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Yu Qing D, Jing B, Bing W, Song W, Fei ZQ, Kun Y, Wei Y. Differential Diagnosis of Pathological Type of Peripheral Lung Cancer with Multimodal Contrast-Enhanced Ultrasound. ULTRASOUND IN MEDICINE & BIOLOGY 2024; 50:1485-1493. [PMID: 39048469 DOI: 10.1016/j.ultrasmedbio.2024.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/02/2024] [Accepted: 05/15/2024] [Indexed: 07/27/2024]
Abstract
OBJECTIVE The goal of the work described here was to investigate the role of multimodal contrast-enhanced ultrasound in the differential diagnosis of peripheral lung cancer. METHODS From April 2017 to July 2021, 109 patients with confirmed pulmonary malignant lesions who underwent CEUS examination were involved in our study. Seven patients were excluded because of the short duration of CEUS video or unsatisfactory imaging. Finally,102 patients with peripheral lung cancer were enrolled in this study. The maximum diameter of the lesions ranged from 1.6 to 13.0 cm (mean 6.2 ± 2.3 cm). On the basis of the pathological results, the patients were divided into the small cell lung cancer (SCLC) group and non-small cell lung cancer (NSCLC) group (including adenocarcinoma, lung squamous cell carcinoma and large cell neuroendocrine carcinoma). A Logiq E9 ultrasonic machine equipped with a 3.5 to 5.0 MHz C5-1 probe was used. Patient clinical information, CEUS features, CPI patterns and TIC parameters were analyzed and compared between different groups. Statistical analyses were performed with SPSS software and MedCalc software. The receiver operating characteristic curve was plotted. RESULTS In the differential diagnosis of SCLC and NSCLC, color parametric imaging indicated great performance. NSCLC exhibited a centripetal enhancement pattern more frequently (72.7%), while SCLC exhibited an eccentric enhancement pattern more frequently (92.9%) (p < 0.001). In the differential diagnosis of adenocarcinoma and squamous cell carcinoma, logistic regression analysis revealed that patient age of onset ≤60 y, difference in arrival time between lung and tumor ≤3.8 s, drop time of the time-intensity curve >23.2 s and absence of internal necrosis on CEUS were independent predictors for adenocarcinoma (area under the curve = 0.861). CONCLUSION In our study, multimodal contrast-enhanced ultrasound provided useful information in the differential diagnosis between small cell lung cancer and non-small cell lung cancer, especially between adenocarcinoma and squamous cell carcinoma.
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Affiliation(s)
- Du Yu Qing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/ Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Bai Jing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/ Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Wang Bing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/ Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Wang Song
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/ Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhang Qi Fei
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/ Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yan Kun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/ Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yang Wei
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/ Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100142, China.
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Arefnezhad R, Helfi M, Okhravijouybari R, Goleij P, Sargolzaeimoghaddam M, Mohammadi H, Mahdaviyan N, Fatemian H, Sarg A, Jahani S, Rezaei-Tazangi F, Nazari A. Umbilical cord mesenchymal stem cells and lung cancer: We should be hopeful or hopeless? Tissue Cell 2024; 88:102410. [PMID: 38772275 DOI: 10.1016/j.tice.2024.102410] [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: 03/24/2024] [Revised: 05/10/2024] [Accepted: 05/15/2024] [Indexed: 05/23/2024]
Abstract
Lung cancer (LC) is one of the leading causes of cancer-caused death that possesses a poor prognosis and low survival rate worldwide. In general, LC is classified into small-cell (SCLC) and non-small-cell carcinoma (NSCLC) (involving 80% of patients). Although chemotherapy, radiotherapy, surgery, and molecular-targeted therapy are considered standard approaches for LC treatment, these options have low success with detrimental effects on the life quality of patients. Ergo, recommending treatment with maximum effectiveness and minimum side effects for LC patients has been a substantial challenge for researchers and clinicians in the present era. Recently, mesenchymal stem cells (MSCs)-based strategies have sparked much interest in preventing or treating numerous illnesses. These multipotent stem cells can be isolated from diverse sources, such as umbilical cord, bone marrow, and adipose tissue. Among these sources, umbilical cord mesenchymal stem cells (UC-MSCs) have been in the spotlight of MSCs-based therapies thanks to their considerable advantages, such as high proliferation ability, low immune reactions and tumorigenesis, and easiness in collection and isolation. Some experimental studies have investigated the functionality of intact UC-MSCs and extracellular vesicles, exosomes, and conditioned medium derived from UC-MSCs, as well as genetically engineered UC-MSCs. In this review, we aimed to highlight the influences of these UMSCs-based methods in LC treatment with cellular and molecular insights.
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Affiliation(s)
- Reza Arefnezhad
- Coenzyme R Research Institute, Tehran, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Maryam Helfi
- Department of Medical Physics, School of Medicine, Mashhad University of Medical Science, Mashhad, Iran
| | | | - Pouya Goleij
- Department of Genetics, Sana Institute of Higher Education, Sari, Iran; International Network of Stem Cell (INSC), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | | | - Hanieh Mohammadi
- Student Research Committee, Tehran University of Medical Science, Tehran, Iran
| | | | - Hossein Fatemian
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Arya Sarg
- Istanbul Medipol University, Medical Student, Istanbul, Turkey
| | - Saleheh Jahani
- Department of pathology, University of California, San Diego, United states
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran.
| | - Ahmad Nazari
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Gorla G, Potenza A, Carrozzini T, Pollaci G, Acerbi F, Vetrano IG, Ferroli P, Canavero I, Rifino N, Bersano A, Gatti L. Angiopoietin-2 associates with poor prognosis in Moyamoya angiopathy. Ann Clin Transl Neurol 2024; 11:1590-1603. [PMID: 38655722 PMCID: PMC11187837 DOI: 10.1002/acn3.52076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/04/2024] [Accepted: 04/09/2024] [Indexed: 04/26/2024] Open
Abstract
OBJECTIVE Moyamoya angiopathy (MA) is a rare cerebrovascular disorder characterized by recurrent ischemic/hemorrhagic strokes due to progressive occlusion of the intracranial carotid arteries. The lack of reliable disease severity biomarkers led us to investigate molecular features of a Caucasian cohort of MA patients. METHODS The participants consisted of 30 MA patients and 40 controls. We measured cerebrospinal fluid (CSF) levels of angiogenic/inflammatory factors (ELISA). We then applied quantitative real-time PCR on cerebral artery specimens for expression analyses of angiogenic factors. By an immunoassay based on microfluidic technology, we examined the potential correlations between plasma protein expression and MA clinical progression. A RNA interference approach toward Ring Finger Protein 213 (RNF213) and a tube formation assay were applied in cellular model. RESULTS We detected a statistically significant (p < 0.000001) up-regulation of Angiopoietin-2 (Ang-2) in CSF and stenotic middle cerebral arteries (RQ >2) of MA patients compared to controls. A high Ang-2 plasma concentration (p = 0.018) was associated with unfavorable outcome in a subset of MA patients. ROC curve analyses indicated Ang-2 as diagnostic CSF biomarker (>3741 pg/mL) and prognostic plasma biomarker (>1162 pg/mL), to distinguish stable-from-progressive MA. Consistently, MA cellular model showed a significant up-regulation (RQ >2) of Ang-2 in RNF213 silenced condition. INTERPRETATION Our results pointed out Ang-2 as a reliable biomarker mirroring arterial steno-occlusion and vascular instability of MA in CSF and blood, providing a candidate factor for patient stratification. This pilot study may pave the way to the validation of a biomarker to identify progressive MA patients deserving a specific treatment path.
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Affiliation(s)
- Gemma Gorla
- Laboratory of Neurobiology and UCV, Neurology IX UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
| | - Antonella Potenza
- Laboratory of Neurobiology and UCV, Neurology IX UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
- Department of Pharmacological and Biomolecular SciencesUniversity of MilanMilan20122Italy
| | - Tatiana Carrozzini
- Laboratory of Neurobiology and UCV, Neurology IX UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
| | - Giuliana Pollaci
- Laboratory of Neurobiology and UCV, Neurology IX UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
- Department of Pharmacological and Biomolecular SciencesUniversity of MilanMilan20122Italy
| | - Francesco Acerbi
- Neurosurgical UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
| | - Ignazio G. Vetrano
- Neurosurgical UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
- Department of Biomedical Sciences for HealthUniversity of MilanMilan20122Italy
| | - Paolo Ferroli
- Neurosurgical UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
| | - Isabella Canavero
- Laboratory of Neurobiology and UCV, Neurology IX UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
| | - Nicola Rifino
- Laboratory of Neurobiology and UCV, Neurology IX UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
| | - Anna Bersano
- Laboratory of Neurobiology and UCV, Neurology IX UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
| | - Laura Gatti
- Laboratory of Neurobiology and UCV, Neurology IX UnitFondazione IRCCS Istituto Neurologico Carlo BestaMilan20133Italy
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Xu J, Tian L, Qi W, Lv Q, Wang T. Advancements in NSCLC: From Pathophysiological Insights to Targeted Treatments. Am J Clin Oncol 2024; 47:291-303. [PMID: 38375734 PMCID: PMC11107893 DOI: 10.1097/coc.0000000000001088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2024]
Abstract
With the global incidence of non-small cell lung cancer (NSCLC) on the rise, the development of innovative treatment strategies is increasingly vital. This review underscores the pivotal role of precision medicine in transforming NSCLC management, particularly through the integration of genomic and epigenomic insights to enhance treatment outcomes for patients. We focus on the identification of key gene mutations and examine the evolution and impact of targeted therapies. These therapies have shown encouraging results in improving survival rates and quality of life. Despite numerous gene mutations being identified in association with NSCLC, targeted treatments are available for only a select few. This paper offers an exhaustive analysis of the pathogenesis of NSCLC and reviews the latest advancements in targeted therapeutic approaches. It emphasizes the ongoing necessity for research and development in this domain. In addition, we discuss the current challenges faced in the clinical application of these therapies and the potential directions for future research, including the identification of novel targets and the development of new treatment modalities.
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Affiliation(s)
- Jianan Xu
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine
| | - Lin Tian
- Pulmonology Department, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, P.R. China
| | - Wenlong Qi
- Pulmonology Department, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, P.R. China
| | - Qingguo Lv
- Pulmonology Department, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, P.R. China
| | - Tan Wang
- Pulmonology Department, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, P.R. China
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Senchukova MA, Kalinin EA, Volchenko NN. Different types of tumor microvessels in stage I-IIIA squamous cell lung cancer and their clinical significance. World J Clin Oncol 2024; 15:614-634. [PMID: 38835849 PMCID: PMC11145955 DOI: 10.5306/wjco.v15.i5.614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/12/2024] [Accepted: 03/28/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Lung cancer (LC) is the leading cause of morbidity and mortality among malignant neoplasms. Improving the diagnosis and treatment of LC remains an urgent task of modern oncology. Previously, we established that in gastric, breast and cervical cancer, tumor microvessels (MVs) differ in morphology and have different prognostic significance. The connection between different types of tumor MVs and the progression of LC is not well understood. AIM To evaluate the morphological features and clinical significance of tumor MVs in lung squamous cell carcinoma (LUSC). METHODS A single-center retrospective cohort study examined medical records and archival paraffin blocks of 62 and 180 patients with stage I-IIIA LUSC in the training and main cohorts, respectively. All patients underwent radical surgery (R0) at the Orenburg Regional Cancer Clinic from May/20/2009 to December/14/2021. Tumor sections were routinely processed, and routine Mayer's hematoxylin and eosin staining and immunohistochemical staining for cluster of differentiation 34 (CD34), podoplanin, Snail and hypoxia-inducible factor-1 alpha were performed. The morphological features of different types of tumor MVs, tumor parenchyma and stroma were studied according to clinicopathological characteristics and LUSC prognosis. Statistical analysis was performed using Statistica 10.0 software. Univariate and multivariate logistic regression analyses were performed to identify potential risk factors for LUSC metastasis to regional lymph nodes (RLNs) and disease recurrence. Receiver operating characteristic curves were constructed to discriminate between patients with and without metastases in RLNs and those with and without disease recurrence. The effectiveness of the predictive models was assessed by the area under the curve. Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves between patient subgroups. A value of P < 0.05 was considered to indicate statistical significance. RESULTS Depending on the morphology, we classified tumor vessels into the following types: normal MVs, dilated capillaries (DCs), atypical DCs, DCs with weak expression of CD34, "contact-type" DCs, structures with partial endothelial linings, capillaries in the tumor solid component and lymphatic vessels in lymphoid and polymorphocellular infiltrates. We also evaluated the presence of loose, fine fibrous connective tissue (LFFCT) and retraction clefts in the tumor stroma, tumor spread into the alveolar air spaces (AASs) and fragmentation of the tumor solid component. According to multivariate analysis, the independent predictors of LUSC metastasis in RLNs were central tumor location (P < 0.00001), the presence of retraction clefts (P = 0.003), capillaries in the tumor solid component (P = 0.023) and fragmentation in the tumor solid component (P = 0.009), whereas the independent predictors of LUSC recurrence were tumor grade 3 (G3) (P = 0.001), stage N2 (P = 0.016), the presence of LFFCT in the tumor stroma (P < 0.00001), fragmentation of the tumor solid component (P = 0.0001), and the absence of tumor spread through the AASs (P = 0.0083). CONCLUSION The results obtained confirm the correctness of our previously proposed classification of different types of tumor vessels and may contribute to improving the diagnosis and treatment of LUSC.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460000, Russia
| | - Evgeniy A Kalinin
- Department of Thoracic Surgery, Orenburg Regional Cancer Clinic, Orenburg 460021, Russia
| | - Nadezhda N Volchenko
- Department of Pathology, PA Hertzen Moscow Oncology Research Centre, Branch of National Medical Research Radiological Center, Moscow 125284, Russia
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Yang Z, Zhang X, Bai X, Xi X, Liu W, Zhong W. Anti-angiogenesis in colorectal cancer therapy. Cancer Sci 2024; 115:734-751. [PMID: 38233340 PMCID: PMC10921012 DOI: 10.1111/cas.16063] [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: 09/18/2023] [Revised: 11/16/2023] [Accepted: 12/16/2023] [Indexed: 01/19/2024] Open
Abstract
The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.
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Affiliation(s)
- Zhenni Yang
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
- Department of Gastroenterology and HepatologyXing'an League People's HospitalXing'an LeagueChina
| | - Xuqian Zhang
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
- Department of Gastroenterology and HepatologyChina Aerospace Science and Industry CorporationBeijingChina
| | - Xiaozhe Bai
- Department of Gastroenterology and HepatologyXing'an League People's HospitalXing'an LeagueChina
| | - Xiaonan Xi
- State Key Laboratory of Medicinal Chemical Biology and College of PharmacyNankai UniversityTianjinChina
| | - Wentian Liu
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
| | - Weilong Zhong
- Department of Gastroenterology and HepatologyGeneral Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive DiseasesTianjinChina
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Carrera-Aguado I, Marcos-Zazo L, Carrancio-Salán P, Guerra-Paes E, Sánchez-Juanes F, Muñoz-Félix JM. The Inhibition of Vessel Co-Option as an Emerging Strategy for Cancer Therapy. Int J Mol Sci 2024; 25:921. [PMID: 38255995 PMCID: PMC10815934 DOI: 10.3390/ijms25020921] [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: 12/14/2023] [Revised: 01/09/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Vessel co-option (VCO) is a non-angiogenic mechanism of vascularization that has been associated to anti-angiogenic therapy. In VCO, cancer cells hijack the pre-existing blood vessels and use them to obtain oxygen and nutrients and invade adjacent tissue. Multiple primary tumors and metastases undergo VCO in highly vascularized tissues such as the lungs, liver or brain. VCO has been associated with a worse prognosis. The cellular and molecular mechanisms that undergo VCO are poorly understood. Recent studies have demonstrated that co-opted vessels show a quiescent phenotype in contrast to angiogenic tumor blood vessels. On the other hand, it is believed that during VCO, cancer cells are adhered to basement membrane from pre-existing blood vessels by using integrins, show enhanced motility and a mesenchymal phenotype. Other components of the tumor microenvironment (TME) such as extracellular matrix, immune cells or extracellular vesicles play important roles in vessel co-option maintenance. There are no strategies to inhibit VCO, and thus, to eliminate resistance to anti-angiogenic therapy. This review summarizes all the molecular mechanisms involved in vessel co-option analyzing the possible therapeutic strategies to inhibit this process.
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Affiliation(s)
- Iván Carrera-Aguado
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (I.C.-A.); (L.M.-Z.); (P.C.-S.); (E.G.-P.); (F.S.-J.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Laura Marcos-Zazo
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (I.C.-A.); (L.M.-Z.); (P.C.-S.); (E.G.-P.); (F.S.-J.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Patricia Carrancio-Salán
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (I.C.-A.); (L.M.-Z.); (P.C.-S.); (E.G.-P.); (F.S.-J.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Elena Guerra-Paes
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (I.C.-A.); (L.M.-Z.); (P.C.-S.); (E.G.-P.); (F.S.-J.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Fernando Sánchez-Juanes
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (I.C.-A.); (L.M.-Z.); (P.C.-S.); (E.G.-P.); (F.S.-J.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - José M. Muñoz-Félix
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (I.C.-A.); (L.M.-Z.); (P.C.-S.); (E.G.-P.); (F.S.-J.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
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Qin H, Xiao Q, Xie Y, Li D, Long X, Li T, Yi S, Liu Y, Chen J, Xu F. The relationship between VEGF-460(T>C) polymorphism and cancer risk: A systematic review and meta-analysis based on 46 reports. Medicine (Baltimore) 2023; 102:e34089. [PMID: 37390249 PMCID: PMC10313293 DOI: 10.1097/md.0000000000034089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 06/02/2023] [Indexed: 07/02/2023] Open
Abstract
BACKGROUND Extensive studies on the link between single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) and various malignancy risks produced conflicting results, notably for VEGF-460(T/C). To evaluate this correlation more comprehensively and accurately, we perform a meta-analysis. METHODS Through retrieving 5 databases (Web of Science (WoS), Embase, Pubmed, Wanfang database (Wangfang), and China National Knowledge Infrastructure (CNKI)) and applying hand search, citation search, and gray literature search, 44 papers included 46 reports were enrolled. To evaluate the relationship between VEGF-460 and cancer risk, we pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS Our results indicated that the VEGF-460 polymorphism is not related to malignancy susceptibility (dominant model, OR = 0.98, 95% CI = 0.87-1.09; recessive model, OR = 0.95, 95% CI = 0.82-1.10; heterozygous model, OR = 0.99, 95% CI = 0.90-1.10; homozygous model, OR = 0.92, 95% CI = 0.76-1.10; additive model, OR = 0.98, 95% CI = 0.90-1.07). While, in subgroup analysis, this SNP may reduce the risk of hepatocellular carcinoma. CONCLUSION this meta-analysis indicated that VEGF-460 was irrelevant to overall malignancy risk, but it might be a protective factor for hepatocellular carcinoma.
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Affiliation(s)
- Haoran Qin
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qiang Xiao
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yufen Xie
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Dan Li
- Department of Mammary Diseases, Zhuhai Hospital of Integrated Chinese and Western Medicine, Zhuhai, China
| | - Xiaozhou Long
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Taiping Li
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Siqing Yi
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yiqin Liu
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jian Chen
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Foyan Xu
- General Surgery Department, Zhuhai Hospital of integrated Traditional Chinese and Western Medicine, Guangdong, China
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Cunningham C, Bolcaen J, Bisio A, Genis A, Strijdom H, Vandevoorde C. Recombinant Endostatin as a Potential Radiosensitizer in the Treatment of Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2023; 16:219. [PMID: 37259367 PMCID: PMC9961924 DOI: 10.3390/ph16020219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/22/2023] [Accepted: 01/24/2023] [Indexed: 11/03/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, which is the leading cause of cancer-related deaths worldwide. Over the past decades, tumour angiogenesis has been intensely studied in the treatment of NSCLC due to its fundamental role in cancer progression. Several anti-angiogenic drugs, such as recombinant endostatin (RE), have been evaluated in several preclinical and clinical trials, with mixed and often disappointing results. However, there is currently an emerging interest in RE due to its ability to create a vascular normalization window, which could further improve treatment efficacy of the standard NSCLC treatment. This review provides an overview of preclinical and clinical studies that combined RE and radiotherapy for NSCLC treatment. Furthermore, it highlights the ongoing challenges that have to be overcome in order to maximize the benefit; as well as the potential advantage of combinations with particle therapy and immunotherapy, which are rapidly gaining momentum in the treatment landscape of NSCLC. Different angiogenic and immunosuppressive effects are observed between particle therapy and conventional X-ray radiotherapy. The combination of RE, particle therapy and immunotherapy presents a promising future therapeutic triad for NSCLC.
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Affiliation(s)
- Charnay Cunningham
- Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Cape Town 7602, South Africa
- Radiation Biophysics Division, SSC Laboratory, NRF Ithemba LABS, Cape Town 7131, South Africa
| | - Julie Bolcaen
- Radiation Biophysics Division, SSC Laboratory, NRF Ithemba LABS, Cape Town 7131, South Africa
| | - Alessandra Bisio
- Department of Cellular, Computational and Integrative Biology—CIBIO, University of Trento, 38123 Trento, Italy
| | - Amanda Genis
- Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Cape Town 7602, South Africa
| | - Hans Strijdom
- Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Stellenbosch University, Cape Town 7602, South Africa
| | - Charlot Vandevoorde
- Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung, Planckstr. 1, 64291 Darmstadt, Germany
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Increase of Circulating Endothelial Progenitor Cells and Released Angiogenic Factors in Children with Moyamoya Arteriopathy. Int J Mol Sci 2023; 24:ijms24021233. [PMID: 36674749 PMCID: PMC9865311 DOI: 10.3390/ijms24021233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/21/2022] [Accepted: 01/03/2023] [Indexed: 01/11/2023] Open
Abstract
Moyamoya arteriopathy (MMA) is a rare cerebrovascular disorder that causes recurrent ischemic and hemorrhagic strokes, leading young patients to severe neurological deficits. The pathogenesis of MMA is still unknown. The disease onset in a wide number of pediatric cases raises the question of the role of genetic factors in the disease's pathogenesis. In these patients, MMA's clinical course, or progression, is largely unclear. By performing a comprehensive molecular and cellular profile in the plasma and CSF, respectively, of MMA pediatric patients, our study is aimed at assessing the levels of circulating endothelial progenitor cells (cEPC) and the release of selected proteins at an early disease stage to clarify MMA pathogenesis and progression. We employed cytofluorimetric methods and immunoassays in pediatric MMA patients and matched control subjects by age and sex. We detected increased levels of cEPC in peripheral blood and an upregulation of angiogenic markers in CSF (i.e., angiopoietin-2 and VEGF-A). This finding is probably associated with deregulated angiogenesis, as stated by the moderate severity of collateral vessel network development (Suzuki III-IV). The absence of significant modulation of neurofilament light in CSF led us to rule out the presence of substantial neuronal injury in MMA children. Despite the limited cohort of pediatric patients, we found some peculiar cellular and molecular characteristics in their blood and CSF samples. Our findings may be confirmed by wider and perspective studies to identify predictive or prognostic circulating biomarkers and potential therapeutic targets for personalized care of MMA pediatric patients.
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Adnani L, Spinelli C, Tawil N, Rak J. Role of extracellular vesicles in cancer-specific interactions between tumour cells and the vasculature. Semin Cancer Biol 2022; 87:196-213. [PMID: 36371024 DOI: 10.1016/j.semcancer.2022.11.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/25/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022]
Abstract
Cancer progression impacts and exploits the vascular system in several highly consequential ways. Among different types of vascular cells, blood cells and mediators that are engaged in these processes, endothelial cells are at the centre of the underlying circuitry, as crucial constituents of angiogenesis, angiocrine stimulation, non-angiogenic vascular growth, interactions with the coagulation system and other responses. Tumour-vascular interactions involve soluble factors, extracellular matrix molecules, cell-cell contacts, as well as extracellular vesicles (EVs) carrying assemblies of molecular effectors. Oncogenic mutations and transforming changes in the cancer cell genome, epigenome and signalling circuitry exert important and often cancer-specific influences upon pathways of tumour-vascular interactions, including the biogenesis, content, and biological activity of EVs and responses of cancer cells to them. Notably, EVs may carry and transfer bioactive, oncogenic macromolecules (oncoproteins, RNA, DNA) between tumour and vascular cells and thereby elicit unique functional changes and forms of vascular growth and remodeling. Cancer EVs influence the state of the vasculature both locally and systemically, as exemplified by cancer-associated thrombosis. EV-mediated communication pathways represent attractive targets for therapies aiming at modulation of the tumour-vascular interface (beyond angiogenesis) and could also be exploited for diagnostic purposes in cancer.
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Affiliation(s)
- Lata Adnani
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Cristiana Spinelli
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Nadim Tawil
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Janusz Rak
- McGill University and Research Institute of the McGill University Health Centre, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
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12
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Cuypers A, Truong ACK, Becker LM, Saavedra-García P, Carmeliet P. Tumor vessel co-option: The past & the future. Front Oncol 2022; 12:965277. [PMID: 36119528 PMCID: PMC9472251 DOI: 10.3389/fonc.2022.965277] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022] Open
Abstract
Tumor vessel co-option (VCO) is a non-angiogenic vascularization mechanism that is a possible cause of resistance to anti-angiogenic therapy (AAT). Multiple tumors are hypothesized to primarily rely on growth factor signaling-induced sprouting angiogenesis, which is often inhibited during AAT. During VCO however, tumors invade healthy tissues by hijacking pre-existing blood vessels of the host organ to secure their blood and nutrient supply. Although VCO has been described in the context of AAT resistance, the molecular mechanisms underlying this process and the profile and characteristics of co-opted vascular cell types (endothelial cells (ECs) and pericytes) remain poorly understood, resulting in the lack of therapeutic strategies to inhibit VCO (and to overcome AAT resistance). In the past few years, novel next-generation technologies (such as single-cell RNA sequencing) have emerged and revolutionized the way of analyzing and understanding cancer biology. While most studies utilizing single-cell RNA sequencing with focus on cancer vascularization have centered around ECs during sprouting angiogenesis, we propose that this and other novel technologies can be used in future investigations to shed light on tumor EC biology during VCO. In this review, we summarize the molecular mechanisms driving VCO known to date and introduce the models used to study this phenomenon to date. We highlight VCO studies that recently emerged using sequencing approaches and propose how these and other novel state-of-the-art methods can be used in the future to further explore ECs and other cell types in the VCO process and to identify potential vulnerabilities in tumors relying on VCO. A better understanding of VCO by using novel approaches could provide new answers to the many open questions, and thus pave the way to develop new strategies to control and target tumor vascularization.
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Affiliation(s)
- Anne Cuypers
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), Vlaams Instituut voor Biotechnologie (VIB) and Department of Oncology, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Anh-Co Khanh Truong
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), Vlaams Instituut voor Biotechnologie (VIB) and Department of Oncology, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Lisa M. Becker
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), Vlaams Instituut voor Biotechnologie (VIB) and Department of Oncology, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Paula Saavedra-García
- Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), Vlaams Instituut voor Biotechnologie (VIB) and Department of Oncology, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
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13
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Elebiyo TC, Rotimi D, Evbuomwan IO, Maimako RF, Iyobhebhe M, Ojo OA, Oluba OM, Adeyemi OS. Reassessing vascular endothelial growth factor (VEGF) in anti-angiogenic cancer therapy. Cancer Treat Res Commun 2022; 32:100620. [PMID: 35964475 DOI: 10.1016/j.ctarc.2022.100620] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 06/02/2022] [Accepted: 08/05/2022] [Indexed: 05/23/2023]
Abstract
Vascularization is fundamental to the growth and spread of tumor cells to distant sites. As a consequence, angiogenesis, the sprouting of new blood vessels from existing ones, is a characteristic trait of cancer. In 1971, Judah Folkman postulated that tumour growth is angiogenesis dependent and that by cutting off blood supply, a neoplastic lesion could be potentially starved into remission. Decades of research have been devoted to understanding the role that vascular endothelial growth factor (VEGF) plays in tumor angiogenesis, and it has been identified as a significant pro-angiogenic factor that is frequently overexpressed within a tumor mass. Today, anti-VEGF drugs such as Sunitinib, Sorafenib, Axitinib, Tanibirumab, and Ramucirumab have been approved for the treatment of advanced and metastatic cancers. However, anti-angiogenic therapy has turned out to be more complex than originally thought. The failure of this therapeutic option calls for a reevaluation of VEGF as the major target in anti-angiogenic cancer therapy. The call for reassessment is based on two rationales: first, tumour blood vessels are abnormal, disorganized, and leaky; this not only prevents optimal drug delivery but it also promotes hypoxia and metastasis; secondly, tumour growth or regrowth might be blood vessel dependent and not angiogenesis dependent as tumour cells can acquire blood vessels via non-angiogenic mechanisms. Therefore, a critical assessment of VEGF, VEGFRs, and their inhibitors could glean newer options such as repurposing anti-VEGF drugs as vascular normalizing agents to enhance drug delivery of immune checkpoint inhibitors.
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Affiliation(s)
| | - Damilare Rotimi
- Department of Biochemistry, Landmark University, Omu-Aran, Nigeria
| | | | | | | | - Oluwafemi Adeleke Ojo
- Phytomedicine, Molecular Toxicology, and Computational Biochemistry Research Laboratory (PMTCB-RL), Department of Biochemistry, Bowen University, Iwo, 232101, Nigeria..
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14
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Role of Anti-Angiogenic Factors in the Pathogenesis of Breast Cancer: A Review of Therapeutic Potential. Pathol Res Pract 2022; 236:153956. [DOI: 10.1016/j.prp.2022.153956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/06/2022] [Accepted: 05/25/2022] [Indexed: 11/23/2022]
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15
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Jiang P, Geng L, Mao Z, Wang Q, Wang W, Jiao M, Yao Y, Chen N, Zhang J, Nan K, Shen Y, Guo H, Jiang L. First-line chemotherapy plus immune checkpoint inhibitors or bevacizumab in advanced non-squamous non-small-cell lung cancer without EGFR mutations or ALK fusions. Immunotherapy 2022; 14:445-457. [PMID: 35259921 DOI: 10.2217/imt-2021-0112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Aim: To compare the efficacy and safety of first-line chemotherapy (Chemo) plus immune checkpoint inhibitors (ICIs) or bevacizumab (Bev) in advanced non-squamous non-small-cell lung cancer without EGFR mutations or ALK fusions. Methods: A network meta-analysis was conducted to synthesize relative treatment outcomes. Results: Chemo + ICIs is superior to Chemo + Bev in both overall survival (hazard ratio: 0.92; 95% CI: 0.88-0.96) and progression-free survival (hazard ratio: 0.93; 95% CI: 0.90-0.97), with comparable severe adverse events. However, for patients with liver metastasis, Chemo + Bev has a 59.8% probability of providing better overall survival benefit. For specific regimens, pembrolizumab + Chemo showed an absolute advantage over other regimens. Conclusion: First-line Chemo + ICIs is superior to Chemo + Bev in advanced non-squamous non-small-cell lung cancer except for patients with liver metastasis.
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Affiliation(s)
- Panpan Jiang
- Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China
| | - Luying Geng
- Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China
| | - Ziyang Mao
- Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China
| | - Qinyang Wang
- Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China
| | - Wenjuan Wang
- Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China
| | - Min Jiao
- Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China
| | - Yu Yao
- Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China
| | - Nanzheng Chen
- Department of Thoracic Surgery, Xi'an Jiaotong University Medical College First Affiliated Hospital, Xi'an, Shaanxi, China
| | - Jia Zhang
- Department of Thoracic Surgery, Xi'an Jiaotong University Medical College First Affiliated Hospital, Xi'an, Shaanxi, China
| | - Kejun Nan
- Oncology Hospital, Xi'an International Medical Center, Xi'an, Shaanxi, China
| | - Yuan Shen
- Department of Statistical Teaching & Research, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hui Guo
- Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China
- Key Laboratory of Environment & Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaanxi, China
- Centre for Translational Medicine, Xi'an Jiaotong University Medical College First Affiliated Hospital, Xi'an, Shaanxi, China
| | - Lili Jiang
- Xi'an Jiaotong University Medical College First Affiliated Hospital Department of Medical Oncology, Xi'an, Shaanxi, China
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16
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Rada M, Tsamchoe M, Kapelanski-Lamoureux A, Hassan N, Bloom J, Petrillo S, Kim DH, Lazaris A, Metrakos P. Cancer Cells Promote Phenotypic Alterations in Hepatocytes at the Edge of Cancer Cell Nests to Facilitate Vessel Co-Option Establishment in Colorectal Cancer Liver Metastases. Cancers (Basel) 2022; 14:1318. [PMID: 35267627 PMCID: PMC8909291 DOI: 10.3390/cancers14051318] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/23/2022] [Accepted: 03/01/2022] [Indexed: 12/24/2022] Open
Abstract
Vessel co-option is correlated with resistance against anti-angiogenic therapy in colorectal cancer liver metastases (CRCLM). Vessel co-opting lesions are characterized by highly motile cancer cells that move toward and along the pre-existing vessels in the surrounding nonmalignant tissue and co-opt them to gain access to nutrients. To access the sinusoidal vessels, the cancer cells in vessel co-opting lesions must displace the hepatocytes and occupy their space. However, the mechanisms underlying this displacement are unknown. Herein, we examined the involvement of apoptosis, autophagy, motility, and epithelial-mesenchymal transition (EMT) pathways in hepatocyte displacement by cancer cells. We demonstrate that cancer cells induce the expression of the proteins that are associated with the upregulation of apoptosis, motility, and EMT in adjacent hepatocytes in vitro and in vivo. Accordingly, we observe the upregulation of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and actin-related protein 2/3 (ARP2/3) in adjacent hepatocytes to cancer cell nests, while we notice a downregulation of E-cadherin. Importantly, the knockdown of runt-related transcription factor 1 (RUNX1) in cancer cells attenuates the function of cancer cells in hepatocytes alterations in vitro and in vivo. Altogether, our data suggest that cancer cells exploit various mechanisms to displace hepatocytes and access the sinusoidal vessels to establish vessel co-option.
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Affiliation(s)
- Miran Rada
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (M.T.); (A.K.-L.); (N.H.); (J.B.); (S.P.); (D.H.K.); (A.L.)
| | | | | | | | | | | | | | | | - Peter Metrakos
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (M.T.); (A.K.-L.); (N.H.); (J.B.); (S.P.); (D.H.K.); (A.L.)
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17
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Golhani V, Ray SK, Mukherjee S. Role of MicroRNAs and Long Non-Coding RNAs in Regulating Angiogenesis in Human Breast Cancer- A Molecular Medicine Perspective. Curr Mol Med 2021; 22:882-893. [PMID: 34923940 DOI: 10.2174/1566524022666211217114527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 10/26/2021] [Accepted: 11/05/2021] [Indexed: 11/22/2022]
Abstract
MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are proficient in regulating gene expression post-transcriptionally. Considering the recent trend in exploiting non-coding RNAs (ncRNAs) as cancer therapeutics, the potential use of miRNAs and lncRNAs as biomarkers and novel therapeutic agents against angiogenesis is an important scientific aspect. An estimated 70% of the genome is actively transcribed, only 2% of which codes for known protein-coding genes. Long noncoding RNAs (lncRNAs) are a large and diverse class of RNAs > 200 nucleotides in length, and not translated into protein, and are of utmost importance and it governs the expression of genes in a temporal, spatial, and cell context-dependent manner. Angiogenesis is an essential process for organ morphogenesis and growth during development, and it is relevant during the repair of wounded tissue in adults. It is coordinated by an equilibrium of pro-and anti-angiogenic factors; nevertheless, when affected, it promotes several diseases, including breast cancer. Signaling pathways involved here are tightly controlled systems that regulate the appropriate timing of gene expression required for the differentiation of cells down a particular lineage essential for proper tissue development. Lately, scientific reports are indicating that ncRNAs, such as miRNAs, and lncRNAs, play critical roles in angiogenesis related to breast cancer. The specific roles of various miRNAs and lncRNAs in regulating angiogenesis in breast cancer, with particular focus on the downstream targets and signaling pathways regulated by these ncRNAs with molecular medicine perspective, are highlighted in this write-up.
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Affiliation(s)
- Vandana Golhani
- Department of Biochemistry. All India Institute of Medical Sciences. Bhopal, Madhya Pradesh-462020, India
| | | | - Sukhes Mukherjee
- Department of Biochemistry. All India Institute of Medical Sciences. Bhopal, Madhya Pradesh-462020, India
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18
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Zhang M, Liu J, Liu G, Xing Z, Jia Z, Li J, Wang W, Wang J, Qin L, Wang X, Wang X. Anti-vascular endothelial growth factor therapy in breast cancer: Molecular pathway, potential targets, and current treatment strategies. Cancer Lett 2021; 520:422-433. [PMID: 34389434 DOI: 10.1016/j.canlet.2021.08.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/30/2021] [Accepted: 08/03/2021] [Indexed: 11/15/2022]
Abstract
As the highest incidence of female malignancy, breast cancer is likewise the leading cause of cancer-related deaths. The development of cancer relies on neo-vascularization, which provides sufficient nutrition and oxygen, and supplies a pathway for distant metastasis. Angiogenesis represents the formation of new blood vessels, and is a principal pathogenetic action in breast cancer. Vascular endothelial growth factor (VEGF) is a major angiogenesis regulator that modulates the maintenance and function of mature vascular networks. Therefore, the VEGF pathway is a promising oncotherapeutic target. This review elaborates an update on the prognostic value of VEGF in breast cancer, summarizes clinical experience and lessons of anti-VEGF therapeutics, meanwhile, provides an overview of biomarkers that predict the effectiveness of anti-angiogenic treatment.
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Affiliation(s)
- Menglu Zhang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiaqi Liu
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Gang Liu
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zeyu Xing
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ziqi Jia
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiaxin Li
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wenyan Wang
- Department of Breast Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Jie Wang
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ling Qin
- Department of Breast Surgical Oncology, Cancer Hospital of HuanXing, Beijing, 100021, China
| | - Xin Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Xiang Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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19
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Alternative Vascularization Mechanisms in Tumor Resistance to Therapy. Cancers (Basel) 2021; 13:cancers13081912. [PMID: 33921099 PMCID: PMC8071410 DOI: 10.3390/cancers13081912] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Tumors rely on blood vessels to grow and metastasize. Malignant tumors can employ different strategies to create a functional vascular network. Tumor cells can use normal processes of vessel formation but can also employ cancer-specific mechanisms, by co-opting normal vessels present in tissues or by turning themselves into vascular cells. These different types of tumor vessels have specific molecular and functional characteristics that profoundly affect tumor behavior and response to therapies, including drugs targeting the tumor vasculature (antiangiogenic therapies). In this review, we discuss how vessels formed by different mechanisms affect the intrinsic sensitivity of tumors to therapy and, on the other hand, how therapies can affect tumor vessel formation, leading to resistance to drugs, cancer recurrence, and treatment failure. Potential strategies to avoid vessel-mediated resistance to antineoplastic therapies will be discussed. Abstract Blood vessels in tumors are formed through a variety of different mechanisms, each generating vessels with peculiar structural, molecular, and functional properties. This heterogeneity has a major impact on tumor response or resistance to antineoplastic therapies and is now emerging as a promising target for strategies to prevent drug resistance and improve the distribution and efficacy of antineoplastic treatments. This review presents evidence of how different mechanisms of tumor vessel formation (vasculogenesis, glomeruloid proliferation, intussusceptive angiogenesis, vasculogenic mimicry, and vessel co-option) affect tumor responses to antiangiogenic and antineoplastic therapies, but also how therapies can promote alternative mechanisms of vessel formation, contributing to tumor recurrence, malignant progression, and acquired drug resistance. We discuss the possibility of tailoring treatment strategies to overcome vasculature-mediated drug resistance or to improve drug distribution and efficacy.
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20
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Daum S, Hagen H, Naismith E, Wolf D, Pircher A. The Role of Anti-angiogenesis in the Treatment Landscape of Non-small Cell Lung Cancer - New Combinational Approaches and Strategies of Neovessel Inhibition. Front Cell Dev Biol 2021; 8:610903. [PMID: 33469537 PMCID: PMC7813779 DOI: 10.3389/fcell.2020.610903] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022] Open
Abstract
Tumor progression depends primarily on vascular supply, which is facilitated by angiogenic activity within the malignant tissue. Non-small cell lung cancer (NSCLC) is a highly vascularized tumor, and inhibition of angiogenesis was projected to be a promising therapeutic approach. Over a decade ago, the first anti-angiogenic agents were approved for advanced stage NSCLC patients, however, they only produced a marginal clinical benefit. Explanations why anti-angiogenic therapies only show modest effects include the highly adaptive tumor microenvironment (TME) as well as the less understood characteristics of the tumor vasculature. Today, advanced methods of in-depth characterization of the NSCLC TME by single cell RNA sequencing (scRNA-Seq) and preclinical observations enable a detailed characterization of individual cancer landscapes, allowing new aspects for a more individualized inhibition of angiogenesis to be identified. Furthermore, the tumor vasculature itself is composed of several cellular subtypes, which closely interact with other cellular components of the TME, and show distinct biological functions such as immune regulation, proliferation, and organization of the extracellular matrix. With these new insights, combinational approaches including chemotherapy, anti- angiogenic and immunotherapy can be developed to yield a more target-oriented anti-tumor treatment in NSCLC. Recently, anti-angiogenic agents were also shown to induce the formation of high endothelial venules (HEVs), which are essential for the formation of tertiary lymphoid structures, and key components in triggering anti-tumor immunity. In this review, we will summarize the current knowledge of tumor-angiogenesis and corresponding anti-angiogenic therapies, as well as new aspects concerning characterization of tumor-associated vessels and the resulting new strategies for anti-angiogenic therapies and vessel inhibition in NSCLC. We will further discuss why anti-angiogenic therapies form an interesting backbone strategy for combinational therapies and how anti-angiogenic approaches could be further developed in a more personalized tumor-oriented fashion with focus on NSCLC.
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Affiliation(s)
- Sophia Daum
- Internal Medicine V, Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria
| | - Hannes Hagen
- Internal Medicine V, Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria
| | - Erin Naismith
- Internal Medicine V, Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria
| | - Dominik Wolf
- Internal Medicine V, Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria
- Medical Clinic 3, Department of Oncology, Hematology, Immunoncology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany
| | - Andreas Pircher
- Internal Medicine V, Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria
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Tian W, Cao C, Shu L, Wu F. Anti-Angiogenic Therapy in the Treatment of Non-Small Cell Lung Cancer. Onco Targets Ther 2020; 13:12113-12129. [PMID: 33262610 PMCID: PMC7699985 DOI: 10.2147/ott.s276150] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 10/14/2020] [Indexed: 12/15/2022] Open
Abstract
Angiogenesis plays an essential role in the development of most solid tumors by delivering nutrients and oxygen to the tumor. Therefore, anti-angiogenic therapy, particularly anti-VEGF and anti-VEGF receptor (VEGFR) therapy, has been a popular strategy to treat cancer. However, anti-angiogenic therapy does not significantly improve patients' outcomes when used alone because the cutdown of the vessels transforms tumor cells to a hypoxia-tolerant phenotype. While combining anti-angiogenic therapy with other therapies, including chemotherapy, radiotherapy, immunotherapy, and anti-epidermal growth factor receptor (EGFR) therapy, has a promising efficacy due to the vessel normalization effect induced by anti-angiogenic agents. Here, we review the characteristics of tumor angiogenesis, the mechanisms, clinical applications, and prospects of combining anti-angiogenic therapy with other therapies in the treatment of non-small cell lung cancer.
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Affiliation(s)
- Wentao Tian
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People's Republic of China.,Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, People's Republic of China
| | - Chenghui Cao
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People's Republic of China.,Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, People's Republic of China
| | - Long Shu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People's Republic of China
| | - Fang Wu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People's Republic of China
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Vanderborght B, Lefere S, Vlierberghe HV, Devisscher L. The Angiopoietin/Tie2 Pathway in Hepatocellular Carcinoma. Cells 2020; 9:cells9112382. [PMID: 33143149 PMCID: PMC7693961 DOI: 10.3390/cells9112382] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 10/23/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023] Open
Abstract
Due to the usually late diagnosis and lack of effective therapies, hepatocellular carcinoma (HCC), which poses a growing global health problem, is characterized by a poor prognosis. Angiogenesis plays an important role in HCC progression, and vascular endothelial growth factor (VEGF) and angiopoietins (Angs) are key drivers of HCC angiogenesis. VEGF-targeting strategies already represent an important component of today’s systemic treatment landscape of HCC, whereas targeting the Ang/Tie2 signaling pathway may harbor future potential in this context due to reported beneficial anticancer effects when targeting this pathway. In addition, a better understanding of the relation between Angs and HCC angiogenesis and progression may reveal their potential as predictive factors for post-treatment disease progression and prognosis. In this review, we give a comprehensive overview of the complex role of Ang/Tie2 signaling in HCC, pinpointing its potential value as biomarker and target for HCC treatments, aiding HCC diagnosis and therapy.
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Affiliation(s)
- Bart Vanderborght
- Department of Internal Medicine and Pediatrics, Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, B-9000 Ghent, Belgium; (B.V.); (S.L.); (H.V.V.)
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, B-9000 Ghent, Belgium
| | - Sander Lefere
- Department of Internal Medicine and Pediatrics, Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, B-9000 Ghent, Belgium; (B.V.); (S.L.); (H.V.V.)
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, B-9000 Ghent, Belgium
| | - Hans Van Vlierberghe
- Department of Internal Medicine and Pediatrics, Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, B-9000 Ghent, Belgium; (B.V.); (S.L.); (H.V.V.)
| | - Lindsey Devisscher
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, B-9000 Ghent, Belgium
- Correspondence: ; Tel.: +32-9-332-56-65
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Angiogenesis inhibition in non-small cell lung cancer: a critical appraisal, basic concepts and updates from American Society for Clinical Oncology 2019. Curr Opin Oncol 2020; 32:44-53. [PMID: 31609741 DOI: 10.1097/cco.0000000000000591] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW Recently, the combination of antiangiogenic agents, chemotherapy and immunotherapy has shown synergistic anticancer effects in non-small cell lung cancer (NSCLC). The future for this approach appears bright in lung cancer treatment; however, many challenges remain to be overcome regarding its true potential, optimal sequence and timing of therapy, and safety profile. In this review, we will discuss the current status and future direction of antiangiogenic therapy for the treatment of NSCLC, and highlight emerging strategies, such as tumor vessel normalization (TVN). RECENT FINDINGS Bevacizumab was the first antiangiogenic agent approved for the treatment of advanced NSCLC. Recently, the combination of chemotherapy/antiangiogenic therapy with immunotherapy showed high efficacy in first-line settings. A subgroup of patients with liver metastasis and driver mutation-addicted tumors benefited most, suggesting that the metastatic location, as well as the genetic background of the tumor, are key determinants for therapy responses. SUMMARY The efficacy of antiangiogenic therapies in unselected patients is rather limited. The tumor microenvironment has appeared to be more complex and heterogeneous than previously assumed. Only a contextual rather than a cell-specific approach might provide valuable insights towards the clinical validation of combinational therapies.
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Rada M, Lazaris A, Kapelanski-Lamoureux A, Mayer TZ, Metrakos P. Tumor microenvironment conditions that favor vessel co-option in colorectal cancer liver metastases: A theoretical model. Semin Cancer Biol 2020; 71:52-64. [PMID: 32920126 DOI: 10.1016/j.semcancer.2020.09.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/03/2020] [Accepted: 09/03/2020] [Indexed: 02/07/2023]
Abstract
Vessel co-option is an alternative strategy by which tumour cells vascularize and gain access to nutrients to support tumour growth, survival and metastasis. In vessel co-option, the cancer cells move towards the pre-existing vasculature and hijack them. Vessel co-option is adopted by a wide range of human tumours including colorectal cancer liver metastases (CRCLM) and is responsible for the effectiveness of treatment in CRCLM. Furthermore, vessel co-option is an intrinsic feature and an acquired mechanism of resistance to anti-angiogenic treatment. In this review, we describe the microenvironment, the molecular players, discovered thus far of co-opting CRCLM lesions and propose a theoretical model. We also highlight key unanswered questions that are critical to improving our understanding of CRCLM vessel co-option and for the development of effective approaches for the treatment of co-opting tumours.
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Affiliation(s)
- Miran Rada
- Cancer Research Program, McGill University Health Centre Research Institute, Montreal, Quebec, H4A3J1, Canada
| | - Anthoula Lazaris
- Cancer Research Program, McGill University Health Centre Research Institute, Montreal, Quebec, H4A3J1, Canada
| | - Audrey Kapelanski-Lamoureux
- Cancer Research Program, McGill University Health Centre Research Institute, Montreal, Quebec, H4A3J1, Canada
| | - Thomas Z Mayer
- Cancer Research Program, McGill University Health Centre Research Institute, Montreal, Quebec, H4A3J1, Canada
| | - Peter Metrakos
- Cancer Research Program, McGill University Health Centre Research Institute, Montreal, Quebec, H4A3J1, Canada.
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25
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Jary M, Hasanova R, Vienot A, Asgarov K, Loyon R, Tirole C, Bouard A, Orillard E, Klajer E, Kim S, Viot J, Colle E, Adotevi O, Bouché O, Lecomte T, Borg C, Feugeas JP. Molecular description of ANGPT2 associated colorectal carcinoma. Int J Cancer 2020; 147:2007-2018. [PMID: 32222972 DOI: 10.1002/ijc.32993] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 02/01/2020] [Accepted: 02/26/2020] [Indexed: 12/20/2022]
Abstract
Angiopoietin-2 (ANGPT2) is a prognostic factor in metastatic colorectal cancer (CRC). Nevertheless, it remains to be elucidated which molecular characteristics make up the ANGPT2-related poor-prognosis CRC subset. Public transcriptomic datasets were collected from Gene Expression Omnibus GEO and with the TCGAbiolinks R-package for the TCGA. After appropriate normalization, differential expression analysis was performed using Benjamini and Hochberg method for false discovery rate. Plasma from two prospective clinical trials were used to investigate the clinical impact of ANGPT2-related biomarkers. In the 935 samples included in four annotated platforms (GPL) and derived from localized CRC, ANGPT2hi expression conferred a worst overall survival (HR = 1.20; p = 0.02). CRC stage, ANGPT2hi expression but not Consortium Molecular Subtype (CMS) predict overall survival in multivariate analysis. ANGPT2 expression was not correlated with a specific CMS nor to RAS, RAF, MSI, p53, CIN, CIMP genomic alterations. Gene expression analysis revealed that ANGPT2hi CRC subset is characterized by angiogenesis-related gene expression, presence of myeloid cells, stromal organization and resistance to chemotherapy. A prognostic model was proposed using seric levels of ANGPT2, STC1 and CD138 in 97 mCRC patients. Our results provide evidence that ANGPT2 is a prognostic factor in localized CRC and defined a specific CRC subset with potential clinical implementation.
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Affiliation(s)
- Marine Jary
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France.,Department of Medical Oncology, University Hospital of Besançon, Besançon, France.,Clinical Investigation Center in Biotherapy, INSERM CIC-BT1431, University Hospital of Besançon, Besançon, France
| | - Reyhan Hasanova
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France
| | - Angélique Vienot
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France.,Department of Medical Oncology, University Hospital of Besançon, Besançon, France
| | - Kamal Asgarov
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France
| | - Romain Loyon
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France.,Department of Medical Oncology, University Hospital of Besançon, Besançon, France
| | - Charline Tirole
- Department of Medical Oncology, University Hospital of Besançon, Besançon, France
| | - Adeline Bouard
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France
| | - Emeline Orillard
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France.,Department of Medical Oncology, University Hospital of Besançon, Besançon, France
| | - Elodie Klajer
- Department of Medical Oncology, University Hospital of Besançon, Besançon, France
| | - Stefano Kim
- Department of Medical Oncology, University Hospital of Besançon, Besançon, France.,Clinical Investigation Center in Biotherapy, INSERM CIC-BT1431, University Hospital of Besançon, Besançon, France
| | - Julien Viot
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France.,Department of Medical Oncology, University Hospital of Besançon, Besançon, France
| | - Elise Colle
- University Hospital St-Antoine, Paris, France
| | - Olivier Adotevi
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France.,Department of Medical Oncology, University Hospital of Besançon, Besançon, France
| | - Olivier Bouché
- Department of Hepato-Gastroenterology and Digestive Oncology, University Hospital Robert Debré, Reims, France
| | - Thierry Lecomte
- Department of Hepato-Gastroenterology and Digestive Oncology, CHRU de Tours, Tours Cedex 09, France.,University of Tours, Tours Cedex 01, France
| | - Christophe Borg
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France.,Department of Medical Oncology, University Hospital of Besançon, Besançon, France.,Clinical Investigation Center in Biotherapy, INSERM CIC-BT1431, University Hospital of Besançon, Besançon, France
| | - Jean P Feugeas
- INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France
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Madu CO, Wang S, Madu CO, Lu Y. Angiogenesis in Breast Cancer Progression, Diagnosis, and Treatment. J Cancer 2020; 11:4474-4494. [PMID: 32489466 PMCID: PMC7255381 DOI: 10.7150/jca.44313] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 04/04/2020] [Indexed: 02/07/2023] Open
Abstract
Angiogenesis is a significant event in a wide range of healthy and diseased conditions. This process frequently involves vasodilation and an increase in vascular permeability. Numerous players referred to as angiogenic factors, work in tandem to facilitate the outgrowth of endothelial cells (EC) and the consequent vascularity. Conversely, angiogenic factors could also feature in pathological conditions. Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers. An increased level of angiogenesis is associated with decreased survival in breast cancer patients. Therefore, a good understanding of the angiogenic mechanism holds a promise of providing effective treatments for breast cancer progression, thereby enhancing patients' survival. Disrupting the initiation and progression of this process by targeting angiogenic factors such as vascular endothelial growth factor (Vegf)-one of the most potent member of the VEGF family- or by targeting transcription factors, such as Hypoxia-Inducible Factors (HIFs) that act as angiogenic regulators, have been considered potential treatment options for several types of cancers. The objective of this review is to highlight the mechanism of angiogenesis in diseases, specifically its role in the progression of malignancy in breast cancer, as well as to highlight the undergoing research in the development of angiogenesis-targeting therapies.
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Affiliation(s)
- Chikezie O. Madu
- Departments of Biological Sciences, University of Memphis, Memphis, TN 38152. USA
| | - Stephanie Wang
- Departments of Biology and Advanced Placement Biology, White Station High School, Memphis, TN 38117. USA
| | - Chinua O. Madu
- Departments of Biology and Advanced Placement Biology, White Station High School, Memphis, TN 38117. USA
| | - Yi Lu
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN 38163. USA
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Haibe Y, Kreidieh M, El Hajj H, Khalifeh I, Mukherji D, Temraz S, Shamseddine A. Resistance Mechanisms to Anti-angiogenic Therapies in Cancer. Front Oncol 2020; 10:221. [PMID: 32175278 PMCID: PMC7056882 DOI: 10.3389/fonc.2020.00221] [Citation(s) in RCA: 242] [Impact Index Per Article: 48.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/10/2020] [Indexed: 12/12/2022] Open
Abstract
Tumor growth and metastasis rely on tumor vascular network for the adequate supply of oxygen and nutrients. Tumor angiogenesis relies on a highly complex program of growth factor signaling, endothelial cell (EC) proliferation, extracellular matrix (ECM) remodeling, and stromal cell interactions. Numerous pro-angiogenic drivers have been identified, the most important of which is the vascular endothelial growth factor (VEGF). The importance of pro-angiogenic inducers in tumor growth, invasion and extravasation make them an excellent therapeutic target in several types of cancers. Hence, the number of anti-angiogenic agents developed for cancer treatment has risen over the past decade, with at least eighty drugs being investigated in preclinical studies and phase I-III clinical trials. To date, the most common approaches to the inhibition of the VEGF axis include the blockade of VEGF receptors (VEGFRs) or ligands by neutralizing antibodies, as well as the inhibition of receptor tyrosine kinase (RTK) enzymes. Despite promising preclinical results, anti-angiogenic monotherapies led only to mild clinical benefits. The minimal benefits could be secondary to primary or acquired resistance, through the activation of alternative mechanisms that sustain tumor vascularization and growth. Mechanisms of resistance are categorized into VEGF-dependent alterations, non-VEGF pathways and stromal cell interactions. Thus, complementary approaches such as the combination of these inhibitors with agents targeting alternative mechanisms of blood vessel formation are urgently needed. This review provides an updated overview on the pathophysiology of angiogenesis during tumor growth. It also sheds light on the different pro-angiogenic and anti-angiogenic agents that have been developed to date. Finally, it highlights the preclinical evidence for mechanisms of angiogenic resistance and suggests novel therapeutic approaches that might be exploited with the ultimate aim of overcoming resistance and improving clinical outcomes for patients with cancer.
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Affiliation(s)
- Yolla Haibe
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Malek Kreidieh
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Hiba El Hajj
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
- Department of Experimental Pathology, Immunology and Microbiology, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Ibrahim Khalifeh
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Deborah Mukherji
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Sally Temraz
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Ali Shamseddine
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
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Ramadan WS, Zaher DM, Altaie AM, Talaat IM, Elmoselhi A. Potential Therapeutic Strategies for Lung and Breast Cancers through Understanding the Anti-Angiogenesis Resistance Mechanisms. Int J Mol Sci 2020; 21:565. [PMID: 31952335 PMCID: PMC7014257 DOI: 10.3390/ijms21020565] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/16/2019] [Accepted: 01/03/2020] [Indexed: 02/07/2023] Open
Abstract
Breast and lung cancers are among the top cancer types in terms of incidence and mortality burden worldwide. One of the challenges in the treatment of breast and lung cancers is their resistance to administered drugs, as observed with angiogenesis inhibitors. Based on clinical and pre-clinical findings, these two types of cancers have gained the ability to resist angiogenesis inhibitors through several mechanisms that rely on cellular and extracellular factors. This resistance is mediated through angiogenesis-independent vascularization, and it is related to cancer cells and their microenvironment. The mechanisms that cancer cells utilize include metabolic symbiosis and invasion, and they also take advantage of neighboring cells like macrophages, endothelial cells, myeloid and adipose cells. Overcoming resistance is of great interest, and researchers are investigating possible strategies to enhance sensitivity towards angiogenesis inhibitors. These strategies involved targeting multiple players in angiogenesis, epigenetics, hypoxia, cellular metabolism and the immune system. This review aims to discuss the mechanisms of resistance to angiogenesis inhibitors and to highlight recently developed approaches to overcome this resistance.
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Affiliation(s)
- Wafaa S. Ramadan
- College of Medicine, University of Sharjah, Sharjah 27272, UAE; (W.S.R.); (D.M.Z.); (A.M.A.); (A.E.)
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE
| | - Dana M. Zaher
- College of Medicine, University of Sharjah, Sharjah 27272, UAE; (W.S.R.); (D.M.Z.); (A.M.A.); (A.E.)
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE
| | - Alaa M. Altaie
- College of Medicine, University of Sharjah, Sharjah 27272, UAE; (W.S.R.); (D.M.Z.); (A.M.A.); (A.E.)
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, UAE
| | - Iman M. Talaat
- College of Medicine, University of Sharjah, Sharjah 27272, UAE; (W.S.R.); (D.M.Z.); (A.M.A.); (A.E.)
- Pathology Department, Faculty of Medicine, Alexandria University, 21526 Alexandria, Egypt
| | - Adel Elmoselhi
- College of Medicine, University of Sharjah, Sharjah 27272, UAE; (W.S.R.); (D.M.Z.); (A.M.A.); (A.E.)
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
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29
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Nicolini G, Forini F, Kusmic C, Iervasi G, Balzan S. Angiopoietin 2 signal complexity in cardiovascular disease and cancer. Life Sci 2019; 239:117080. [PMID: 31756341 DOI: 10.1016/j.lfs.2019.117080] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/12/2019] [Accepted: 11/13/2019] [Indexed: 12/12/2022]
Abstract
The angiopoietin signal transduction system is a complex of vascular-specific kinase pathways that plays a crucial role in angiogenesis and maintenance of vascular homeostasis. Angiopoietin1 (Ang1) and 2 (Ang2), the ligand proteins of the pathway, belong to a family of glycoproteins that signal primarily through the transmembrane Tyrosine-kinase-2 receptor. Despite a considerable sequence homology, Ang1 and Ang2 manifest antagonistic effects in pathophysiological conditions. While Ang1 promotes the activation of survival pathways and the stabilization of the normal mature vessels, Ang2 can either favor vessel destabilization and leakage or promote abnormal EC proliferation in a context-dependent manner. Altered Ang1/Ang2 balance has been reported in various pathological conditions in association with inflammation and deregulated angiogenesis. In particular, increased Ang2 levels have been documented in human cancer and cardiovascular disease (CVD), including ischemic myocardial injury, heart failure and other cardiovascular complications secondary to diabetes, chronic renal damage and hypertension. Despite the obvious phenotypic differences, CVD and cancer share some common Ang2-dependent etiopathological mechanisms such as inflammation, epithelial (or endothelial) to mesenchymal transition, and adverse vascular network remodeling. Interestingly, both cancer and CVD are negatively affected by thyroid hormone dyshomeostasis. This review provides an overview of the complex Ang2-dependent signaling involved in CVD and cancer, as well as a survey of the related clinical literature. Moreover, on the basis of recent molecular acquisitions in an experimental model of post ischemic cardiac disease, the putative novel role of the thyroid hormone in the regulation of Ang1/Ang2 balance is also briefly discussed.
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Affiliation(s)
| | - Francesca Forini
- Institute of Clinical Physiology, CNR, Via G.Moruzzi 1, 56124 Pisa, Italy.
| | - Claudia Kusmic
- Institute of Clinical Physiology, CNR, Via G.Moruzzi 1, 56124 Pisa, Italy.
| | - Giorgio Iervasi
- Institute of Clinical Physiology, CNR, Via G.Moruzzi 1, 56124 Pisa, Italy.
| | - Silvana Balzan
- Institute of Clinical Physiology, CNR, Via G.Moruzzi 1, 56124 Pisa, Italy.
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Vessel co-option in glioblastoma: emerging insights and opportunities. Angiogenesis 2019; 23:9-16. [PMID: 31679081 PMCID: PMC7012982 DOI: 10.1007/s10456-019-09691-z] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 10/05/2019] [Indexed: 12/13/2022]
Abstract
Vessel co-option is the movement of cancer cells towards and along the pre-existing vasculature and is an alternative to angiogenesis to gain access to nutrients. Vessel co-option has been shown as a strategy employed by some glioblastoma (GBM) cells to invade further into the brain, leading to one of the greatest challenges in treating GBM. In GBM, vessel co-option may be an intrinsic feature or an acquired mechanism of resistance to anti-angiogenic treatment. Here, we describe the histological features and the dynamics visualized through intravital microscopy of vessel co-option in GBM, as well as the molecular players discovered until now. We also highlight key unanswered questions, as answering these is critical to improve understanding of GBM progression and for developing more effective approaches for GBM treatment.
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Senchukova MA, Makarova EV, Kalinin EA, Tkachev VV. Modern ideas about the origin, features of morphology, prognostic and predictive significance of tumor vessels. RUSSIAN JOURNAL OF BIOTHERAPY 2019; 18:6-15. [DOI: 10.17650/1726-9784-2019-18-1-6-15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The review presents modern ideas about the origin of tumor vessels and the features of their morphology. The various approaches to the classification of tumor vessel types and to the assessment of their clinical and prognostic significance are described. Also, the main problems associated with the use of angiogenesis blockers in the treatment of malignancies and their possible solutions are reflected in the review.
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Affiliation(s)
- M. A. Senchukova
- Orenburg State Medical University of the Ministry of Health of the Russian Federation; Orenburg Regional Clinical Oncology Dispensary
| | - E. V. Makarova
- Orenburg State Medical University of the Ministry of Health of the Russian Federation; Orenburg Regional Clinical Oncology Dispensary
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Katayama Y, Uchino J, Chihara Y, Tamiya N, Kaneko Y, Yamada T, Takayama K. Tumor Neovascularization and Developments in Therapeutics. Cancers (Basel) 2019; 11:cancers11030316. [PMID: 30845711 PMCID: PMC6468754 DOI: 10.3390/cancers11030316] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/28/2019] [Accepted: 03/04/2019] [Indexed: 12/12/2022] Open
Abstract
Tumors undergo fast neovascularization to support the rapid proliferation of cancer cells. Vasculature in tumors, unlike that in wound healing, is immature and affects the tumor microenvironment, resulting in hypoxia, acidosis, glucose starvation, immune cell infiltration, and decreased activity, all of which promote cancer progression, metastasis, and drug resistance. This innate defect of tumor vasculature can however represent a useful therapeutic target. Angiogenesis inhibitors targeting tumor vascular endothelial cells important for angiogenesis have attracted attention as cancer therapy agents that utilize features of the tumor microenvironment. While angiogenesis inhibitors have the advantage of targeting neovascularization factors common to all cancer types, some limitations to their deployment have emerged. Further understanding of the mechanism of tumor angiogenesis may contribute to the development of new antiangiogenic therapeutic approaches to control tumor invasion and metastasis. This review discusses the mechanism of tumor angiogenesis as well as angiogenesis inhibition therapy with antiangiogenic agents.
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Affiliation(s)
- Yuki Katayama
- Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Junji Uchino
- Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Yusuke Chihara
- Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Nobuyo Tamiya
- Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Yoshiko Kaneko
- Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
| | - Koichi Takayama
- Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
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Estrogen receptor β promotes the vasculogenic mimicry (VM) and cell invasion via altering the lncRNA-MALAT1/miR-145-5p/NEDD9 signals in lung cancer. Oncogene 2018; 38:1225-1238. [DOI: 10.1038/s41388-018-0463-1] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 05/30/2018] [Accepted: 05/31/2018] [Indexed: 12/13/2022]
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Lou W, Liu J, Gao Y, Zhong G, Chen D, Shen J, Bao C, Xu L, Pan J, Cheng J, Ding B, Fan W. MicroRNAs in cancer metastasis and angiogenesis. Oncotarget 2017; 8:115787-115802. [PMID: 29383201 PMCID: PMC5777813 DOI: 10.18632/oncotarget.23115] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 11/17/2017] [Indexed: 12/15/2022] Open
Abstract
Cancer metastasis is a malignant process by which tumor cells migrate from their primary site of origin to other organs. It is the main cause of poor prognosis in cancer patients. Angiogenesis is the process of generating new blood capillaries from pre-existing vasculature. It plays a vital role in primary tumor growth and distant metastasis. MicroRNAs are small non-coding RNAs involved in regulating normal physiological processes as well as cancer pathogenesis. They suppress gene expression by specifically binding to the 3′-untranslated region (3′-UTR) of their target genes. They can thus act as oncogenes or tumor suppressors depending on the function of their target genes. MicroRNAs have shown great promise for use in anti-metastatic cancer therapy. In this article, we review the roles of various miRNAs in cancer angiogenesis and metastasis and highlight their potential for use in future therapies against metastatic cancer.
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Affiliation(s)
- Weiyang Lou
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
| | - Jingxing Liu
- Department of Intensive Care Unit, Changxing People's Hospital of Zhejiang, Zhejiang Province, Huzhou 313100, China
| | - Yanjia Gao
- Department of Anesthesiology, International Hospital of Zhejiang University, Shulan (Hangzhou) Hospital, Zhejiang Province, Hangzhou 310003, China
| | - Guansheng Zhong
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
| | - Danni Chen
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
| | - Jiaying Shen
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
| | - Chang Bao
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
| | - Liang Xu
- Clinical Research Center, First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou 310003, China
| | - Jie Pan
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
| | - Junchi Cheng
- Department of Chemotherapy, Zhejiang Cancer Hospital, Zhejiang Province, Hangzhou 310003, China
| | - Bisha Ding
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
| | - Weimin Fan
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China.,Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
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Pre- and post-diagnostic β-blocker use and lung cancer survival: A population-based cohort study. Sci Rep 2017; 7:2911. [PMID: 28588274 PMCID: PMC5460218 DOI: 10.1038/s41598-017-02913-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 04/20/2017] [Indexed: 11/08/2022] Open
Abstract
Beta-blockers have been associated with decreased cancer mortality. However, evidence for lung cancer is sparse and reported beneficial effects might be based on biased analyses. In this so far largest study we investigated the association between β-blocker use and lung cancer survival. Therefore, patients with a lung cancer diagnosis between April 1998 and December 2011 were selected from a database linkage of the Netherlands Cancer Registry and the PHARMO Database Network. After matching eligible patients on the propensity score, adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were calculated using Cox proportional hazards regression to investigate the association between pre-diagnostic and time-dependent β-blocker use and overall survival. Duration and dose-response analyses and stratified analyses by β-blocker type, histological subgroups and stage were conducted. Of 3,340 eligible lung cancer patients, 1437 (43%) took β-blockers four months prior to diagnosis. Pre-diagnostic β-blocker use was not associated with overall survival (HR 1.00 (0.92–1.08)) in the adjusted model. Time-dependent post-diagnostic analysis showed similar results with a HR of 1.03 (0.94–1.11). Trend analyses showed no association for cumulative dose (HR 0.99 (0.97–1.02)) and cumulative duration (HR 1.00 (0.96–1.05)). In conclusion, β-blocker use is not associated with reduced mortality among lung cancer patients.
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Xue D, Yang Y, Liu Y, Wang P, Dai Y, Liu Q, Chen L, Shen J, Ju H, Li Y, Tan Z. MicroRNA-206 attenuates the growth and angiogenesis in non-small cell lung cancer cells by blocking the 14-3-3ζ/STAT3/HIF-1α/VEGF signaling. Oncotarget 2016; 7:79805-79813. [PMID: 27806334 PMCID: PMC5346752 DOI: 10.18632/oncotarget.12972] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 10/14/2016] [Indexed: 01/09/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Angiogenesis is the major hallmark in NSCLC. So, further elucidation of molecular mechanisms underlying the angiogenesis of NSCLC is urgently needed. Here, we found that microRNA-206 (miR-206) decreased the angiogenic ability in NSCLC via inhibiting the 14-3-3ζ/STAT3/HIF-1α/VEGF pathway. Briefly, 14-3-3ζ bond with phosphorylated-STAT3, and in turn, elevated the expression of HIF-1α. Then, by enhancing the recruitment of HIF-1α to VEGF promoter, 14-3-3ζ increased the angiogenesis. However, miR-206 decreased the angiogenesis by targeting 14-3-3ζ, and inhibiting the STAT3/HIF-1α/VEGF pathway. In NSCLC cell xenograft model, either overexpression of miR-206 or inhibition of 14-3-3ζ inhibited the STAT3/HIF-1α/VEGF pathway and decreased the tumor growth and angiogenesis. Furthermore, there was a negative correlation between miR-206 and 14-3-3ζ in NSCLC specimens. NSCLC patients with low expressions of miR-206 but high expressions of 14-3-3ζ had the worst survival. Collectively, our findings provided the underlying mechanisms of miR-206/14-3-3ζ in tumor growth and angiogenesis, and implicated miR-206 and 14-3-3ζ as potential therapeutic targets for NSCLC.
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Affiliation(s)
- Dong Xue
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Ye Yang
- Department of Nutrition And Food Hygiene, School Of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Yawei Liu
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Peiwen Wang
- Department of Nutrition And Food Hygiene, School Of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Yi Dai
- Department of Nutrition And Food Hygiene, School Of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Qinqiang Liu
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Lijun Chen
- Department of Nutrition And Food Hygiene, School Of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Jian Shen
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Huanyu Ju
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Yuan Li
- Department of Nutrition And Food Hygiene, School Of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Zhenguo Tan
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
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Eldridge L, Moldobaeva A, Zhong Q, Jenkins J, Snyder M, Brown RH, Mitzner W, Wagner EM. Bronchial Artery Angiogenesis Drives Lung Tumor Growth. Cancer Res 2016; 76:5962-5969. [PMID: 27569207 DOI: 10.1158/0008-5472.can-16-1131] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 08/11/2016] [Indexed: 02/06/2023]
Abstract
Angiogenesis is vital for tumor growth but in well-vascularized organs such as the lung its importance is unclear. This situation is complicated by the fact that the lung has two separate circulations, the pulmonary and the systemic bronchial circulation. There are few relevant animal models of non-small cell lung cancer, which can be used to study the lung's complex circulations, and mice, lacking a systemic bronchial circulation cannot be used. We report here a novel orthotopic model of non-small cell lung cancer in rats, where we have studied the separate contributions of each of the two circulations for lung tumor growth. Results show that bronchial artery perfusion, quantified by fluorescent microspheres (206% increase in large tumors) or high-resolution computed tomography scans (276% increase in large tumors), parallels the growth in tumor volume, whereas pulmonary artery perfusion remained unchanged. Ablation of the bronchial artery after the initiation of tumor growth resulted in a decrease in tumor volume over a subsequent course of 4 weeks. These results demonstrate that although the existing pulmonary circulation can supply the metabolic needs for tumor initiation, further growth of the tumor requires angiogenesis from the highly proliferative bronchial circulation. This model may be useful to investigate new therapeutic approaches that target specifically the bronchial circulation. Cancer Res; 76(20); 5962-9. ©2016 AACR.
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Affiliation(s)
- Lindsey Eldridge
- Departments of Medicine and Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland
| | - Aigul Moldobaeva
- Departments of Medicine and Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland
| | - Qiong Zhong
- Departments of Medicine and Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland
| | - John Jenkins
- Departments of Medicine and Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland
| | - Michael Snyder
- Departments of Medicine and Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland
| | - Robert H Brown
- Departments of Medicine and Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland
| | - Wayne Mitzner
- Departments of Medicine and Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland
| | - Elizabeth M Wagner
- Departments of Medicine and Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland.
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