RESUMO
Prostate cancer (PCa) is the second cause of cancer death among men worldwide. Several processes are involved in the development and progression of PCa such as angiogenesis, inflammation and oxidative stress. The present study investigated the effect of short- or long-term Tempol treatment at different stages of prostate adenocarcinoma progression, focusing on angiogenic, proliferative, and stromal remodeling processes in TRAMP mice. The dorsolateral lobe of the prostate of TRAMP mice were evaluated at two different stages of PCa progression; early and late stages. Early stage was again divided into, short- or long-term. 50 mg/kg Tempol dose was administered orally. The results demonstrated that Tempol mitigated the prostate histopathological lesion progressions in the TRAMP mice in all treated groups. However, Tempol increased molecules involved in the angiogenic process such as CD31 and VEGFR2 relative frequencies, particularly in long-term treatment. In addition, Tempol upregulated molecule levels involved in angiogenesis and stromal remodeling process VEGF, TGF-ß1, VE-cadherin and vimentin, particularly, in T8-16 group. Thus, it was concluded that Tempol treatment delayed prostatic lesion progression in the dorsolateral lobe of the TRAMP mice. However, Tempol also led to pro-angiogenic effects and glandular stromal microenvironment imbalance, especially, in the long-term treatment.
Assuntos
Óxidos N-Cíclicos , Neovascularização Patológica , Neoplasias da Próstata , Marcadores de Spin , Masculino , Animais , Óxidos N-Cíclicos/farmacologia , Óxidos N-Cíclicos/uso terapêutico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Camundongos , Progressão da Doença , AngiogêneseRESUMO
INTRODUCTION AND OBJECTIVES: Prostate cancer is one of the most commonly diagnosed cancers in American men. Apelin is an endogenous peptide identified as the ligand of the G protein-associated apelin receptor. Apelin and apelin receptor have many tissues distribution and they participate in pathological processes, such as cancer. Apelin stimulates cancer angiogenesis. However, there are insufficient data in the literature regarding the role of apelin/apelin receptor in normal tissue, highgrade prostatic intraepithelial neoplasia, and prostatic adenocarcinoma tissues. Therefore, this study aimed to investigate the apelin and apelin receptor expression levels in tissues of normal prostate tissue, high-grade prostatic intraepithelial neoplasia, and prostatic adenocarcinoma. MATERIALS AND METHODS: In this study, 38 samples of patients undergoing radical prostatectomy were used. Among 38 samples; 20 patients were with prostatic adenocarcinoma, 18 patients were with high-grade prostatic intraepithelial neoplasia and adjacent normal prostatic tissue areas. The immunolocalisation of apelin and apelin receptor in these tissues were determined immunohistochemically. RESULTS: Apelin and apelin receptor expressions were higher in prostatic adenocarcinoma than normal prostate tissue and high-grade prostatic intraepithelial neoplasia. Apelin receptor expression was also increased in high-grade prostatic intraepithelial neoplasia compared to normal tissue. CONCLUSION: Apelin and apelin receptor are increase in the process of prostate carcinogenesis. This increase may adversely affect the clinical course of prostate cancer patients by stimulating angiogenesis, which is important for invasion and metastasis in prostate cancer.
Assuntos
Adenocarcinoma , Receptores de Apelina , Apelina , Próstata , Neoplasia Prostática Intraepitelial , Neoplasias da Próstata , Humanos , Masculino , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Apelina/genética , Apelina/metabolismo , Receptores de Apelina/genética , Receptores de Apelina/metabolismo , Próstata/metabolismo , Próstata/patologia , Próstata/cirurgia , Neoplasia Prostática Intraepitelial/irrigação sanguínea , Neoplasia Prostática Intraepitelial/genética , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasia Prostática Intraepitelial/cirurgia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Prostatectomia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologiaRESUMO
Prostate cancer (PC) is the most common cancer in men and the second leading cause of cancer-related death worldwide. Many therapeutic advances over the last two decades have led to an improvement in the survival of patients with metastatic PC, yet the majority of these patients still succumb to their disease. Antiagiogenic therapies have shown substantial benefits for many types of cancer but only a marginal benefit for PC. Ongoing clinical trials investigate antiangiogenic monotherapies or combination therapies. Despite the important role of angiogenesis in PC, clinical trials in refractory castration-resistant PC (CRPC) have demonstrated increased toxicity with no clinical benefit. A better understanding of the mechanism of angiogenesis may help to understand the failure of trials, possibly leading to the development of new targeted anti-angiogenic therapies in PC. These could include the identification of specific subsets of patients who might benefit from these therapeutic strategies. This paper provides a comprehensive review of the pathways involved in the angiogenesis, the chemotherapeutic agents with antiangiogenic activity, the available studies on anti-angiogenic agents and the potential mechanisms of resistance.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Terapia de Alvo Molecular , Neovascularização Patológica/tratamento farmacológico , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , MasculinoRESUMO
PURPOSE: FOXA1, as a pioneering transcription factor, has been shown to drive prostate cancer progression. Previous studies showed that FOXA1 expression in prostate cancer was positively associated with cancer angiolymphatic invasion and metastasis. However, the mechanism underlying the correlation between FOXA1 and prostate cancer angiolymphatic invasion and metastasis remains largely unclear. METHODS: Herein, we set out to investigate the role of FOXA1 in the interactions between prostate cancer cells and endothelial cells. Endothelial cells' phenotypes were assessed through CCK-8 assay, Transwell migration assay, and tube formation assay. The angiogenic factors acting on endothelial cells mediated by FOXA1were characterized by RNA-seq, qPCR array, angiogenesis cytokines array, and ELISA assay. The impact of FOXA1 on tumor angiogenesis was examined in a xenograft model in nude mice. The effect of FOXA1 on prostate cancer angiogenesis was validated on a primary prostate cancer tissue microarray. RESULTS: FOXA1 expression in prostate cancer cells promoted endothelial cell proliferation, migration, and tube formation in vitro. Mechanistically, FOXA1 increased pro-angiogenic factors production, including EGF, Endothelin-1, and Endoglin. Moreover, in vivo study showed that FOXA1 facilitated tumor angiogenesis. Furthermore, clinical samples investigation indicated that FOXA1 enhanced prostate cancer angiogenesis. CONCLUSION: Overall, these findings illustrated a tumor angiogenesis-promoting role of FOXA1 in prostate cancer.
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Indutores da Angiogênese/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Neoplasias da Próstata/irrigação sanguínea , Animais , Comunicação Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Técnicas de Cocultura , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Expressão Gênica , Células HEK293 , Fator 3-alfa Nuclear de Hepatócito/biossíntese , Fator 3-alfa Nuclear de Hepatócito/genética , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologiaRESUMO
BACKGROUND: There is a need to improve the treatment of prostate cancer (PCa) and reduce treatment side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy for low-risk low-volume localised PCa, which rapidly disrupts targeted tumour vessels. There is interest in expanding the use of VTP to higher-risk disease. Tumour vasculature is characterised by vessel immaturity, increased permeability, aberrant branching and inefficient flow. FRT alters the tumour microenvironment and promotes transient 'vascular normalisation'. We hypothesised that multimodality therapy combining fractionated radiotherapy (FRT) and VTP could improve PCa tumour control compared against monotherapy with FRT or VTP. METHODS: We investigated whether sequential delivery of FRT followed by VTP 7 days later improves flank TRAMP-C1 PCa tumour allograft control compared to monotherapy with FRT or VTP. RESULTS: FRT induced 'vascular normalisation' changes in PCa flank tumour allografts, improving vascular function as demonstrated using dynamic contrast-enhanced magnetic resonance imaging. FRT followed by VTP significantly delayed tumour growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP, and improved overall survival. CONCLUSION: Combining FRT and VTP may be a promising multimodal approach in PCa therapy. This provides proof-of-concept for this multimodality treatment to inform early phase clinical trials.
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Neovascularização Patológica/terapia , Fotoquimioterapia/métodos , Neoplasias da Próstata/terapia , Animais , Linhagem Celular Tumoral , Terapia Combinada , Fracionamento da Dose de Radiação , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Neoplasias da Próstata/irrigação sanguínea , Análise de Sobrevida , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Toll-like receptor 2 (TLR2) is implicated in various pathologies, mainly in terms of its function within innate immune cells. However, TLR2 is also present in endothelial cells. Here, we explored the physiological and pathophysiological roles of endothelial TLR2 signaling. We found that TLR2 was highly abundant in the endothelium within various tissues using TLR2-IRES-EGFP reporter mice and was required for proinflammatory endothelial cell function. Endothelial cells lacking TLR2 exhibited reduced proinflammatory potential at the protein, cell, and tissue levels. Loss of endothelial TLR2 blunted the inflammatory response to both exogenous and endogenous danger signals in endothelial cells in culture and in vivo. Endothelial TLR2 promoted tumor growth, angiogenesis, and protumorigenic immune cell recruitment in a mouse model of prostate cancer. Furthermore, the cell surface localization of P-selectin and the subsequent production of other critical cell adhesion molecules (such as E-selectin, ICAM-1 and VCAM-1) that recruit immune cells required endothelial TLR2. Our findings demonstrate that endothelial cells actively contribute to innate immune pathways and propose that endothelial TLR2 has a pathological role in proinflammatory conditions.
Assuntos
Endotélio/metabolismo , Neovascularização Patológica , Neoplasias da Próstata/metabolismo , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Animais , Endotélio/fisiopatologia , Inflamação , Masculino , Camundongos , Selectina-P , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/fisiopatologiaRESUMO
BACKGROUND: Ephrin-A2, a member of the Eph receptor subgroup, is used in diagnosing and determining the prognosis of prostate cancer. However, the role of ephrin-A2 in prostate cancer is remains elusive. METHODS: We established stable clones overexpressing or silencing ephrin-A2 from prostate cancer cells. Then, CCK-8 was used in analyzing the proliferation ability of cells. CD31 staining was used in evaluating angiogenesis. Migration and invasion assay were conducted in vivo and in vitro. The expression of EMT-related markers was evaluated in prostate cancer cells through Western blotting. RESULTS: We revealed that the ectopic expression of ephrin-A2 in prostate cancer cells facilitated cell migration and invasion in vitro and promoted tumor metastasis and angiogenesis in vivo and that the silencing of ephrin-A2 completely reversed this effect. Although ephrin-A2 did not affect tumor cell proliferation in vitro, ephrin-A2 significantly promoted primary tumor growth in vivo. Furthermore, to determine the biological function of ephrin-A2, we assayed the expression of EMT-related markers in stable-established cell lines. Results showed that the overexpression of ephrin-A2 in prostate cancer cells down-regulated the expression of epithelial markers (ZO-1, E-cadherin, and claudin-1) and up-regulated the expression of mesenchymal markers (N-cadherin, ß-catenin, vimentin, Slug, and Snail), but the knocking out of ephrin-A2 opposed the effects on the expression of EMT markers. CONCLUSIONS: These findings indicate that ephrin-A2 promotes prostate cancer metastasis by enhancing angiogenesis and promoting EMT and may be a potentially therapeutic target in metastatic prostate cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Efrina-A2/metabolismo , Transição Epitelial-Mesenquimal , Neovascularização Patológica/patologia , Neoplasias da Próstata/secundário , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Efrina-A2/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Neovascularização Patológica/metabolismo , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Accurate tumor identification and staging can be difficult. Aptamer-targeted indocyanine green (ICG)-nanoparticles can enhance near-infrared fluorescent imaging of pancreatic and prostate tumors and could improve early cancer detection. This project explored whether calcium-phosphosilicate nanoparticles, also known as NanoJackets (NJs), that were bioconjugated with a tumor-specific targeting DNA aptamer could improve the non-invasive detection of pancreatic and prostate tumors. METHODS: Using in vivo near-infrared optical imaging and ex vivo fluorescence analysis, DNA aptamer-targeted ICG-loaded NJs were compared to untargeted NJs for detection of tumors. RESULTS: Nanoparticles were bioconjugated with the DNA aptamer AP1153, which binds to the CCK-B receptor (CCKBR). Aptamer bioconjugated NJs were not significantly increased in size compared with unconjugated nanoparticles. AP1153-ICG-NJ accumulation in orthotopic pancreatic tumors peaked at 18 h post-injection and the ICG signal was cleared by 36 h with no evidence on uptake by non-tumor tissues. Ex vivo tumor imaging confirmed the aptamer-targeted NJs accumulated to higher levels than untargeted NJs, were not taken up by normal pancreas, exited from the tumor vasculature, and were well-dispersed throughout pancreatic and prostate tumors despite extensive fibrosis. Specificity for AP1153-NJ binding to the CCK-B receptor on pancreatic tumor cells was confirmed by pre-treating tumor-bearing mice with the CCK receptor antagonist proglumide. Proglumide pre-treatment reduced the in vivo tumoral accumulation of AP1153-NJs to levels comparable to that of untargeted NJs. CONCLUSION: Through specific interactions with CCK-B receptors, tumor-targeted nanoparticles containing either ICG or rhodamine WT were well distributed throughout the matrix of both pancreatic and prostate tumors. Tumor-targeted NJs carrying various imaging agents can enhance tumor detection.
Assuntos
Aptâmeros de Nucleotídeos/química , Diagnóstico por Imagem , Nanopartículas/química , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Silicatos/química , Animais , Cálcio , Linhagem Celular Tumoral , Corantes , Fluorescência , Humanos , Verde de Indocianina/química , Raios Infravermelhos , Masculino , Camundongos , Neovascularização Patológica/diagnóstico por imagem , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias da Próstata/irrigação sanguínea , Receptores da Colecistocinina/metabolismo , Rodaminas/química , Microambiente TumoralRESUMO
The dramatic impact of the COVID-19 pandemic has resulted in an "all hands on deck" approach to find new therapies to improve outcomes in this disease. In addition to causing significant respiratory pathology, infection with SARS-CoV-2 (like infection with other respiratory viruses) directly or indirectly results in abnormal vasculature, which may contribute to hypoxemia. These vascular effects cause significant morbidity and may contribute to mortality from the disease. Given that abnormal vasculature and poor oxygenation are also hallmarks of solid tumors, lessons from the treatment of cancer may help identify drugs that can be repurposed to treat COVID-19. Although the mechanisms that result in vascular abnormalities in COVID-19 are not fully understood, it is possible that there is dysregulation of many of the same angiogenic and thrombotic pathways as seen in patients with cancer. Many anticancer therapeutics, including androgen deprivation therapy (ADT) and immune checkpoint blockers (ICB), result in vascular normalization in addition to their direct effects on tumor cells. Therefore, these therapies, which have been extensively explored in clinical trials of patients with cancer, may have beneficial effects on the vasculature of patients with COVID-19. Furthermore, these drugs may have additional effects on the disease course, as some ADTs may impact viral entry, and ICBs may accelerate T-cell-mediated viral clearance. These insights from the treatment of cancer may be leveraged to abrogate the vascular pathologies found in COVID-19 and other forms of hypoxemic respiratory failure.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Vasos Sanguíneos/efeitos dos fármacos , COVID-19/prevenção & controle , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , COVID-19/epidemiologia , COVID-19/virologia , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , Masculino , Neoplasias Hormônio-Dependentes/irrigação sanguínea , Avaliação de Resultados em Cuidados de Saúde , Pandemias , Neoplasias da Próstata/irrigação sanguínea , Fatores de Risco , SARS-CoV-2/fisiologiaRESUMO
With the advent of potent second-line anti-androgen therapy, we and others have observed an increased incidence of androgen receptor (AR)-null small cell or neuroendocrine prostate cancer (SCNPC) in metastatic castration-resistant prostate cancer (mCRPC). Our study was designed to determine the effect of cabozantinib, a multi-targeted tyrosine kinase inhibitor that inhibits VEGFR2, MET and RET on SCNPC. Transcriptome analysis of the University of Washington rapid autopsy and SU2C mCRPC datasets revealed upregulated MET and RET expression in SCNPCs relative to adenocarcinomas. Additionally, increased MET expression correlated with attenuated AR expression and activity. In vitro treatment of SCNPC patient-derived xenograft (PDX) cells with the MET inhibitor AMG-337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability of LuCaP 93, but not LuCaP 173.1. Notably, MET+/RET+ LuCaP 93 and MET-/RET- LuCaP 173.1 tumor volumes were significantly decreased with cabozantinib treatment in vivo, and this activity was independent of MET or RET expression in LuCaP 173.1. Tissue analysis indicated that cabozantinib did not inhibit tumor cell proliferation (Ki67), but significantly decreased microvessel density (CD31) and increased hypoxic stress and glycolysis (HK2) in LuCaP 93 and LuCaP 173.1 tumors. RNA-Seq and gene set enrichment analysis revealed that hypoxia and glycolysis pathways were increased in cabozantinib-treated tumors relative to control tumors. Our data suggest that the most likely mechanism of cabozantinib-mediated tumor growth suppression in SCNPC PDX models is through disruption of the tumor vasculature. Thus, cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.
Assuntos
Anilidas/farmacologia , Carcinoma Neuroendócrino , Neovascularização Patológica , Neoplasias da Próstata , Piridinas/farmacologia , Animais , Carcinoma Neuroendócrino/irrigação sanguínea , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos SCID , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: To evaluate the feasibility of prostatic artery embolization in patients with low-risk prostate cancer (PC) under active surveillance (AS). METHODS: This monocentric prospective pilot study, running from June 2018 to June 2019, included 10 patients with low-risk PC under AS, median age 72 years (range, 62-77 years), with a unilateral focal lesion visible on magnetic resonance (MR) imaging, with Prostate Imaging Reporting and Data System v2 score ≥3/5 confirmed by multiparametric MR imaging-targeted biopsy and Gleason score 6. The patients underwent unilateral prostatic artery embolization with 300-500 µm Embospheres in the affected prostatic lobe. The primary endpoint was technical feasibility (prostate and no off-target ischemia in the imaging). The secondary endpoints included safety, negative biopsies/MR imaging response/functional outcomes at 6 months, and oncologic efficacy at 1 year. RESULTS: Embolization was successfully achieved in all patients; prostate ischemia was confirmed on multiparametric MR imaging, and no off-target ischemia was reported. No major complications were reported. Four patients (40%) presented with both negative targeted and systematic biopsies at 6 months. No lesions were seen on the MR imaging in 30% of patients. The mean International Prostate Symptom Score and International Index of Erectile Function score were 7 and 19 and 5 and 20 at baseline and 6 months, respectively, with no significant difference. Nine patients (90%) were still under AS at 1 year. One patient (10%) had PC progression outside the target lesion and was switched over to curative radiotherapy. CONCLUSIONS: Prostatic artery embolization is feasible and appears safe for prostate cancer patients under AS, with no impact on erectile function or continence status. These results justify the pursuit of further studies.
Assuntos
Embolização Terapêutica , Próstata/irrigação sanguínea , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/terapia , Conduta Expectante , Idoso , Embolização Terapêutica/efeitos adversos , Estudos de Viabilidade , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Carbon- (12C-) ion radiotherapy exhibits enhanced biological effectiveness compared to photon radiotherapy, however, the contribution of its interaction with the vasculature remains debatable. The effect of high-dose 12C-ion and photon irradiation on vascular permeability in moderately differentiated rat prostate tumors was compared using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Syngeneic R3327-HI rat prostate tumors were irradiated with a single dose of either 18 or 37 Gy 12C ions, or 37 or 75 Gy 6-MV photons (sub-curative and curative dose levels, respectively). DCE-MRI was performed one day prior to and 3, 7, 14 and 21 days postirradiation. Voxel-based tumor concentration-time curves were clustered based on their curve shape and treatment response was assessed as the longitudinal changes in the relative abundance per cluster. Radiation-induced vascular damage and increased permeability occurred at day 7 postirradiation for all treatment groups except for the 75 Gy photon-irradiated group, where the onset of vascular damage was delayed until day 14. No differences between irradiation modalities were found. Therefore, early vascular damage cannot explain the higher effectiveness of 12C ions relative to photons in terms of local tumor control for this moderately differentiated prostate tumor and the applied single high doses.
Assuntos
Adenocarcinoma/radioterapia , Permeabilidade Capilar/efeitos da radiação , Carbono/uso terapêutico , Radioterapia com Íons Pesados , Imageamento por Ressonância Magnética/métodos , Fótons/uso terapêutico , Neoplasias da Próstata/radioterapia , Adenocarcinoma/sangue , Adenocarcinoma/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Masculino , Transplante de Neoplasias , Análise de Componente Principal , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/diagnóstico por imagem , Distribuição Aleatória , Ratos , Transplante HeterotópicoRESUMO
Bone metastatic prostate cancer significantly impacts patient quality of life and overall survival, and despite available therapies, it is presently incurable with an unmet need for improved treatment options. As mediators of tumor progression, matrix metalloproteinases (MMPs) can degrade extracellular matrix components and regulate growth factor and cytokine bioactivity. Depending on tissue context, MMPs can either promote or inhibit tumorigenesis. Therefore, it is essential to study individual MMPs in specific cancer contexts and microenvironments to support the design and application of selective MMP inhibitors. Here we report that tumor-derived MMP-3 contributes to bone metastatic prostate cancer progression via intrinsic and extrinsic routes. MMP-3 ablation in prostate cancer cell lines significantly reduced in vitro growth combined with lowered AKT and ERK phosphorylation and total VEGFR1 and FGFR3 protein levels. In vivo, MMP-3 ablated tumors grew at a slower rate and were significantly less vascularized. Quantitative PCR analyses of wild type and MMP-3 silenced prostate cancer cells also demonstrate downregulation of a wide array of angiogenic factors. The extrinsic role for MMP-3 in angiogenesis was supported by in vitro endothelial tube formation assays where the lack of MMP-3 in prostate cancer conditioned media resulted in slower rates of tube formation. Taken together, our results suggest that tumor-derived MMP-3 contributes to prostate cancer growth in bone. These data indicate that selective inhibition of MMP-3 and/or targeting MMP generated products could be efficacious for the treatment of prostate to bone metastases.
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Neoplasias Ósseas/irrigação sanguínea , Neoplasias Ósseas/secundário , Metaloproteinase 3 da Matriz/metabolismo , Neovascularização Patológica/patologia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , Animais , Apoptose , Neoplasias Ósseas/enzimologia , Proliferação de Células , Modelos Animais de Doenças , Humanos , Masculino , Metaloproteinase 3 da Matriz/genética , Camundongos , Neovascularização Patológica/enzimologia , Neoplasias da Próstata/enzimologia , Células Tumorais CultivadasRESUMO
BACKGROUND: Inhibition of angiogenesis in prostatic cancer could be a brand-new method to suppress tumour progression. Nodal/ALK4 has been associated with vascularization in many cancers. However, the relationship between and role of Nodal/ALK4 and miR-185 in human prostatic cancer is still unknown. METHODS: Prostatic cancer DU145 cells and LNCaP cells were used to investigate the angiogenic effect induced by Nodal and the anti-angiogenic roles of miR-185. Colony formation assay, MTT assay, transwell assay and tube formation assay were used to explore cell proliferation, migration and tube-forming ability, respectively. A luciferase reporter assay confirmed the binding relationship between miR-185 and ALK4. The expression levels of miR-185, ALK4 and VEGF were detected by qRT-PCR and Western blotting. The effects of miR-185 and Nodal in prostate cancer were also investigated in animal experiments. RESULTS: VEGF expression was increased in DU145 cells and LNCaP cells after Nodal incubation, and Nodal activated the proliferation ability of prostatic cancer cells and the migration and tube-forming ability of human umbilical vein endothelial cells (HUVECs), which were all inhibited by treatment with the Nodal inhibitor SB431524. Bioinformatics analysis and luciferase assay were used to verify miR-185 as a target of ALK4. Prostatic cancer cell proliferation was inhibited by overexpression of miR-185, which was shown to regulate the migration and angiogenesis of HUVECs by targeting ALK4 for suppression. miR-185 also showed a significant inverse correlation with Nodal treatment and reversed the angiogenic effects induced by Nodal. More importantly, for the first time, xenograft experiments indicated that overexpression of miR-185 suppressed tumour development. CONCLUSION: The Nodal/ALK4 pathway is important in the angiogenesis of prostate cancer and can be inhibited by targeting miR-185 to downregulate ALK4. These findings provide a new perspective on the mechanism of prostate cancer formation.
Assuntos
Receptores de Ativinas Tipo I/fisiologia , MicroRNAs/fisiologia , Proteína Nodal/fisiologia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/genética , Humanos , Masculino , Neovascularização Patológica , Neoplasias da Próstata/patologia , Células Tumorais CultivadasRESUMO
PURPOSE: To investigate use of a novel imaging approach, hyperpolarized (HP) 13C magnetic resonance imaging (MRI) for simultaneous metabolism and perfusion assessment, to evaluate early and dose-dependent response to radiation therapy (RT) in a prostate cancer mouse model. METHODS AND MATERIALS: Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice (n = 18) underwent single-fraction RT (4-14 Gy steep dose across the tumor) and were imaged serially at pre-RT baseline and 1, 4, and 7 days after RT using HP 13C MRI with combined [1-13C]pyruvate (metabolic active agent) and [13C]urea (perfusion agent), coupled with conventional multiparametric 1H MRI including T2-weighted, dynamic contrast-enhanced, and diffusion-weighted imaging. Tumor tissues were collected 4 and 7 days after RT for biological correlative studies. RESULTS: We found a significant decrease in HP pyruvate-to-lactate conversion in tumors responding to RT, with concomitant significant increases in HP pyruvate-to-alanine conversion and HP urea signal; the opposite changes were observed in tumors resistant to RT. Moreover, HP lactate change was dependent on radiation dose; tumor regions treated with higher radiation doses (10-14 Gy) exhibited a greater decrease in HP lactate signal than low-dose regions (4-7 Gy) as early as 1 day post-RT, consistent with lactate dehydrogenase enzyme activity and expression data. We also found that HP [13C]urea MRI provided assessments of tumor perfusion similar to those provided by 1H dynamic contrast-enhanced MRI in this animal model. However, apparent diffusion coefficien , a conventional 1H MRI functional biomarker, did not exhibit statistically significant changes within 7 days after RT. CONCLUSION: These results demonstrate the ability of HP 13C MRI to monitor radiation-induced physiologic changes in a timely and dose-dependent manner, providing the basic science premise for further clinical investigation and translation.
Assuntos
Imageamento por Ressonância Magnética , Imagem de Perfusão , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Animais , Isótopos de Carbono , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Masculino , Camundongos , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/metabolismo , Ácido Pirúvico , Fatores de Tempo , Resultado do Tratamento , UreiaRESUMO
Late recurrence of prostate cancer after remission with prior radical prostatectomy is uncommon. This is a unique case of biochemical recurrence after being in remission for 12 years. The patient presented with swelling of the right lower extremity with pelvic MRI demonstrating an arterially enhancing filling defect in the right common iliac. An F-fluciclovine PET/CT showed corresponding increased intravascular radiotracer activity. Targeted biopsy of the intravascular lesion showed poorly differentiated carcinoma, suggestive of prostate origin. Although MRI evaluation is the mainstay for pelvic evaluation, characterization with F-fluciclovine PET/CT imaging adds high whole-body specificity and diagnostic accuracy.
Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Ácidos Carboxílicos , Ciclobutanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata/diagnóstico por imagem , Idoso , Biópsia , Vasos Sanguíneos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prostatectomia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Sensibilidade e EspecificidadeRESUMO
Vasculogenic mimicry (VM) is the alternative process of forming vessel-like networks by aggressive tumor cells, and it has an important role in tumor survival, growth, and metastasis. Epigallocatechin-3-gallate (EGCG) is well known to have diverse bioactivities including anti-cancer effects. However, the efficacy of EGCG on VM is elusive. In this study, we explored whether and how EGCG affects VM in human prostate cancer (PCa) PC-3 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Invasive and VM formation abilities were assessed by an invasion assay and a three-dimensional (3D) culture VM tube formation assay, respectively. Western blots were carried out. An immunofluorescence assay was performed to detect nuclear twist expression. EGCG effectively inhibited the invasive ability, as well as tubular channel formation, without affecting cell viability. EGCG significantly downregulated the expression of vascular endothelial cadherin (VE-cadherin) and its transcription factor, twist, N-cadherin, vimentin, phosphor-AKT, and AKT, but not phospho-erythropoietin-producing hepatocellular receptor A2 (EphA2) and EphA2. In addition, EGCG diminished the nuclear localization of twist. Treatment with SC79, an AKT activator, effectively rescued EGCG-inhibited VM formation. These results demonstrated for the first time that EGCG causes marked suppression of VM through inhibiting the twist/VE-cadherin/AKT pathway in human PCa PC-3 cells.
Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Catequina/análogos & derivados , Neovascularização Patológica/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Proteína 1 Relacionada a Twist/metabolismo , Catequina/química , Catequina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Invasividade Neoplásica , Transdução de Sinais/efeitos dos fármacosRESUMO
Early studies suggest that the androgen receptor (AR) may play differential roles in influencing prostate cancer (PCa) and bladder cancer (BCa) metastasis, but the underlying mechanisms remain unclear. Here, we found that the AR might function via differentially altering vasculogenic mimicry (VM) formation to either decrease PCa metastasis or increase BCa metastasis. Mechanism dissection showed that the AR could differentially alter the expression of the VM marker SLPI through miR-525-5p to regulate SLPI; moreover, it could either increase miR-525-5p transcription in PCa or decrease it in BCa via binding to different androgen-response-elements (AREs) located at different positions in the miR-525 precursor promoter. Further, results from liquid chromatography-mass spectrometry (LC-MS) showed that the co-factors of AR in PCa and BCa are NFIX and HDAC2, respectively. Together, these results provide the first detailed mechanism of how the AR can differentially alter PCa and BCa metastasis; thus, targeting the newly identified AR-miR-525-5p-SLPI axis may help suppress metastasis.
Assuntos
MicroRNAs/genética , Neovascularização Patológica/genética , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Neoplasias da Bexiga Urinária/genética , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzamidas , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Histona Desacetilase 2/metabolismo , Humanos , Masculino , Fatores de Transcrição NFI/metabolismo , Metástase Neoplásica/genética , Metástase Neoplásica/prevenção & controle , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/genética , Inibidor Secretado de Peptidases Leucocitárias/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Gênica/efeitos dos fármacos , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: Angiogenesis is a critical biological process essential for solid cancer growth and metastasis. It has been shown that microRNAs (miRNAs) play a vital role in a variety of biological processes in cancers. However, whether miR-130b is involved in prostate cancer angiogenesis remains ill-defined. METHODS: We performed the miRNA microarray to analyze miRNA expression in human prostate cancer specimens. In vitro gain-of-function assays and loss-of-function assays were conducted to explore the potential functions of miR-130b in human prostate cancer cells. Correlation analysis and dual-luciferase reporter assay were performed to validate whether tumor necrosis factor-α (TNF-α) was a direct target of miR-130b. The Matrigel plug and tumor vascular imaging assays were performed to confirm the anti-angiogenic activity of miR-130b in nude mice. RESULTS: We found that miR-130b was one of the miRNAs being most significantly downregulated. Subsequently, we found that miR-130b expression was markedly downregulated in human prostate cancer cell lines. Down-regulation of miR-130b in prostate cancer cells significantly promoted the proliferation, invasion and tubule formation of human umbilical vein endothelial cells (HUVECs), while ectopic expression of miR-130b blocked prostate cancer angiogenesis in vitro and in vivo. Mechanistic analyses indicated that tumor necrosis factor-α (TNF-α) was regulated by miR-130b directly. MiR-130b attenuated nuclear factor-κB (NF-κB) signaling and its downstream gene vascular endothelial growth factor-A (VEGFA) by directly inhibiting TNF-α expression. Additionally, subsequent investigations identified that the ectopic level of VEGFA markedly abrogated the anti-angiogenic effect induced by miR-130b. Interestingly, VEGFA could in turn decrease the expression of miR-130b, thus forming a negative feedback loop that drives the angiogenesis of prostate cancer. CONCLUSION: These findings show that miR-130b/TNF-α/NF-κB/VEGFA feedback loop is significantly correlated with angiogenesis in prostate cancer and miR-130b could be regarded as potential therapeutic target for prostate cancer anti-angiogenesis treatment.
Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , NF-kappa B/metabolismo , Neovascularização Patológica/patologia , Neoplasias da Próstata/irrigação sanguínea , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/genética , Neovascularização Patológica/metabolismo , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/genética , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The antiangiogenic therapy for prostate cancer with Nintedanib, a potent inhibitor of important growth factor receptors, has been proven to delay tumor progression and arrest tumor growth; thus, the aim herein is to evaluate Nintedanib effects on tumor cells, besides angiogenesis and apoptosis processes, metalloproteinases and hypoxia factor in an animal model. Nintedanib promoted growth inhibition and cell death in a dose-dependent manner, showing no tumor selectivity. Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) were treated with Nintedanib (10 mg/kg/day) in different stages of tumor development and the ventral prostate was examined for protein levels by means of immunohistochemistry and Western blotting and apoptosis evaluation. In vitro antiproliferative activity of Nintedanib was also assessed in nine human tumor cell lines. Early Nintedanib treatment has shown decreased levels of FGF-2, VEGFR-1, MMP-9 and HIF-1α and a significantly increased apoptosis of epithelial cells. Furthermore, late Nintedanib treatment decreased FGF-2, VEGFR-1 and FGFR-3 levels. Importantly, even after treatment discontinuation, treated animals displayed a significant decrease in VEGFR-1 as well as MMP-9. Although Nintedanib treatment in late stages of tumor growth has shown some good results, it is noteworthy that the drug presents the best tissue response when administered in the early stages of disease development. Nintedanib treatment has shown to be a promising approach for prostate cancer therapy, especially in the early stages of the disease, interfering in different carcinogenesis progression pathways.