Vascular Cell最新文献

{"title":"Lysosomal drug sequestration as a mechanism of drug resistance in vascular sarcoma cells marked by high CSF-1R expression.","authors":"Brandi H Gorden,&nbsp;Jhuma Saha,&nbsp;Ali Khammanivong,&nbsp;Gary K Schwartz,&nbsp;Erin B Dickerson","doi":"10.1186/2045-824X-6-20","DOIUrl":"https://doi.org/10.1186/2045-824X-6-20","url":null,"abstract":"<p><strong>Background: </strong>Human angiosarcoma and canine hemangiosarcoma are thought to arise from vascular tissue or vascular forming cells based upon their histological appearance. However, recent evidence indicates a hematopoietic or angioblastic cell of origin for these tumors. In support of this idea, we previously identified an endothelial-myeloid progenitor cell population with high expression of endothelial cell markers and the myeloid cell marker, colony stimulating factor 1 receptor (CSF-1R). Here, we further characterized these cells to better understand how their cellular characteristics may impact current therapeutic applications.</p><p><strong>Methods: </strong>We performed cell enrichment studies from canine hemangiosarcoma and human angiosarcoma cell lines to generate cell populations with high or low CSF-1R expression. We then utilized flow cytometry, side population and cell viability assays, and fluorescence based approaches to elucidate drug resistance mechanisms and to determine the expression of hematopoietic and endothelial progenitor cell markers.</p><p><strong>Results: </strong>We demonstrated that cells with high CSF-1R expression enriched from hemangiosarcoma and angiosarcoma cell lines are more drug resistant than cells with little or no CSF-1R expression. We determined that the increased drug resistance may be due to increased ABC transporter expression in hemangiosarcoma and increased drug sequestration within cellular lysosomes in both hemangiosarcoma and angiosarcoma.</p><p><strong>Conclusions: </strong>We identified drug sequestration within cellular lysosomes as a shared drug resistance mechanism in human and canine vascular sarcomas marked by high CSF-1R expression. Taken together, our results demonstrate that studies in highly prevalent canine hemangiosarcoma may be especially relevant to understanding and addressing drug resistance mechanisms in both the canine and human forms of this disease.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-824X-6-20","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32730054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Previously differentiated medial vascular smooth muscle cells contribute to neointima formation following vascular injury.","authors":"Brian Paul Herring,&nbsp;April M Hoggatt,&nbsp;Christopher Burlak,&nbsp;Stefan Offermanns","doi":"10.1186/2045-824X-6-21","DOIUrl":"https://doi.org/10.1186/2045-824X-6-21","url":null,"abstract":"<p><strong>Background: </strong>The origins of neointimal smooth muscle cells that arise following vascular injury remains controversial. Studies have suggested that these cells may arise from previously differentiated medial vascular smooth muscle cells, resident stem cells or blood born progenitors. In the current study we examined the contribution of the previously differentiated vascular smooth muscle cells to the neointima that forms following carotid artery ligation.</p><p><strong>Methods: </strong>We utilized transgenic mice harboring a cre recombinase-dependent reporter gene (mTmG). These mice express membrane targeted tandem dimer Tomato (mTomato) prior to cre-mediated excision and membrane targeted EGFP (mEGFP) following excision. The mTmG mice were crossed with transgenic mice expressing either smooth muscle myosin heavy chain (Myh11) or smooth muscle α-actin (Acta2) driven tamoxifen regulated cre recombinase. Following treatment of adult mice with tamoxifen these mice express mEGFP exclusively in differentiated smooth muscle cells. Subsequently vascular injury was induced in the mice by carotid artery ligation and the contribution of mEGFP positive cells to the neointima determined.</p><p><strong>Results: </strong>Analysis of the cellular composition of the neointima that forms following injury revealed that mEGFP positive cells derived from either Mhy11 or Acta2 tagged medial vascular smooth muscle cells contribute to the majority of neointima formation (79 ± 17% and 81 ± 12%, respectively).</p><p><strong>Conclusion: </strong>These data demonstrate that the majority of the neointima that forms following carotid ligation is derived from previously differentiated medial vascular smooth muscle cells.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-824X-6-21","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32741352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ageing and microvasculature.","authors":"Maria Giovanna Scioli,&nbsp;Alessandra Bielli,&nbsp;Gaetano Arcuri,&nbsp;Amedeo Ferlosio,&nbsp;Augusto Orlandi","doi":"10.1186/2045-824X-6-19","DOIUrl":"https://doi.org/10.1186/2045-824X-6-19","url":null,"abstract":"<p><p>A decline in the function of the microvasculature occurs with ageing. An impairment of endothelial properties represents a main aspect of age-related microvascular alterations. Endothelial dysfunction manifests itself through a reduced angiogenic capacity, an aberrant expression of adhesion molecules and an impaired vasodilatory function. Increased expression of adhesion molecules amplifies the interaction with circulating factors and inflammatory cells. The latter occurs in both conduit arteries and resistance arterioles. Age-related impaired function also associates with phenotypic alterations of microvascular cells, such as endothelial cells, smooth muscle cells and pericytes. Age-related morphological changes are in most of cases organ-specific and include microvascular wall thickening and collagen deposition that affect the basement membrane, with the consequent perivascular fibrosis. Data from experimental models indicate that decreased nitric oxide (NO) bioavailability, caused by impaired eNOS activity and NO inactivation, is one of the causes responsible for age-related microvascular endothelial dysfunction. Consequently, vasodilatory responses decline with age in coronary, skeletal, cerebral and vascular beds. Several therapeutic attempts have been suggested to improve microvascular function in age-related end-organ failure, and include the classic anti-atherosclerotic and anti-ischemic treatments, and also new innovative strategies. Change of life style, antioxidant regimens and anti-inflammatory treatments gave the most promising results. Research efforts should persist to fully elucidate the biomolecular basis of age-related microvascular dysfunction in order to better support new therapeutic strategies aimed to improve quality of life and to reduce morbidity and mortality among the elderly patients. </p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-824X-6-19","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32686056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage.","authors":"Yuji Yamamoto,&nbsp;Junji Matsui,&nbsp;Tomohiro Matsushima,&nbsp;Hiroshi Obaishi,&nbsp;Kazuki Miyazaki,&nbsp;Katsuji Nakamura,&nbsp;Osamu Tohyama,&nbsp;Taro Semba,&nbsp;Atsumi Yamaguchi,&nbsp;Sachi Suzuki Hoshi,&nbsp;Fusayo Mimura,&nbsp;Toru Haneda,&nbsp;Yoshio Fukuda,&nbsp;Jun-Ichi Kamata,&nbsp;Keiko Takahashi,&nbsp;Masayuki Matsukura,&nbsp;Toshiaki Wakabayashi,&nbsp;Makoto Asada,&nbsp;Ken-Ichi Nomoto,&nbsp;Tatsuo Watanabe,&nbsp;Zoltan Dezso,&nbsp;Kentaro Yoshimatsu,&nbsp;Yasuhiro Funahashi,&nbsp;Akihiko Tsuruoka","doi":"10.1186/2045-824X-6-18","DOIUrl":"https://doi.org/10.1186/2045-824X-6-18","url":null,"abstract":"<p><strong>Background: </strong>Lenvatinib is an oral inhibitor of multiple receptor tyrosine kinases (RTKs) targeting vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor (FGFR1-4), platelet growth factor receptor α (PDGFR α), RET and KIT. Antiangiogenesis activity of lenvatinib in VEGF- and FGF-driven angiogenesis models in both in vitro and in vivo was determined. Roles of tumor vasculature (microvessel density (MVD) and pericyte coverage) as biomarkers for lenvatinib were also examined in this study.</p><p><strong>Method: </strong>We evaluated antiangiogenesis activity of lenvatinib against VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. Effects of lenvatinib on in vivo angiogenesis, which was enhanced by overexpressed VEGF or FGF in human pancreatic cancer KP-1 cells, were examined in the mouse dorsal air sac assay. We determined antitumor activity of lenvatinib in a broad panel of human tumor xenograft models to test if vascular score, which consisted of high MVD and low pericyte coverage, was associated with sensitivity to lenvatinib treatment. Vascular score was also analyzed using human tumor specimens with 18 different types of human primary tumors.</p><p><strong>Result: </strong>Lenvatinib inhibited VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. In vivo angiogenesis induced by overexpressed VEGF (KP-1/VEGF transfectants) or FGF (KP-1/FGF transfectants) was significantly suppressed with oral treatments of lenvatinib. Lenvatinib showed significant antitumor activity in KP-1/VEGF and five 5 of 7 different types of human tumor xenograft models at between 1 to 100 mg/kg. We divided 19 human tumor xenograft models into lenvatinib-sensitive (tumor-shrinkage) and relatively resistant (slow-growth) subgroups based on sensitivity to lenvatinib treatments at 100 mg/kg. IHC analysis showed that vascular score was significantly higher in sensitive subgroup than relatively resistant subgroup (p < 0.0004). Among 18 types of human primary tumors, kidney cancer had the highest MVD, while liver cancer had the lowest pericyte coverage, and cancers in Kidney and Stomach had highest vascular score.</p><p><strong>Conclusion: </strong>These results indicated that Lenvatinib inhibited VEGF- and FGF-driven angiogenesis and showed a broad spectrum of antitumor activity with a wide therapeutic window. MVD and pericyte-coverage of tumor vasculature might be biomarkers and suggest cases that would respond for lenvatinib therapy.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-824X-6-18","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32648001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Limitations of the dorsal skinfold window chamber model in evaluating anti-angiogenic therapy during early phase of angiogenesis.","authors":"Nikolett M Biel,&nbsp;Jennifer A Lee,&nbsp;Brian S Sorg,&nbsp;Dietmar W Siemann","doi":"10.1186/2045-824X-6-17","DOIUrl":"https://doi.org/10.1186/2045-824X-6-17","url":null,"abstract":"<p><strong>Background: </strong>Angiogenesis is an essential process during tumor development and growth. The murine dorsal skinfold window chamber model has been used for the study of both tumor microvasculature and other vascular diseases, including the study of anti-angiogenic agents in cancer therapy. Hyperspectral imaging of oxygen status of the microvasculature has not been widely used to evaluate response to inhibition of angiogenesis in early tumor cell induced vascular development. This study demonstrates the use of two different classes of anti-angiogenic agents, one targeting the Vascular Endothelial Growth Factor (VEGF) pathway involved with vessel sprouting and the other targeting the Angiopoietin/Tie2 pathway involved in vascular destabilization. Studies evaluated the tumor microvascular response to anti-angiogenic inhibitors in the highly angiogenic renal cell carcinoma induced angiogenesis model.</p><p><strong>Methods: </strong>Human renal cell carcinoma, Caki-2 cells, were implanted in the murine skinfold window chamber. Mice were treated with either VEGF pathway targeted small molecule inhibitor Sunitinib (100 mg/kg) or with an anti-Ang-2 monoclonal antibody (10 mg/kg) beginning the day of window chamber surgery and tumor cell implantation. Hyperspectral imaging of hemoglobin saturation was used to evaluate both the development and oxygenation of the tumor microvasculature. Tumor volume over time was also assessed over an 11-day period post surgery.</p><p><strong>Results: </strong>The window chamber model was useful to demonstrate the inhibition of angiogenesis using the VEGF pathway targeted agent Sunitinib. Results show impairment of tumor microvascular development, reduced oxygenation of tumor-associated vasculature and impairment of tumor volume growth compared to control. On the other hand, this model failed to demonstrate the anti-angiogenic effect of the Ang-2 targeted agent. Follow up experiments suggest that the initial surgery of the window chamber model may interfere with such an agent thus skewing the actual effects on angiogenesis.</p><p><strong>Conclusions: </strong>Results show that this model has great potential to evaluate anti-VEGF, or comparable, targeted agents; however the mere protocol of the window chamber model interferes with proper evaluation of Ang-2 targeted agents. The limitations of this in vivo model in evaluating the response of tumor vasculature to anti-angiogenic agents are discussed.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-824X-6-17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32567041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VEGFR-1 blockade disrupts peri-implantation decidual angiogenesis and macrophage recruitment.","authors":"Nataki C Douglas,&nbsp;Ralf C Zimmermann,&nbsp;Qian Kun Tan,&nbsp;Chantae S Sullivan-Pyke,&nbsp;Mark V Sauer,&nbsp;Jan K Kitajewski,&nbsp;Carrie J Shawber","doi":"10.1186/2045-824X-6-16","DOIUrl":"https://doi.org/10.1186/2045-824X-6-16","url":null,"abstract":"<p><strong>Background: </strong>Angiogenesis and macrophage recruitment to the uterus are key features of uterine decidualization; the progesterone-mediated uterine changes that allow for embryo implantation and initiation of pregnancy. In the current study, we characterized the expression of vascular endothelial growth factor receptor-1 (VEGFR-1) in macrophages and endothelial cells of the peri-implantation uterus and determined if VEGFR-1 function is required for decidual angiogenesis, macrophage recruitment, and/or the establishment of pregnancy.</p><p><strong>Methods: </strong>Expression of VEGFR-1 in uterine endothelial cells and macrophages was determined with immunohistochemistry. To assess the effect of continuous VEGFR-1 blockade, adult female mice were given VEGFR-1 blocking antibody, MF-1, every 3 days for 18 days. After 6 doses, females were mated and a final dose of MF-1 was given on embryonic day 3.5. Endothelial cells and macrophages were quantified on embryonic day 7.5. Pregnancy was analyzed on embryonic days 7.5 and 10.5.</p><p><strong>Results: </strong>F4/80(+) macrophages are observed throughout the stroma and are abundant adjacent to the endometrial lumen and glands prior to embryo implantation and scatter throughout the decidua post implantation. VEGFR-1 expression is restricted to the uterine endothelial cells. F4/80(+) macrophages were often found adjacent to VEGFR-1(+) endothelial cells in the primary decidual zone. Continuous VEGFR-1 blockade correlates with a significant reduction in decidual vascular and macrophage density, but does not affect embryo implantation or maintenance of pregnancy up to embryonic day 10.5.</p><p><strong>Conclusions: </strong>We found that VEGFR-1 functions in both decidual angiogenesis and macrophage recruitment to the implantation site during pregnancy. VEGFR-1 is expressed by endothelial cells, however blocking VEGFR-1 function in endothelial cells results in reduced macrophage recruitment to the uterus. VEGFR-1 blockade did not compromise the establishment and/or maintenance of pregnancy.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-824X-6-16","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32567040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of side effects of radiofrequency capacitive hyperthermia with magnetite on the blood vessel walls of tumor metastatic lesion surrounding the abdominal large vessels: an agar phantom study.","authors":"Noriyasu Kawai,&nbsp;Daichi Kobayashi,&nbsp;Takahiro Yasui,&nbsp;Yukihiro Umemoto,&nbsp;Kentaro Mizuno,&nbsp;Atsushi Okada,&nbsp;Keiichi Tozawa,&nbsp;Takeshi Kobayashi,&nbsp;Kenjiro Kohri","doi":"10.1186/2045-824X-6-15","DOIUrl":"https://doi.org/10.1186/2045-824X-6-15","url":null,"abstract":"<p><strong>Background: </strong>Magnetite used in an 8-MHz radiofrequency (RF) capacitive heating device can increase the temperature of a specific site up to 45°C. When treating a metastatic lesion around large abdominal vessels via hyperthermia with magnetite, heating-induced adverse effects on these vessels need to be considered. Therefore, this study examined hyperthermia-induced damage to blood vessel walls in vitro.</p><p><strong>Methods: </strong>A large agar phantom with a circulatory system consisting of a swine artery and vein connected to a peristaltic pump was prepared. The blood vessels were placed on the magnetite-containing agar piece. Heating was continued for 30 min at 45°C. After heating, a histological study for injury to the blood vessels was performed.</p><p><strong>Results: </strong>The inner membrane temperature did not reach 45°C due to the cooling effect of the blood flow. In the heated vessels, vascular wall collagen degenerated and smooth muscle cells were narrowed; however, no serious changes were noted in the vascular endothelial cells or vascular wall elastic fibers. The heated vessel wall was not severely damaged; this was attributed to cooling by the blood flow.</p><p><strong>Conclusions: </strong>Our findings indicate that RF capacitive heating therapy with magnetite may be used for metastatic lesions without injuring the surrounding large abdominal vessels.</p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-824X-6-15","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32577627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flow-regulated lymphatic vasculature development and signaling.","authors":"Yingdi Wang,&nbsp;Michael Simons","doi":"10.1186/2045-824X-6-14","DOIUrl":"https://doi.org/10.1186/2045-824X-6-14","url":null,"abstract":"<p><p>The role of blood flow in regulating signaling pathways and gene expression in the blood vasculature is well known. Recent studies have identified equally important roles of flow-mediated signaling in the lymphatic circulation including control of lymphatic vascular growth, remodeling, regeneration and maintenance of the lymphatic fate. In this review, we summarize these advances focusing on the role of fluid dynamics in control of lymphatic vasculature formation. </p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-824X-6-14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32529402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro pre-vascularisation of tissue-engineered constructs A co-culture perspective.","authors":"Jeremy Baldwin, Mélanie Antille, Ulrich Bonda, Elena M De-Juan-Pardo, Kiarash Khosrotehrani, Saso Ivanovski, Eugen Bogdan Petcu, Dietmar Werner Hutmacher","doi":"10.1186/2045-824X-6-13","DOIUrl":"10.1186/2045-824X-6-13","url":null,"abstract":"<p><p>In vitro pre-vascularization is one of the main vascularization strategies in the tissue engineering field. Culturing cells within a tissue-engineered construct (TEC) prior to implantation provides researchers with a greater degree of control over the fate of the cells. However, balancing the diverse range of different cell culture parameters in vitro is seldom easy and in most cases, especially in highly vascularized tissues, more than one cell type will reside within the cell culture system. Culturing multiple cell types in the same construct presents its own unique challenges and pitfalls. The following review examines endothelial-driven vascularization and evaluates the direct and indirect role other cell types have in vessel and capillary formation. The article then analyses the different parameters researchers can modulate in a co-culture system in order to design optimal tissue-engineered constructs to match desired clinical applications. </p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32542985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells.","authors":"Edmund Chinchar,&nbsp;Kristina L Makey,&nbsp;John Gibson,&nbsp;Fang Chen,&nbsp;Shelby A Cole,&nbsp;Gail C Megason,&nbsp;Srinivassan Vijayakumar,&nbsp;Lucio Miele,&nbsp;Jian-Wei Gu","doi":"10.1186/2045-824X-6-12","DOIUrl":"https://doi.org/10.1186/2045-824X-6-12","url":null,"abstract":"<p><p>The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 10(6) MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm(3), sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44(+)/CD24(-) or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an innovative therapeutic strategy in TNBC therapy by using sunitinib plus γ-secretase inhibitor to simultaneously target angiogenesis and CSC. </p>","PeriodicalId":23948,"journal":{"name":"Vascular Cell","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2045-824X-6-12","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32410358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}