Anti-angiogenic therapies in prostate cancer

Martínez-Jabaloyas, José María; March-Villalba, J.A.; Navarro-García, María Mercedes; Dası́, Francisco

doi:10.1517/14712598.2013.733366

Cited by 5 publications

(6 citation statements)

References 14 publications

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“…PTEC may therefore represent a suitable model to assess the response to anti-angiogenic drugs and the related cell signal mechanisms. Indeed, although the results of anti-angiogenic therapy in preclinical models of prostate cancer provided promising results, some discrepancy between these data and those obtained in clinical trials were observed [ 32 ]. In particular, monotherapy treatment of patients with advanced prostate cancer partially failed the endpoints [ 27 , 33 – 36 ].…”

Section: Discussionmentioning

confidence: 99%

Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib

et al. 2014

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BackgroundProstate cancer is the second leading cause of male cancer death in developed countries. Although the role of angiogenesis in its progression is well established, the efficacy of anti-angiogenic therapy is not clearly proved. Whether this could depend on differential responses between tumor and normal endothelial cells has not been tested.MethodsWe isolated and characterized three lines of endothelial cells from prostate cancer and we tested the effect of Sunitinib and Sorafenib, and the combined treatment with the anti-androgen Casodex, on their angiogenic functions.ResultsEndothelial cells isolated from prostate tumors showed angiogenic properties and expression of androgen and vascular endothelial cell growth factor receptors. Sunitinib affected their proliferation, survival and motility while Sorafenib only showed a minor effect. At variance, Sunitinib and Sorafenib showed similar cytotoxic and anti-angiogenic effects on normal endothelial cells. Sorafenib and Sunitinib inhibited vascular endothelial cell growth factor receptor2 phosphorylation of prostate cancer endothelial cells, while they differentially modulated Akt phosphorylation as no inhibitory effect of Sorafenib was observed on Akt activation. The combined treatment of Casodex reverted the observed resistance to Sorafenib both on cell viability and on Akt activation, whereas it did not modify the response to Sunitinib.ConclusionsOur study demonstrates a resistant behavior of endothelial cells isolated from prostate cancer to Sorafenib, but not Sunitinib. Moreover, it shows the benefit of a multi-target therapy combining anti-angiogenic and anti-hormonal drugs to overcome resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-939) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib

et al. 2014

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“…Inhibiting angiogenesis is a very important approach for the treatment of numerous diseases, particularly neoplasias, because tumor growth requires adequate vascularization (Collinson et al, 2012;Plate et al, 2012;Wang et al, 2012;Johannessen et al, 2013;Martínez-Jabaloyas et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Microcirculation of the brain: morphological assessment in degenerative diseases and restoration processes

Kolinko¹,

Krakorova

Cendelín³

et al. 2015

Reviews in the Neurosciences

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AbstractBrain microcirculation plays an important role in the pathogenesis of various brain diseases. Several specific features of the circulation in the brain and its functions deserve special attention. The brain is extremely sensitive to hypoxia, and brain edema is more dangerous than edema in other tissues. Brain vessels are part of the blood-brain barrier, which prevents the penetration of some of the substances in the blood into the brain tissue. Herein, we review the processes of angiogenesis and the changes that occur in the brain microcirculation in the most prevalent neurodegenerative diseases. There are no uniform vascular changes in the neurodegenerative diseases. In some cases, the vascular changes are secondary consequences of the pathological process, but they could also be involved in the pathogenesis of the primary disease and contribute to the degeneration of neurons, based on their quantitative characteristics. Additionally, we described the stereological methods that are most commonly used for generating qualitative and quantitative data to assess changes in the microvascular bed of the brain.

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“…In addition, network analysis of the differentially expressed genes led to the identification of HIF1α, a crucial inducer of angiogenesis, as a key transcription factor activated by Klf5 deletion, which transcriptionally activated 34 genes upon Klf5 deletion (Figure 2 B). Among the 34 genes, secretory protein Pdgf-b is a well-established transcriptional target of HIF1α and a crucial regulator of angiogenesis [ 2 , 20 ] (Figure 2 C). Although VEGF, another key angiogenesis regulator and secretory protein induced by HIF1α [ 17 ], was not identified by the microarray analysis as being upregulated by Klf5 deletion, our expression analyses demonstrated that KLF5 loss indeed upregulated HIF1α at the protein level and VEGF and PDGF at both the mRNA and protein levels in both mouse prostate tumors and human prostate cancer cells with deficient or insufficient PTEN (Figure 2 , 3 and 5 ).…”

Section: Discussionmentioning

confidence: 99%

“…Angiogenesis, the process of forming new blood vessels from pre-existing vessels, is vital for development, tissue wound healing, and tumor initiation and progression [ 1 ]. Tumor angiogenesis is activated by multiple pro-angiogenic secretory factors including VEGF, PDGF-B, bFGF and TNF-α, which are all transcriptionally activated by hypoxia inducible factor 1 (HIF1) [ 2 ], composed of HIF1α and HIF1β subunits. HIF1α is mainly regulated at the protein level by the ubiquitin proteasome pathway, whose activation depends on the oxygen level, or by the activation of PI3K/AKT and MAPK signaling in a tumor, which is independent of oxygen level [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Tumor angiogenesis is activated by multiple pro-angiogenic secretory factors including VEGF, PDGF-B, bFGF and TNF-α, which are all transcriptionally activated by hypoxia inducible factor 1 (HIF1) [ 2 ], composed of HIF1α and HIF1β subunits. HIF1α is mainly regulated at the protein level by the ubiquitin proteasome pathway, whose activation depends on the oxygen level, or by the activation of PI3K/AKT and MAPK signaling in a tumor, which is independent of oxygen level [ 2 , 3 ]. Targeting angiogenesis has been proposed as a therapeutic approach in prostate and other types of solid tumors for decades, and a number of candidate drugs have been tested in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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KLF5 inhibits angiogenesis in PTEN-deficient prostate cancer by attenuating AKT activation and subsequent HIF1α accumulation

Xing

Zhang

et al. 2015

Mol Cancer

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BackgroundKLF5 is a basic transcriptional factor that regulates multiple physiopathological processes. Our recent study showed that deletion of Klf5 in mouse prostate promotes tumorigenesis initiated by the deletion of Pten. While molecular characterization of Klf5-null tumors suggested that angiogenesis was partially responsible for tumor promotion, the precise function and mechanism of KLF5 deletion in prostate tumor angiogenesis remain unclear.ResultsApplying histological staining to Pten-null mouse prostates, we observed that deletion of Klf5 significantly increased the number of microvessels, accompanied by the upregulation of multiple angiogenesis-related genes based on microarray analysis with MetaCore software. In human umbilical vein endothelial cells (HuVECs), tube formation and migration, both of which are indicators of angiogenic activities, were decreased by conditioned media from PC-3 and DU 145 human prostate cancer cells with KLF5 overexpression, but increased by media from cells with KLF5 knockdown. HIF1α, a key angiogenesis inducer, was upregulated by KLF5 loss at the protein but not the mRNA level in both mouse tissues and human cell lines, as determined by immunohistochemical staining, real-time RT-PCR and Western blotting. Consistently, KLF5 loss also upregulated VEGF and PDGF, two pro-angiogenic mediators of HIF1α function, as analyzed by immunohistochemical staining in mouse tissues and ELISA in conditioned media. Mechanistically, AKT activity, which caused the accumulation of HIF1α, was increased by KLF5 knockout or knockdown but decreased by KLF5 overexpression. PI3K/AKT inhibitors consistently abolished the effects of KLF5 knockdown on angiogenic activity, HIF1α accumulation, and VEGF and PDGF expression.ConclusionKLF5 loss enhances tumor angiogenesis by attenuating PI3K/AKT signaling and subsequent accumulation of HIF1α in PTEN deficient prostate tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0365-6) contains supplementary material, which is available to authorized users.

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Anti-angiogenic therapies in prostate cancer

Cited by 5 publications

References 14 publications

Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib

Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib

Microcirculation of the brain: morphological assessment in degenerative diseases and restoration processes

KLF5 inhibits angiogenesis in PTEN-deficient prostate cancer by attenuating AKT activation and subsequent HIF1α accumulation

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