JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells.
Neuro-oncology
PUBLISHED: 07-09-2014
Show Abstract
Hide Abstract
Recent evidence suggests that astrocytes protect cancer cells from chemotherapy by stimulating upregulation of anti-apoptotic genes in those cells. We investigated the possibility that activation of the endothelin axis orchestrates survival gene expression and chemoprotection in MDA-MB-231 breast cancer cells and H226 lung cancer cells.
Related JoVE Video
Antiangiogenic Therapy with Human Apolipoprotein(a) Kringle V and Paclitaxel in a Human Ovarian Cancer Mouse Model.
Transl Oncol
PUBLISHED: 06-17-2014
Show Abstract
Hide Abstract
The present study compared the effect of combination therapy using human apolipoprotein(a) kringle V (rhLK8) to conventional chemotherapy with paclitaxel for human ovarian carcinoma producing high or low levels of vascular endothelial growth factor (VEGF).
Related JoVE Video
Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity.
Sci Transl Med
PUBLISHED: 05-31-2013
Show Abstract
Hide Abstract
Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor used in the treatment of human malignancies. A substantial number of sunitinib-treated patients develop cardiac dysfunction, but the mechanism of sunitinib-induced cardiotoxicity is poorly understood. We show that mice treated with sunitinib develop cardiac and coronary microvascular dysfunction and exhibit an impaired cardiac response to stress. The physiological changes caused by treatment with sunitinib are accompanied by a substantial depletion of coronary microvascular pericytes. Pericytes are a cell type that is dependent on intact platelet-derived growth factor receptor (PDGFR) signaling but whose role in the heart is poorly defined. Sunitinib-induced pericyte depletion and coronary microvascular dysfunction are recapitulated by CP-673451, a structurally distinct PDGFR inhibitor, confirming the role of PDGFR in pericyte survival. Thalidomide, an anticancer agent that is known to exert beneficial effects on pericyte survival and function, prevents sunitinib-induced pericyte cell death in vitro and prevents sunitinib-induced cardiotoxicity in vivo in a mouse model. Our findings suggest that pericytes are the primary cellular target of sunitinib-induced cardiotoxicity and reveal the pericyte as a cell type of concern in the regulation of coronary microvascular function. Furthermore, our data provide preliminary evidence that thalidomide may prevent cardiotoxicity in sunitinib-treated cancer patients.
Related JoVE Video
DNA-damage-induced nuclear export of precursor microRNAs is regulated by the ATM-AKT pathway.
Cell Rep
PUBLISHED: 04-25-2013
Show Abstract
Hide Abstract
Expression of microRNAs (miRNAs) involves transcription of miRNA genes and maturation of the primary transcripts. Recent studies have shown that posttranscriptional processing of primary and precursor miRNAs is induced after DNA damage through regulatory RNA-binding proteins in the Drosha and Dicer complexes, such as DDX5 and KSRP. However, little is known about the regulation of nuclear export of pre-miRNAs in the DNA-damage response, a critical step in miRNA maturation. Here, we show that nuclear export of pre-miRNAs is accelerated after DNA damage in an ATM-dependent manner. The ATM-activated AKT kinase phosphorylates Nup153, a key component of the nucleopore, leading to enhanced interaction between Nup153 and Exportin-5 (XPO5) and increased nuclear export of pre-miRNAs. These findings define an important role of DNA-damage signaling in miRNA transport and maturation.
Related JoVE Video
Biologic effects of dopamine on tumor vasculature in ovarian carcinoma.
Neoplasia
PUBLISHED: 02-27-2013
Show Abstract
Hide Abstract
Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA), an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2), our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine mono-phosphate (cAMP) levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth.
Related JoVE Video
ATP11B mediates platinum resistance in ovarian cancer.
J. Clin. Invest.
PUBLISHED: 02-14-2013
Show Abstract
Hide Abstract
Platinum compounds display clinical activity against a wide variety of solid tumors; however, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. We found that ATP11B expression was correlated with higher tumor grade in human ovarian cancer samples and with cisplatin resistance in human ovarian cancer cell lines. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-targeted siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux kinetics indicated that ATP11B enhances the export of cisplatin from cells. The colocalization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins, such as syntaxin-6 (STX6) and vesicular-associated membrane protein 4 (VAMP4), strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, inhibition of ATP11B expression could serve as a therapeutic strategy to overcome cisplatin resistance.
Related JoVE Video
Biological roles of the Delta family Notch ligand Dll4 in tumor and endothelial cells in ovarian cancer.
Cancer Res.
PUBLISHED: 07-27-2011
Show Abstract
Hide Abstract
Emerging evidence suggests that the Notch/Delta-like ligand 4 (Dll4) pathway may offer important new targets for antiangiogenesis approaches. In this study, we investigated the clinical and biological significance of Dll4 in ovarian cancer. Dll4 was overexpressed in 72% of tumors examined in which it was an independent predictor of poor survival. Patients with tumors responding to anti-VEGF therapy had lower levels of Dll4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased Dll4 expression in the tumor vasculature. Immobilized Dll4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of Dll4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining Dll4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared with control or treatment with bevacizumab alone. Together, our findings establish that Dll4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer and that targeting Dll4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment.
Related JoVE Video
The seed and soil hypothesis revisited--the role of tumor-stroma interactions in metastasis to different organs.
Int. J. Cancer
PUBLISHED: 02-01-2011
Show Abstract
Hide Abstract
The fact that certain tumors exhibit a predilection for metastasis to specific organs has been recognized for well over a century now. An extensive body of clinical data and experimental research has confirmed Stephen Pagets original "seed and soil" hypothesis that proposed the organ-preference patterns of tumor metastasis are the product of favorable interactions between metastatic tumor cells (the "seed") and their organ microenvironment (the "soil"). Indeed, many of the first-line therapeutic regimens, currently in use for the treatment of human cancer are designed to target cancer cells (such as chemotherapy) and also to modulate the tumor microenvironment (such as antiangiogenic therapy). While some types of tumors are capable of forming metastases in virtually every organ in the body, the most frequent target organs of metastasis are bone, brain, liver and the lung. In this review, we discuss how tumor-stromal interactions influence metastasis in each of these organs.
Related JoVE Video
Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma.
J. Clin. Invest.
PUBLISHED: 01-26-2011
Show Abstract
Hide Abstract
Angiogenesis is critical for tumor growth and metastasis, and several inhibitors of angiogenesis are currently in clinical use for the treatment of cancer. However, not all patients benefit from antiangiogenic therapy, and those tumors that initially respond to treatment ultimately become resistant. The mechanisms underlying this, and the relative contributions of tumor cells and stroma to resistance, are not completely understood. Here, using species-specific profiling of mouse xenograft models of human lung adenocarcinoma, we have shown that gene expression changes associated with acquired resistance to the VEGF inhibitor bevacizumab occurred predominantly in stromal and not tumor cells. In particular, components of the EGFR and FGFR pathways were upregulated in stroma, but not in tumor cells. Increased activated EGFR was detected on pericytes of xenografts that acquired resistance and on endothelium of tumors with relative primary resistance. Acquired resistance was associated with a pattern of pericyte-covered, normalized revascularization, whereas tortuous, uncovered vessels were observed in relative primary resistance. Importantly, dual targeting of the VEGF and EGFR pathways reduced pericyte coverage and increased progression-free survival. These findings demonstrated that alterations in tumor stromal pathways, including the EGFR and FGFR pathways, are associated with, and may contribute to, resistance to VEGF inhibitors and that targeting these pathways may improve therapeutic efficacy. Understanding stromal signaling may be critical for developing biomarkers for angiogenesis inhibitors and improving combination regimens.
Related JoVE Video
Selection of brain metastasis-initiating breast cancer cells determined by growth on hard agar.
Am. J. Pathol.
PUBLISHED: 01-07-2011
Show Abstract
Hide Abstract
An approach that facilitates rapid isolation and characterization of tumor cells with enhanced metastatic potential is highly desirable. Here, we demonstrate that plating GI-101A human breast cancer cells on hard (0.9%) agar selects for the subpopulation of metastasis-initiating cells. The agar-selected cells, designated GI-AGR, were homogeneous for CD44(+) and CD133(+) and five times more invasive than the parental GI-101A cells. Moreover, mice injected with GI-AGR cells had significantly more experimental brain metastases and shorter overall survival than did mice injected with GI-101A cells. Comparative gene expression analysis revealed that GI-AGR cells were markedly distinct from the parental cells but shared an overlapping pattern of gene expression with the GI-101A subline GI-BRN, which was generated by repeated in vivo recycling of GI-101A cells in an experimental brain metastasis model. Data mining on 216 genes shared between GI-AGR and GI-BRN breast cancer cells suggested that the molecular phenotype of these cells is consistent with that of cancer stem cells and the aggressive basal subtype of breast cancer. Collectively, these results demonstrate that analysis of cell growth in a hard agar assay is a powerful tool for selecting metastasis-initiating cells in a heterogeneous population of breast cancer cells, and that such selected cells have properties similar to those of tumor cells that are selected based on their potential to form metastases in mice.
Related JoVE Video
Consistent interactions between tumor cell IL-6 and macrophage TNF-? enhance the growth of human prostate cancer cells in the bone of nude mouse.
Int. Immunopharmacol.
PUBLISHED: 01-06-2011
Show Abstract
Hide Abstract
To test the hypothesis that tumor-associated macrophages (TAMs) enhance the growth and metastasis of human prostate cancer in the bone, we evaluated the effects of decreasing interleukin-6 (IL-6) production by tumor cells and TAMs in a mouse model of bone metastasis. Human PC-3MM2 cells that produce IL-6 were transfected with lentivirus containing IL-6 small hairpin RNA (shRNA) or nonspecific RNA and injected into the tibias of nude mice treated intraperitoneally every 5days for 5weeks with phosphate-buffered saline (PBS), liposomes containing PBS, or liposomes containing clodronate (to decrease the number of macrophages). Transfection of PC-3MM2 cells with IL-6 shRNA significantly decreased cellular expression of IL-6 and the number of TAMs and osteoclasts in bone tumors, which correlated with significant decreases in tumor size, bone lysis, and incidence of lymph node metastasis. Treatment of mice with clodronate liposomes significantly decreased the number of TAMs and osteoclasts in the bone tumors, the expression of IL-6 in the PC3-MM2 cells, and the production of tumor necrosis factor (TNF)-? by TAMs. These findings correlated with a significant decrease in tumor size, bone lysis, and lymph node metastasis. Knocking down IL-6 in tumor cells and decreasing TAMs was associated with the lowest incidences of bone tumors and lymph node metastasis. These results suggest that TAMs enhance the growth of prostate cancer cells in the bone.
Related JoVE Video
Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy.
Neoplasia
PUBLISHED: 01-05-2011
Show Abstract
Hide Abstract
In the United States, more than 40% of cancer patients develop brain metastasis. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with conventional radiotherapy and chemotherapy. The growth and survival of metastasis depend on the interaction of tumor cells with host factors in the organ microenvironment. Brain metastases are surrounded and infiltrated by activated astrocytes and are highly resistant to chemotherapy. We report here that coculture of human breast cancer cells or lung cancer cells with murine astrocytes (but not murine fibroblasts) led to the up-regulation of survival genes, including GSTA5, BCL2L1, and TWIST1, in the tumor cells. The degree of up-regulation directly correlated with increased resistance to all tested chemotherapeutic agents. We further show that the up-regulation of the survival genes and consequent resistance are dependent on the direct contact between the astrocytes and tumor cells through gap junctions and are therefore transient. Knocking down these genes with specific small interfering RNA rendered the tumor cells sensitive to chemotherapeutic agents. These data clearly demonstrate that host cells in the microenvironment influence the biologic behavior of tumor cells and reinforce the contention that the organ microenvironment must be taken into consideration during the design of therapy.
Related JoVE Video
Nitric oxide-mediated tumoricidal activity of murine microglial cells.
Transl Oncol
PUBLISHED: 07-26-2010
Show Abstract
Hide Abstract
Experimental metastases in the brain of mice are infiltrated by microglia, and parabiosis experiments of green fluorescent protein (GFP(+)) and GFP(-) mice revealed that these microglia are derived from circulating monocytes (GFP(+), F4/80(+), and CD68(+)). These findings raised the question as to whether microglia (specialized macrophages) possess tumoricidal activity. C8-B4 murine microglia cells were incubated in vitro in medium (control) or in medium containing both lipopolysaccharide and interferon-?. Control microglia were not tumoricidal against a number of murine and human tumor cells, whereas lipopolysaccharide/interferon-?-activated microglia lysed murine and human tumor cells by release of nitric oxide. Parallel experiments with murine peritoneal macrophages produced identical results. Neither activated microglia nor activated macrophages lysed nontumorigenic murine or human cells. Collectively, these data demonstrate that brain metastasis-associated microglia are derived from circulating mononuclear cells and exhibit selective and specific tumoricidal activity.
Related JoVE Video
Role of the gp85/trans-sialidases in Trypanosoma cruzi tissue tropism: preferential binding of a conserved peptide motif to the vasculature in vivo.
PLoS Negl Trop Dis
PUBLISHED: 03-30-2010
Show Abstract
Hide Abstract
Transmitted by blood-sucking insects, the unicellular parasite Trypanosoma cruzi is the causative agent of Chagas disease, a malady manifested in a variety of symptoms from heart disease to digestive and urinary tract dysfunctions. The reasons for such organ preference have been a matter of great interest in the field, particularly because the parasite can invade nearly every cell line and it can be found in most tissues following an infection. Among the molecular factors that contribute to virulence is a large multigene family of proteins known as gp85/trans-sialidase, which participates in cell attachment and invasion. But whether these proteins also contribute to tissue homing had not yet been investigated. Here, a combination of endothelial cell immortalization and phage display techniques has been used to investigate the role of gp85/trans-sialidase in binding to the vasculature.
Related JoVE Video
Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies.
PLoS ONE
PUBLISHED: 03-03-2010
Show Abstract
Hide Abstract
Vimentin is a ubiquitous mesenchymal intermediate filament supporting mechano-structural integrity of quiescent cells while participating in adhesion, migration, survival, and cell signaling processes via dynamic assembly/disassembly in activated cells. Soft tissue sarcomas and some epithelial cancers exhibiting "epithelial to mesenchymal transition" phenotypes express vimentin. Withaferin-A, a naturally derived bioactive compound, may molecularly target vimentin, so we sought to evaluate its effects on tumor growth in vitro and in vivo thereby elucidating the role of vimentin in drug-induced responses.
Related JoVE Video
Regulation of tumor angiogenesis by EZH2.
Cancer Cell
PUBLISHED: 02-15-2010
Show Abstract
Hide Abstract
Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibited angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth, which is further enhanced in combination with ezh2 silencing in tumor cells. Collectively, these data support the potential for targeting ezh2 as an important therapeutic approach.
Related JoVE Video
Constitutive expression of the alpha4 integrin correlates with tumorigenicity and lymph node metastasis of the B16 murine melanoma.
Neoplasia
PUBLISHED: 02-04-2010
Show Abstract
Hide Abstract
The lymphatic system plays a critical role in melanoma metastasis, and yet, virtually no information exists regarding the cellular and molecular mechanisms that take place between melanoma cells and the lymphatic vasculature. Here, we generated B16-F1 melanoma cells that expressed high (B16alpha(4)+) and negligible (B16alpha(4)-) levels of alpha(4) integrin to determine how the expression of alpha(4) integrins affects tumor cell interactions with lymphatic endothelial cells in vitro and how it impacts lymphatic metastasis in vivo. We found a direct correlation between alpha(4) integrin expression on B16-F1 melanoma cells and their ability to form adhesive interactions with monolayers of lymphatic endothelial cells. Adhesion of B16-F1 melanoma cells to lymphatic endothelial cells was mediated by the melanoma cell alpha(4) integrin binding to its counterreceptor, vascular cell adhesion molecule 1 (VCAM-1), that was constitutively expressed on the lymphatic endothelial cells. VCAM-1 was also expressed on the tumor-associated lymphatic vessels of B16-F1 and B16alpha(4)+ tumors growing in the subcutaneous space of C57BL/6J mice. B16-F1 tumors metastasized to lymph nodes in 30% of mice, whereas B16alpha(4)+ tumors generated lymph node metastases in 80% of mice. B16-F1 melanoma cells that were deficient in alpha(4) integrins (B16alpha(4)-) were nontumorigenic. Collectively, these data show that the alpha(4) integrin expressed by melanoma cells contributes to tumorigenesis and may also facilitate metastasis to regional lymph nodes by promoting stable adhesion of melanoma cells to the lymphatic vasculature.
Related JoVE Video
Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress.
J. Clin. Invest.
PUBLISHED: 01-11-2010
Show Abstract
Hide Abstract
PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-beta expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to load-induced stress resulted in cardiac dysfunction and heart failure. Mechanistically, we showed that cardiomyocyte PDGFR-beta signaling plays a vital role in stress-induced cardiac angiogenesis. Specifically, we demonstrated that cardiomyocyte PDGFR-beta was an essential upstream regulator of the stress-induced paracrine angiogenic capacity (the angiogenic potential) of cardiomyocytes. These results demonstrate that cardiomyocyte PDGFR-beta is a regulator of the compensatory cardiac response to pressure overload-induced stress. Furthermore, our findings may provide insights into the mechanism of cardiotoxicity due to anticancer PDGFR inhibitors.
Related JoVE Video
Generation of an immortalized astrocyte cell line from H-2Kb-tsA58 mice to study the role of astrocytes in brain metastasis.
Int. J. Oncol.
PUBLISHED: 09-03-2009
Show Abstract
Hide Abstract
Astrocytes play a critical role in maintaining cerebral homeostasis and their dysregulation is thought to contribute to the pathogenesis of several diseases, including brain cancer and metastasis. Similar to the human disease, we found that lung and melanoma metastases in the mouse brain are accompanied by a reactive gliosis. To begin to study the biology of astrocytes and examine how these cells might contribute to metastasis formation and progression in the brain, we generated a conditionally immortal astrocyte cell line from H-2Kb-tsA58 mice. Astrocytes grown in culture expressed glial fibrillary acid protein (GFAP), glutamate receptor 1, and the N-methyl-D-aspartate (NMDA) receptor. Astrocytes also expressed the glial-specific transporters excitatory amino acid transporter 1 (EAAT1) and EAAT2. Astrocytes grown under permissive conditions (33 degrees C) expressed SV40 large T antigen and had a doubling time of 36 h, whereas expression of SV40 large T antigen was negligible in astrocytes grown at 37 degrees C for 72 h, which coincided with a plateau in cell division. In a co-culture assay with human lung adenocarcinoma cells (PC14-PE6), astrocytes activated programs in the tumor cells that signal for cell division and survival. Hence, the immortalized cell line will be useful for studying the role of astrocytes in disease processes in the brain, such as metastasis.
Related JoVE Video
EphA2 immunoconjugate as molecularly targeted chemotherapy for ovarian carcinoma.
J. Natl. Cancer Inst.
PUBLISHED: 07-29-2009
Show Abstract
Hide Abstract
EphA2 is overexpressed in many types of human cancer but is absent or expressed at low levels in normal epithelial tissues. We investigated whether a novel immunoconjugate containing an anti-EphA2 monoclonal antibody (1C1) linked to a chemotherapeutic agent (monomethyl auristatin phenylalanine [MMAF]) through a noncleavable linker maleimidocaproyl (mc) had antitumor activity against ovarian cancer cell lines and tumor models.
Related JoVE Video
The ADMR receptor mediates the effects of adrenomedullin on pancreatic cancer cells and on cells of the tumor microenvironment.
PLoS ONE
PUBLISHED: 06-04-2009
Show Abstract
Hide Abstract
Adrenomedullin (AM) is highly expressed in pancreatic cancer and stimulates pancreatic cancer cells leading to increased tumor growth and metastasis. The current study examines the role of specific AM receptors on tumor and cells resembling the tumor microenvironment (human pancreatic stellate--HPSC, human umbilical vein-- HUVEC and mouse lung endothelial cells--MLEC).
Related JoVE Video
Estrous cycle modulates ovarian carcinoma growth.
Clin. Cancer Res.
PUBLISHED: 04-21-2009
Show Abstract
Hide Abstract
The effects of reproductive hormones on ovarian cancer growth are not well understood. Here, we examined the effects of estrous cycle variation and specific reproductive hormones on ovarian cancer growth.
Related JoVE Video
Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis.
Am. J. Pathol.
PUBLISHED: 04-06-2009
Show Abstract
Hide Abstract
To identify the roles of various circulating cells (eg, endothelial and/or stem and progenitor cells) in angiogenesis, we parabiosed a wild-type syngeneic mouse with a transgenic syngeneic green fluorescent protein mouse. Following the establishment of a common circulation between these parabionts, we investigated acute (7 to 10 days), subacute (2 to 3 weeks), and chronic (4 to 6 weeks) phases of angiogenesis in wild-type mice using wound healing, implanted gel foam fragments, and subcutaneous tumor assays, respectively. We found that under in vitro conditions, circulating murine monocytes expressed F4/80, CD31, and vascular endothelial growth factor receptor 2, but neither CD133 nor von Willebrand factor, whereas murine endothelial cells expressed CD31, vascular endothelial growth factor receptor 2, and von Willebrand factor, but neither CD133 nor F4/80. Immunofluorescence analysis revealed that green fluorescent protein-positive cells in the walls of new vessels in wounds, gel foam blocks, and tumors expressed both F4/80 and CD31, that is, macrophages. Pericytes, cells that express both CD31 and desmin, were found both in the walls of tumor-associated vessels and within tumors. Collectively, these data demonstrate that monocytes (ie, cells that express both CD31 and F4/80) may be recruited to the site of tissue injury and directly contribute to angiogenesis, reaffirming the close relationships between various cell types within the reticuloendothelial system and suggesting possible targets for anticancer treatments.
Related JoVE Video
Neoadjuvant platelet derived growth factor receptor inhibitor therapy combined with docetaxel and androgen ablation for high risk localized prostate cancer.
J. Urol.
PUBLISHED: 01-28-2009
Show Abstract
Hide Abstract
Platelet derived growth factor receptor inhibitor therapy improves the efficacy of taxane chemotherapy in preclinical models of prostate cancer. Men with high risk localized prostate cancer were treated with platelet derived growth factor receptor inhibitor therapy, docetaxel and hormone ablation in the preoperative setting, and clinicopathological outcomes were evaluated.
Related JoVE Video
Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis.
ChemMedChem
PUBLISHED: 01-09-2009
Show Abstract
Hide Abstract
Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted triclosan derivatives was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC(50) value of 21 nM, which was 50-fold more potent than triclosan. X-ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid-sensitive and resistant strains of M. tuberculosis. Among those, the best inhibitor had an MIC value of 4.7 microg mL(-1) (13 microM), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid-resistant M. tuberculosis strains, demonstrating the significant potential for structure-based design in the development of next generation antitubercular drugs.
Related JoVE Video
The biology of brain metastasis.
Clin. Chem.
Show Abstract
Hide Abstract
It is estimated that at least 200 000 cases of brain metastases occur each year in the US, which is 10 times the number of patients diagnosed with primary brain tumors. Brain metastasis is associated with poor prognosis, neurological deterioration, diminished quality of life, and extremely short survival. Favorable interactions between tumor cells and cerebral microvascular endothelial cells encourage tumor growth in the central nervous system, while tumor cell interactions with astrocytes protect brain metastases from the cytotoxic effects of chemotherapy.
Related JoVE Video
Association of a deficit of arousal with fatigue in multiple sclerosis: effect of modafinil.
Neuropharmacology
Show Abstract
Hide Abstract
Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, leading to chronic disability. Fatigue is a common and distressing symptom of MS which is unrelated to its clinical form, stage of development, the degree of disability, or the lesion load on magnetic resonance imaging. Fatigue in MS is associated with excessive daytime sleepiness and autonomic dysfunction. Recently it has been reported that the wakefulness-promoting drug modafinil may relieve fatigue in MS patients and ameliorate the associated cognitive difficulties. However, it is not clear to what extent the anti-fatigue effect of modafinil may be related to its alerting and sympathetic activating effects. We addressed this question by comparing three groups of subjects, MS patients with fatigue, MS patients without fatigue and healthy controls, matched for age and sex, on measures of alertness (self-ratings on the Epworth and Stanford Sleepiness Scales and on a battery of visual analogue scales; critical flicker fusion frequency; Pupillographic Sleepiness Test; choice reaction time) and autonomic function (systolic and diastolic blood pressure, heart rate, pupil diameter), and by examining the effect of a single dose (200 mg) of modafinil on these measures. MS patients with fatigue, compared with healthy controls, had reduced level of alertness on all the tests used; MS patients without fatigue did not differ from healthy controls. MS patients with fatigue had a reduced level of cardiovascular sympathetic activation compared to the other two groups. Modafinil displayed alerting and sympathomimetic effects in all three groups of subjects. As fatigue in MS is associated with reduced levels of alertness and sympathetic activity, modafinil may exert its anti-fatigue effect in MS by correcting these deficiencies. The anti-fatigue effect of modafinil may reflect the activation of the noradrenergic locus coeruleus (LC), since there is evidence that this wakefulness-promoting nucleus is damaged in MS, and that modafinil, probably via the dopaminergic system, can stimulate the LC. This article is part of a Special Issue entitled Cognitive Enhancers.
Related JoVE Video
Combinatorial targeting and discovery of ligand-receptors in organelles of mammalian cells.
Nat Commun
Show Abstract
Hide Abstract
Phage display screening allows the study of functional protein-protein interactions at the cell surface, but investigating intracellular organelles remains a challenge. Here we introduce internalizing-phage libraries to identify clones that enter mammalian cells through a receptor-independent mechanism and target-specific organelles as a tool to select ligand peptides and identify their intracellular receptors. We demonstrate that penetratin, an antennapedia-derived peptide, can be displayed on the phage envelope and mediate receptor-independent uptake of internalizing phage into cells. We also show that an internalizing-phage construct displaying an established mitochondria-specific localization signal targets mitochondria, and that an internalizing-phage random peptide library selects for peptide motifs that localize to different intracellular compartments. As a proof-of-concept, we demonstrate that one such peptide, if chemically fused to penetratin, is internalized receptor-independently, localizes to mitochondria, and promotes cell death. This combinatorial platform technology has potential applications in cell biology and drug development.
Related JoVE Video
Crosstalk between the DNA damage response pathway and microRNAs.
Cell. Mol. Life Sci.
Show Abstract
Hide Abstract
MicroRNAs (miRNAs) are a family of small, non-coding RNAs that control gene expression at the post-transcriptional level by destabilizing and inhibiting translation of their target messenger RNAs. MiRNAs are involved in the regulation of a number of fundamental biological processes, and their dysregulation is thought to contribute to several disease processes. Emerging evidence suggests that miRNAs also play a critical role in protecting the heritable genome by contributing to the regulation of the DNA damage response. Consequently, much recent investigative effort has been directed towards an improved understanding of how miRNAs are regulated in response to DNA damage. In this review, we discuss the most recent findings regarding the regulation of miRNA expression and the functional roles of miRNAs in the DNA damage response.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.