the orthotopic liver metastasis model (25 vs. 90% and 4±1 vs. 709±190 mm3, p<0.001 and p<0.05). Collectively, our findings indicate that NT-4 overexpression decreases colorectal lung metastasis and its associated lymph node involvement. NT-4 overexpression decreases tumor recurrence and metastasis after surgical resection, likely via an anti-angiogenic effect. These observations suggest that NT-4 may hold therapeutic potential in the treatment of colorectal cancer growth and major metastatic sites.
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Affiliation(s)
- Clarisse Eveno
- INSERM U965 Angiogenesis and Translational Research, Department of Digestive Diseases, Paris Diderot, Paris 7 University, Lariboisière Hospital, AP-HP, 75010 Paris, France
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25
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Shen AL, Hong F, Liu LY, Lin JM, Zhuang QC, Hong ZF, Peng J. Effects of Pien Tze Huang on angiogenesis in vivo and in vitro. Chin J Integr Med 2012; 18:431-436. [PMID: 22821655 DOI: 10.1007/s11655-012-1121-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To investigate the anti-angiogenic effects of Pien Tze Huang in vivo and in vitro. METHODS Human umbilical vein endothelial cells (HUVECs) were treated with 0 mg/mL, 0.25 mg/mL, 0.5 mg/mL, and 1 mg/mL of PZH for 24 h, 48 h and 72 h, respectively. Chicken embryo chorioallantoic membrane (CAM) model was used to evaluate in vivo angiogenesis. An ECMatrix gel system was used to evaluate in vitro angiogenesis by examining the tube formation of HUVECs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to determine HUVEC viability. Cell density of HUVECs was observed by phase-contrast microscopy. HUVEC migration was determined by wound healing method. The mRNA and protein expression of vascular endothelial growth factor A (VEGF-A) and basic fibroblast growth factor (bFGF) in both HUVEC and human colon adenocarcinoma cells (HT-29) was examined by reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immune sorbent assay (ELISA), respectively. RESULTS PZH treatment significantly reduced the total number of blood vessels compared with the untreated control in the chicken embryos and resulted in a significant decrease in capillary tube formation and cell density of HUVECs (P<0.05). In addition, treatment with 0.25-1 mg/mL of PZH for 24 h, 48 h, and 72 h respectively reduced cell viability by 9%-52%, 24%-87% or 25%-87%, compared with the untreated control cells (P<0.05). Moreover, PZH treatment decreased the migration of HUVECs. Furthermore, PZH dose-dependently suppressed the expression of VEGF-A and bFGF on both mRNA and protein levels (P<0.05). CONCLUSION PZH could inhibit angiogenesis in vivo in CAM model and in vitro on HUVECs, suggesting that inhibiting tumor angiogenesis might be one of the mechanisms by which PZH treats cancer.
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Affiliation(s)
- A-ling Shen
- Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou (350108), China
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26
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Hamilton EP, Blackwell KL. Safety of bevacizumab in patients with metastatic breast cancer. Oncology 2011; 80:314-25. [PMID: 21778772 DOI: 10.1159/000328757] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2010] [Accepted: 04/09/2011] [Indexed: 12/14/2022]
Abstract
Five randomized phase III trials - AVF2119g, E2100, AVADO, RIBBON-1, and RIBBON-2 - have reported data on the efficacy and safety of bevacizumab, combined with a variety of chemotherapy agents and in various settings, in patients with metastatic breast cancer (MBC). The E2100 trial demonstrated a significant improvement in progression-free survival according to the independent review facility, from 5.8 to 11.3 months when bevacizumab was combined with paclitaxel (p < 0.0001) as first-line therapy in patients with HER2-nonamplified MBC; subsequent trials of bevacizumab as first-line (AVADO, RIBBON-1) and second-line (RIBBON-2) therapy for patients with HER2-nonamplified MBC have also met their primary end point of prolonging progression-free survival (PFS). Accumulating safety data for bevacizumab in MBC show that it is generally well tolerated and associated with predictable adverse events, including hypertension and proteinuria. The majority of adverse events are mild and manageable, but bevacizumab is also associated with some severe toxicities. The management of bevacizumab-related adverse events in MBC has improved with increased experience. This review summarizes bevacizumab efficacy in MBC and focuses on bevacizumab-related toxicities as reported in 5 phase III clinical trials. Current adverse event management strategies, based on guidelines and experience from these trials, are outlined.
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Abstract
Cancer immunotherapy consists of approaches that modify the host immune system, and/or the utilization of components of the immune system, as cancer treatment. During the past 25 years, 17 immunologic products have received regulatory approval based on anticancer activity as single agents and/or in combination with chemotherapy. These include the nonspecific immune stimulants BCG and levamisole; the cytokines interferon-α and interleukin-2; the monoclonal antibodies rituximab, ofatumumab, alemtuzumab, trastuzumab, bevacizumab, cetuximab, and panitumumab; the radiolabeled antibodies Y-90 ibritumomab tiuxetan and I-131 tositumomab; the immunotoxins denileukin diftitox and gemtuzumab ozogamicin; nonmyeloablative allogeneic transplants with donor lymphocyte infusions; and the anti-prostate cancer cell-based therapy sipuleucel-T. All but two of these products are still regularly used to treat various B- and T-cell malignancies, and numerous solid tumors, including breast, lung, colorectal, prostate, melanoma, kidney, glioblastoma, bladder, and head and neck. Positive randomized trials have recently been reported for idiotype vaccines in lymphoma and a peptide vaccine in melanoma. The anti-CTLA-4 monoclonal antibody ipilumumab, which blocks regulatory T-cells, is expected to receive regulatory approval in the near future, based on a randomized trial in melanoma. As the fourth modality of cancer treatment, biotherapy/immunotherapy is an increasingly important component of the anticancer armamentarium.
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Affiliation(s)
- Robert O Dillman
- Hoag Cancer Institute of Hoag Hospital , Newport Beach, California 92658, USA.
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Kümler I, Nielsen DL. Trials of bevacizumab in breast cancer – a safety review. Expert Opin Drug Saf 2011; 11 Suppl 1:S37-48. [DOI: 10.1517/14740338.2011.594038] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Iben Kümler
- University of Copenhagen, Herlev Hospital, Department of Oncology,
Herlev Ringvej 75, DK-2730, Herlev, Denmark ;
| | - Dorte Lisbet Nielsen
- University of Copenhagen, Herlev Hospital, Department of Oncology,
Herlev Ringvej 75, DK-2730, Herlev, Denmark ;
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Pistollato F, Abbadi S, Rampazzo E, Persano L, Della Puppa A, Frasson C, Sarto E, Scienza R, D'avella D, Basso G. Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem Cells 2010; 28:851-62. [PMID: 20309962 DOI: 10.1002/stem.415] [Citation(s) in RCA: 211] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Glioblastoma multiforme (GBM) are highly proliferative tumors currently treated by surgical removal, followed by radiotherapy and chemotherapy, which are counteracted by intratumoral hypoxia. Here we exploited image guided surgery to sample multiple intratumoral areas to define potential cellular heterogeneity in correlation to the oxygen tension gradient within the GBM mass. Our results indicate that more immature cells are localized in the inner core and in the intermediate layer of the tumor mass, whereas more committed cells, expressing glial fibrillary acidic protein and beta-III-tubulin, are distributed along the peripheral and neo-vascularized area, where Smad1/5/8 and Stat3 result to be activated. Moreover, GBM stem cells, identified with the stem cell marker CD133, express high level of DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) known to be involved in chemotherapy resistance and highly expressed in the inner core of the tumor mass. Importantly, these cells and, particularly, CD133(+) cells result to be resistant to temozolomide (TMZ), the most used oral alkylating agent for the treatment of GBM, which specifically causes apoptosis only in GBM cells derived from the peripheral layer of the tumor mass. These results indicate a correlation between the intratumoral hypoxic gradient, the tumor cell phenotype, and the tumor resistance to chemotherapy leading to a novel concentric model of tumor stem cell niche, which may be useful to define the real localization of the chemoresistant GBM tumor cells in order to design more effective treatment strategies.
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Affiliation(s)
- Francesca Pistollato
- Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, 3-35128 Padova, Italy.
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30
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Yang MY, Chaudhary A, Seaman S, Dunty J, Stevens J, Elzarrad MK, Frankel AE, St Croix B. The cell surface structure of tumor endothelial marker 8 (TEM8) is regulated by the actin cytoskeleton. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2010; 1813:39-49. [PMID: 21129411 DOI: 10.1016/j.bbamcr.2010.11.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Revised: 11/17/2010] [Accepted: 11/19/2010] [Indexed: 01/01/2023]
Abstract
Tumor endothelial marker 8 (TEM8) is an integrin-like cell surface protein upregulated on tumor blood vessels and a potential vascular target for cancer therapy. Here, we found that the ability of an anti-TEM8 antibody, clone SB5, to recognize the extracellular domain of TEM8 on the cell surface depends on other host-cell factors. By taking advantage of SB5's ability to distinguish different forms of cell surface TEM8, we identified alpha-smooth muscle actin and transgelin, an actin binding protein, as intracellular factors able to alter TEM8 cell surface structure. Overexpression of either of these proteins in cells converted TEM8 from an SB5-exposed to an SB5-masked form and protected cells from SB5-saporin immunotoxins. Because the predominant form of TEM8 on the cell surface is not recognized by SB5, we also developed a new monoclonal antibody, called AF334, which is able to recognize both the SB5-exposed and the SB5-masked forms of TEM8. AF334-saporin selectively killed TEM8-positive cells independent of TEM8 cell surface structure. These studies reveal that TEM8 exists in different forms at the cell surface, a structure dependent on interactions with components of the actin cytoskeleton, and should aid in the rational design of the most effective diagnostic and therapeutic anti-TEM8 monoclonal antibodies.
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Affiliation(s)
- Mi Young Yang
- National Cancer Institute, Frederick, MD 21702-1201, USA
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31
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Cheng G, Zhang L. [Adverse events related to bevacizumab and the management principles in non-small cell lung cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2010; 13:563-7. [PMID: 20681440 PMCID: PMC6015160 DOI: 10.3779/j.issn.1009-3419.2010.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Abstract
Angiogenesis has become an attractive target for drug therapy because of its key role in tumor growth. An extensive array of compounds is currently in preclinical development, with many now entering the clinic and/or achieving approval from the US Food and Drug Administration. Several regulatory and signaling molecules governing angiogenesis are of interest, including growth factors (eg, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor), receptor tyrosine kinases, and transcription factors such as hypoxia inducible factor, as well as molecules involved in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling. Pharmacologic agents have been identified that target these pathways, yet for some agents (notably thalidomide), an understanding of the specific mechanisms of antitumor action has proved elusive. The following review describes key molecular mechanisms and novel therapies that are on the horizon for antiangiogenic tumor therapy.
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Affiliation(s)
| | - William D. Figg
- To whom correspondence should be addressed: 10 Center Drive, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD 20892 USA Phone: 301-402-3622 Fax: 301-402-8606
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Korpanty G, Smyth E, Sullivan LA, Brekken RA, Carney DN. Antiangiogenic therapy in lung cancer: focus on vascular endothelial growth factor pathway. Exp Biol Med (Maywood) 2010; 235:3-9. [PMID: 20404013 DOI: 10.1258/ebm.2009.009191] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Lung cancer (LC) is a leading cause of death worldwide. Recent advances in chemotherapeutic agents have not yielded any significant improvement in the prognosis of patients with LC. The five-year survival rate for all combined disease stages remains about 15%. For this reason, new therapies such as those that inhibit tumor angiogenesis or block activity of growth factor receptors are of special interest in this group of patients. In this review we will summarize the most recent clinical data on biologic therapies that inhibit tumor angiogenesis in LC, focusing on those that are most clinically relevant.
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Affiliation(s)
- Grzegorz Korpanty
- Department of Medical Oncology, Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland.
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Abstract
Bevacizumab is a recombinant humanized monoclonal IgG(1) antibody that binds to human vascular endothelial growth factor and inhibits angiogenesis and hence tumour growth. It is available in the US and other countries for the treatment of several types of cancer, including glioblastoma that has recurred after previous treatment. Two prospective phase II trials have evaluated bevacizumab 10 mg/kg every 2 weeks for the treatment of previously treated glioblastoma. In the randomized, noncomparative, multicentre AVF3708g trial in patients with glioblastoma in first or second relapse, the rate of progression-free survival at 6 months was 42.6% and the objective response rate was 28.2% in recipients of bevacizumab alone (n = 85). In the bevacizumab plus irinotecan treatment arm (n = 82), the 6-month progression-free survival rate was 50.3% and the objective response rate was 37.8%. These rates were all significantly higher than historical control data. In the supporting, single-arm, single-centre, phase II NCI 06-C-0064E trial of bevacizumab in patients with glioblastoma that had recurred after radiotherapy and temozolomide chemotherapy (n = 48), the rate of progression-free survival at 6 months was 29% and the overall response rate based on Macdonald criteria was 35%. Given the nature of the disease, bevacizumab was generally well tolerated in these two phase II trials. In the AVF3708g trial, grade 3 or higher treatment-emergent adverse events occurred in 46.4% of bevacizumab and 65.8% of bevacizumab plus irinotecan recipients.
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Affiliation(s)
- Marit D Moen
- Adis, a Wolters Kluwer Business, Auckland, New Zealand.
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Bose D, Meric-Bernstam F, Hofstetter W, Reardon DA, Flaherty KT, Ellis LM. Vascular endothelial growth factor targeted therapy in the perioperative setting: implications for patient care. Lancet Oncol 2010; 11:373-82. [PMID: 20171141 DOI: 10.1016/s1470-2045(09)70341-9] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Vascular endothelial growth factor (VEGF) targeted therapy, either alone or in combination with chemotherapy, has become the standard of care in several solid tumours, including colorectal cancer, renal-cell carcinoma, breast cancer, non-small-cell lung cancer, and glioblastoma. VEGF is crucial in the process of angiogenesis and wound healing and, thus, its inhibition has the potential to affect wound healing in patients undergoing surgery. In this review, we summarise the data available on the use of VEGF-targeted therapies, and their effect on perioperative wound complications. Surgery in patients receiving VEGF-targeted therapies seems to be safe when an appropriate interval of time is allowed between surgical procedures and treatment. Recommendations regarding this interval are provided in a disease and agent site-specific manner. We also discuss complications arising from the use of VEGF-directed therapies that might require surgical intervention and the considerations important in their management. At this juncture, safety data on the use of VEGF-targeted therapies in the perioperative period are sparse, and investigators are urged to continue to study this issue prospectively in current and future clinical trials to establish firm guidelines.
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Affiliation(s)
- Debashish Bose
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA
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Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2010. [DOI: 10.1002/pds.1847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Müller V, Witzel I, Stickeler E. Immunological Approaches in the Treatment of Metastasized Breast Cancer. Breast Care (Basel) 2009; 4:359-366. [PMID: 20877670 PMCID: PMC2941998 DOI: 10.1159/000262454] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
A better understanding of tumor biology has led to the development of a number of antibody-based targeted therapies in breast cancer. Several of these newer agents, such as trastuzumab and bevacizumab have demonstrated clinical activity and have improved the treatment of patients with metastatic breast cancer (MBC). Trastuzumab is a monoclonal antibody that binds to the extracellular domain of the HER2 receptor. The addition of trastuzumab to chemotherapy and also to endocrine therapy has enhanced efficacy of treatment. New antibody-based strategies directed against HER2 are under development. These new approaches include pertuzumab, an antibody with a different binding epitope that inhibits dimerization of HER2 with other members of the HER receptor family and TDM1, a trastuzumab-based antibody chemotherapeutic conjugate. Another approach to the treatment of solid tumors is inhibition of angiogenesis. The anti-VEGF antibody bevacizumab has been approved for treatment of MBC. Although the mechanism of action is still under investigation, bevacizumab is tested in other clinical settings such as adjuvant therapy, maintenance therapy, and in combination with both chemotherapy and other targeted agents. In this review, we will summarize the most important studies on trastuzumab and bevacizumab, and describe new antibodies currently under clinical development.
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Affiliation(s)
- Volkmar Müller
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Germany
| | - Isabell Witzel
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Germany
| | - Elmar Stickeler
- Department of Obstetrics and Gynecology, University of Freiburg i.Br., Germany
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