Prostatic angiogenic responses in late life: Antiangiogenic therapy influences and relation with the glandular microenvironment in the transgenic adenocarcinoma of mouse prostate (TRAMP) model

Montico, Fábio; Kido, Larissa Akemi; Hetzl, Amanda Cia; Cagnon, Valéria Helena Alves

doi:10.1002/pros.22934

Cited by 18 publications

(24 citation statements)

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“…Recently, two studies from our research group showed the effects of antiangiogenic therapy, where there was a decrease of microvessel density in TRAMP animals. In addition to this, there was also a reduction of tissue inflammation [26, 27]. However, it is known that there is an occurrence of a compensatory mechanism for signaling exchange between VEGF, PDGF and FGF pathways, as angiogenesis is regulated by multiple factors, resulting in tumor resistance to therapy which only inhibits VEGF [25, 28].…”

Section: Discussionmentioning

confidence: 99%

“…Increased VEGF expression is related to tumor formation and progression [41]. A recent study of our research group showed that VEGF as well as the microvessel density increased in 8 to 18-week-old TRAMP mice in the prostatic tissue [26], assessed by CD31 immunoreactivity in endothelial cells. Similar findings were seen in the present study, which showed a progressive increase in VEGF and CD31 in the prostate of 8 to 22 week-old TRAMP mice.…”

Section: Discussionmentioning

confidence: 99%

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Nintedanib antiangiogenic inhibitor effectiveness in delaying adenocarcinoma progression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP)

et al. 2017

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BackgroundIn recent times, anti-cancer treatments have focused on Fibroblast Growth Factor (FGF) and Vascular-Endothelial Growth Factor (VEGF) pathway inhibitors so as to target tumor angiogenesis and cellular proliferation. One such drug is Nintedanib; the present study evaluated the effectiveness of Nintedanib treatment against in vitro proliferation of human prostate cancer (PCa) cell lines, and growth and progression of different grades of PCa lesions in pre-clinical PCa transgenic adenocarcinoma for the mouse prostate (TRAMP) model.MethodsBoth androgen-independent (LNCaP) and androgen-dependent (PC3) PCa cell lines were treated with a range of Nintedanib doses for 72 h, and effect on cell growth and expression of angiogenesis associated VEGF receptors was analyzed. In pre-clinical efficacy evaluation, male TRAMP mice starting at 8 and 12 weeks of age were orally-fed with vehicle control (10% Tween 20) or Nintedanib (10 mg/Kg/day in vehicle control) for 4 weeks, and sacrificed immediately after 4 weeks of drug treatment or sacrificed 6–10 weeks after stopping drug treatments. At the end of treatment schedule, mice were sacrificed and ventral lobe of prostate was excised along with essential metabolic organ liver, and subjected to histopathological and extensive molecular evaluations.ResultsThe total cell number decreased by 56–80% in LNCaP and 45–93% in PC3 cells after 72 h of Nintedanib treatment at 2.5–25 μM concentrations. In pre-clinical TRAMP studies, Nintedanib led to a delay in tumor progression in all treatment groups; the effect was more pronounced when treatment was given at the beginning of the glandular lesion development and continued till study end. A decreased microvessel density and VEGF immunolocalization was observed, besides decreased expression of Androgen Receptor (AR), VEGFR-1 and FGFR-3 in some of the treated groups. No changes were observed in the histological liver analysis.ConclusionsNintedanib treatment was able to significantly decrease the growth of PCa cell lines and also delay growth and progression of PCa lesions to higher grades of malignancy (without inducing any hepatotoxic effects) in TRAMP mice. Furthermore, it was observed that Nintedanib intervention is more effective when administered during the early stages of neoplastic development, although the drug is capable of reducing cell proliferation even after treatment interruption.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nintedanib antiangiogenic inhibitor effectiveness in delaying adenocarcinoma progression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP)

et al. 2017

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“…Based on histological and immunohistochemical analysis, TRAMP mice tumors also showed high VEGF and FGF-2 expression, with increased microvessel density. Importantly, these mice recapitulate the stimulation of angiogenesis that has been observed in the aged mouse prostate, which is sensitive to treatment with antiangiogenic drugs (TNP-470 alone or in combination with SU5416) and finasteride (Montico et al 2014). The role of VEGF in advanced PCa has also been studied in Pten-conditional knockout mice.…”

Section: Mouse Models Of Pca and Relevant Aspects Of Angiogenesis/vegmentioning

confidence: 93%

Regulation of vascular endothelial growth factor in prostate cancer

Brot¹,

Ntekim²,

Cardenas³

et al. 2015

Endocrine-Related Cancer

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Prostate cancer (PCa) is the most common malignancy affecting men in the western world. Although radical prostatectomy and radiation therapy can successfully treat PCa in the majority of patients, up to w30% will experience local recurrence or metastatic disease. Prostate carcinogenesis and progression is typically an androgen-dependent process. For this reason, therapies for recurrent PCa target androgen biosynthesis and androgen receptor function. Such androgen deprivation therapies (ADT) are effective initially, but the duration of response is typically %24 months. Although ADT and taxane-based chemotherapy have delivered survival benefits, metastatic PCa remains incurable. Therefore, it is essential to establish the cellular and molecular mechanisms that enable localized PCas to invade and disseminate. It has long been accepted that metastases require angiogenesis. In the present review, we examine the essential role for angiogenesis in PCa metastases, and we focus in particular on the current understanding of the regulation of vascular endothelial growth factor (VEGF) in localized and metastatic PCa. We highlight recent advances in understanding the role of VEGF in regulating the interaction of cancer cells with tumor-associated immune cells during the metastatic process of PCa. We summarize the established mechanisms of transcriptional and post-transcriptional regulation of VEGF in PCa cells and outline the molecular insights obtained from preclinical animal models of PCa. Finally, we summarize the current state of anti-angiogenesis therapies for PCa and consider how existing therapies impact VEGF signaling.

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“…The COX2, STAT3, IGFR1 and PCNA antigens were detected, respectively, using the following antibodies: mouse monoclonal anti-COX2 (sc-376861; Santa Cruz Biotechnology), rabbit polyclonal anti-STAT3 (sc-7179; Santa Cruz Biotechnology), rabbit polyclonal anti-IGFR1 (sc-712; Santa Cruz Biotechnology), and mouse monoclonal anti-PCNA (ab-29; Abcam). The pattern of protocols was the same as those described by Kido et al (2014) and Montico et al (2015) and all the primary antibodies were diluted in a 1:50 ratio, except for PCNA 1:250. Then, the sections were incubated for 2 h with HRP-conjugated secondary antibodies, goat anti-mouse IgG (W4021; Promega), and goat anti-rabbit IgG (W4018; Promega).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Anti-inflammatory therapies in TRAMP mice: delay in PCa progression

Kido¹,

Montico²,

Sauce³

et al. 2016

Endocrine-Related Cancer

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The aim of this study was to characterize the structural and molecular biology as well as evaluate the immediate and late responses of prostatic cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model after treatment with goniothalamin (GTN) and celecoxib. The treated mice received GTN (150 mg/kg, gavage) or celecoxib (10 mg/kg, gavage) from 8 to 12 weeks of age. They were killed at different ages: the immediate-response groups at 12 weeks and the late-response groups at 22 weeks. The ventral prostate was collected for light microscopy, immunohistochemistry, western blotting, TUNEL, and ELISA. Morphological analyses indicated that GTN treatment delayed the progression of prostatic adenocarcinoma, leading to a significant decrease of prostatic lesion frequency in both experimental period responses to this treatment, mainly high-grade prostatic intraepithelial neoplasia and well-differentiated adenocarcinoma. Also, the celecoxib treatment showed a particular decrease in the proliferative processes (PCNA) in both the experimental periods. Despite celecoxib diminishing the COX2 and IGFR1 levels, GTN presented higher action spectrum considering the decrease of a greater molecular number involved in the proliferative and inflammatory processes in prostatic cancer. Goniothalamin attenuated the pro-inflammatory response in TRAMP prostatic microenvironment, delaying prostate cancer (PCa) progression. Celecoxib treatment was efficient in the regulation of COX2 in the TRAMP mice, mainly in the advanced disease grade. Finally, we concluded that inflammatory process control in early grades of PCa was crucial for the downregulation of the signaling pathways involved in the proliferative processes in advanced cancer grades.

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Prostatic angiogenic responses in late life: Antiangiogenic therapy influences and relation with the glandular microenvironment in the transgenic adenocarcinoma of mouse prostate (TRAMP) model

Cited by 18 publications

References 74 publications

Nintedanib antiangiogenic inhibitor effectiveness in delaying adenocarcinoma progression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP)

Nintedanib antiangiogenic inhibitor effectiveness in delaying adenocarcinoma progression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP)

Regulation of vascular endothelial growth factor in prostate cancer

Anti-inflammatory therapies in TRAMP mice: delay in PCa progression

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