RESUMEN
Background: Canine prostatic carcinoma (cPC) is a urogenital tumour with a poor prognosis, for which no effective treatment has been established. Recently, it has been shown that human epidermal growth factor receptor type 2 (HER2) is overexpressed in cPC cells; however, the efficacy of HER2-targeted therapy remains unclear. Aim: Investigate the anti-tumour effect of lapatinib on HER2-positive cPC cell lines. Methods: Two cell lines (muPC and bePC) were established from two dogs with cPC and the effects of lapatinib treatment on cell proliferation, apoptosis, and HER2 downstream signalling were investigated. Furthermore, muPC was used to generate tumour-bearing mice, and the anti-tumour effects of lapatinib were examined in vivo. Results: Lapatinib treatment inhibited the proliferation and phosphorylation of Erk1/2 and Akt, which are downstream signals of HER2. Furthermore, the TUNEL assay showed that lapatinib induced apoptosis in both cell lines. The muPC-engrafted nude mouse model showed that lapatinib significantly inhibited tumour growth and increased the area of necrotic tumour tissue compared to the vehicle-treated groups. Conclusion: Lapatinib exerts anti-tumour effects on cPC cells by inhibiting HER-2 signalling.
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Antineoplásicos , Enfermedades de los Perros , Lapatinib , Ratones Desnudos , Neoplasias de la Próstata , Receptor ErbB-2 , Lapatinib/farmacología , Lapatinib/uso terapéutico , Animales , Perros , Masculino , Línea Celular Tumoral , Enfermedades de los Perros/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/veterinaria , Neoplasias de la Próstata/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Ratones , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quinazolinas/farmacología , Quinazolinas/uso terapéuticoRESUMEN
Canine urothelial carcinoma (UC) and prostate carcinoma (PC) frequently exhibit the BRAFV595E mutation, akin to the BRAFV600E mutation common in various human cancers. Since the initial discovery of the BRAF mutation in canine cancers in 2015, PCR has been the standard method for its detection in both liquid and tissue biopsies. Considering the similarity between the canine BRAFV595E and human BRAFV600E mutations, we hypothesized that immunohistochemistry (IHC) using a BRAFV600E-specific antibody could effectively identify the canine mutant BRAFV595E protein. We tested 122 canine UC (bladder n = 108, urethra n = 14), 21 PC, and benign tissue using IHC and performed digital droplet PCR (ddPCR) on all 122 UC and on 14 IHC positive PC cases. The results from ddPCR and IHC were concordant in 99% (135/136) of the tumours. Using IHC, BRAFV595E was detected in 72/122 (59%) UC and 14/21 (65%) PC. Staining of all benign bladder and prostate tissues was negative. If present, mutant BRAF staining was homogenous, with rare intratumour heterogeneity in three (4%) cases of UC. Additionally, the BRAFV595E mutation was more prevalent in tumours with urothelial morphology, and less common in glandular PC or UC with divergent differentiation. This study establishes that BRAFV600-specific IHC is a reliable and accurate method for detecting the mutant BRAFV595E protein in canine UC and PC. Moreover, the use of IHC, especially with tissue microarrays, provides a cost-efficient test for large-scale screening of canine cancers for the presence of BRAF mutations. This advancement paves the way for further research to define the prognostic and predictive role of this tumour marker in dogs and use IHC to stratify dogs for the treatment with BRAF inhibitors.
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Enfermedades de los Perros , Inmunohistoquímica , Mutación , Neoplasias de la Próstata , Proteínas Proto-Oncogénicas B-raf , Neoplasias de la Vejiga Urinaria , Perros , Animales , Enfermedades de los Perros/genética , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/patología , Proteínas Proto-Oncogénicas B-raf/genética , Masculino , Neoplasias de la Próstata/veterinaria , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Inmunohistoquímica/veterinaria , Neoplasias de la Vejiga Urinaria/veterinaria , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/diagnóstico , Femenino , Carcinoma/veterinaria , Carcinoma/genética , Carcinoma/patología , Carcinoma/metabolismo , Carcinoma/diagnóstico , Carcinoma de Células Transicionales/veterinaria , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/patologíaRESUMEN
Canine prostatic carcinoma (PC) has incompletely defined CT features. The purpose of this multicenter retrospective case series was to assess prostatic, regional, and distant findings of PC. Thirty dogs were enrolled. Consistent prostatic features included postcontrast heterogeneity with hypoattenuating, nonenhancing areas (30/30), capsular distortion (29/30), prostatic urethral effacement, displacement, or invasion (28/30), precontrast heterogeneity (27/30), and mineralization (24/30) which was always within or at the margin of the hypoattenuating areas. Consistent extraprostatic features included medial iliac lymph node enlargement (20/30), internal iliac lymph node enlargement (15/30), and periprostatic fat streaking or fluid (15/29). In a minority of dogs, there was lymph node mineralization, bladder trigone invasion, ureteral dilation, ductus deferens invasion, and bony changes consistent with hypertrophic osteopathy. Strongly suspected and potential bony metastases were noted infrequently (8/26), all in vertebrae regional to the prostate. In conclusion, these findings provide guidance on the expected CT features of canine PC.
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Enfermedades de los Perros , Neoplasias de la Próstata , Tomografía Computarizada por Rayos X , Perros , Animales , Masculino , Enfermedades de los Perros/diagnóstico por imagen , Enfermedades de los Perros/patología , Neoplasias de la Próstata/veterinaria , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/veterinaria , Próstata/diagnóstico por imagen , Próstata/patología , Carcinoma/veterinaria , Carcinoma/diagnóstico por imagen , Carcinoma/patología , Carcinoma/secundarioRESUMEN
BACKGROUND: Prostatic carcinoma (PCA) is a rare but severe condition in dogs that is similar to the androgen-independent form of PCA in men. In contrast to humans, PCA is difficult to diagnose in dogs as reliable biomarkers, available for PCA screening in human medicine, are currently lacking in small animal oncology. Calprotectin (S100A8/A9) and S100A12 are Ca2+-binding proteins of the innate immune system with promising potential to distinguish malignant from benign urogenital tract conditions, similar to the blood neutrophil-to-lymphocyte-ratio (NLR). However, both have not yet been extensively investigated in dogs with PCA. Thus, this study aimed to evaluate the expression of the S100/calgranulins (calprotectin, S100A12, and their ratio [Cal-ratio]) in prostatic biopsies from nine dogs with PCA and compare them to those in dogs with benign prostatic lesions (eight dogs with prostatitis and ten dogs with benign prostatic hyperplasia [BPH]) as well as five healthy controls. In addition, blood NLRs were investigated in twelve dogs with PCA and 22 dogs with benign prostatic conditions. RESULTS: Tissue S100A8/A9+ cell counts did not differ significantly between tissue from PCA and prostatitis cases (P = 0.0659) but were significantly higher in dogs with prostatitis than BPH (P = 0.0013) or controls (P = 0.0033). S100A12+ cell counts were significantly lower in PCA tissues than in prostatitis tissue (P = 0.0458) but did not differ compared to BPH tissue (P = 0.6499) or tissue from controls (P = 0.0622). Cal-ratios did not differ significantly among the groups but were highest in prostatitis tissues and significantly higher in those dogs with poor prostatitis outcomes than in patients that were still alive at the end of the study (P = 0.0455). Blood NLR strongly correlated with prostatic tissue S100A8/A9+ cell counts in dogs with PCA (ρ = 0.81, P = 0.0499) but did not differ among the disease groups of dogs. CONCLUSIONS: This study suggests that the S100/calgranulins play a role in malignant (PCA) and benign (prostatic inflammation) prostatic conditions and supports previous results in lower urinary tract conditions in dogs. These molecules might be linked to the inflammatory environment with potential effects on the inflammasome. The blood NLR does not appear to aid in distinguishing prostatic conditions in dogs. Further investigation of the S100/calgranulin pathways and their role in modulation of tumor development, progression, and metastasis in PCA is warranted.
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Enfermedades de los Perros , Hiperplasia Prostática , Neoplasias de la Próstata , Prostatitis , Masculino , Humanos , Perros , Animales , Complejo de Antígeno L1 de Leucocito , Hiperplasia Prostática/veterinaria , Prostatitis/veterinaria , Proteína S100A12 , Neutrófilos/patología , Neoplasias de la Próstata/veterinaria , Calgranulina A , Linfocitos , Enfermedades de los Perros/diagnósticoRESUMEN
Prostate cancer (PCa) is a prevalent malignancy affecting men worldwide. Animal models play a crucial role in studying PCa pathology and discovering novel approaches to prevent, detect and treat this disease. However, the challenge of translational medicine is the limited reproducibility and inadequate recapitulation of human conditions in animal models. Therefore, a comprehensive understanding of the macroscopic and microscopic anatomy of the prostate gland among distinct animal species is essential for better translating research findings to clinical practice. This review aims to compare and describe the macroscopic and microscopic anatomy of the prostate gland in humans, rats, and dogs, emphasizing the relevant features. Despite the anatomical differences between these species, rats are a valuable model to study human prostate diseases, once they share some features implicated in carcinogenesis in humans. Dogs, on the other hand, are considered the best model for studying PCa due to the development of spontaneous cancer with a higher incidence when compared with other animals and the development of bone metastases. Moreover, the lymphatic system and the sentinel lymph node role and mapping are similar in dogs and humans. However, it is important to recognize that no animal model can directly mimic all aspects of PCa as the human prostate is anatomically different from that of rats and dogs. Therefore, it is essential to analyze and understand the intra- and interspecies variability when translating research findings into clinical practice. This review highlights the importance of a thorough understanding of the anatomical differences between the prostate gland in humans, rats, and dogs when selecting the appropriate animal model for studying PCa.
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Neoplasias Óseas , Enfermedades de los Perros , Neoplasias de la Próstata , Masculino , Humanos , Ratas , Animales , Perros , Próstata/patología , Reproducibilidad de los Resultados , Ciencia Traslacional Biomédica , Neoplasias de la Próstata/veterinaria , Neoplasias Óseas/secundario , Neoplasias Óseas/veterinaria , Enfermedades de los Perros/patologíaRESUMEN
Pulsatile secretion of gonadotropin-releasing hormone (GnRH) is essential for the activation and maintenance of the function of the hypothalamic-pituitary-gonadal (HPG) axis, which controls the onset of puberty and fertility. Two provocative recent studies suggest that, in addition to control reproduction, the neurons in the brain that produce GnRH are also involved in the control postnatal brain maturation, odour discrimination and adult cognition. Long-acting GnRH antagonists and agonists are commonly used to control fertility and behaviour in veterinary medicine, primarily in males. This review puts into perspective the potential risks of these androgen deprivation therapies and immunization on olfactory and cognitive performances and well-aging in domestic animals, including pets. We will also discuss the results reporting beneficial effects of pharmacological interventions restoring physiological GnRH levels on olfactory and cognitive alterations in preclinical models of Alzheimer's disease, which shares many pathophysiological and behavioural hallmarks with canine cognitive dysfunction. These novel findings raise the intriguing possibility that pulsatile GnRH therapy holds therapeutic potential for the management of this behavioural syndrome affecting older dogs.
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Enfermedades de los Perros , Neoplasias de la Próstata , Masculino , Animales , Perros , Hormona Liberadora de Gonadotropina , Olfato , Antagonistas de Andrógenos , Neoplasias de la Próstata/veterinaria , CogniciónRESUMEN
Cancers of the breast, prostate and intestinal tract account for most cancer-associated deaths in humans and represent several of the highest incidence human neoplasms. Therefore, understanding the underlying pathophysiology, including the formation and propagation of these cancers, is key to designing potential treatments. Over the last 50 years or more, genetically engineered mouse models (GEMMs) have been instrumental platforms to our discovery of neoplastic disease as many follow near-identical molecular and histological progression as human tumours. In this mini review, we summarize three key preclinical models and focus on some of the major findings in relation to clinical care. We discuss the MMTV-PyMT (polyomavirus middle T antigen) mouse, TRAMP (transgenic adenocarcinoma mouse prostate) mouse and APCMin (multiple intestinal neoplasm mutation of APC gene) mouse, which mimic breast, prostate and intestinal cancers, respectively. We aim to describe the significant contributions these GEMMs have made to our collective understanding of high-incidence cancers as well as briefly discuss the limitations of each model as a device for therapeutic discovery.
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Neoplasias de la Próstata , Masculino , Ratones , Humanos , Animales , Ratones Transgénicos , Modelos Animales de Enfermedad , Neoplasias de la Próstata/veterinaria , Genes APC , MutaciónRESUMEN
Canine prostate cancer (cPCa) is a malignant neoplasm with no effective therapy. The BRAF V595E mutation, corresponding to the human BRAF V600E mutation, is found frequently in cPCa. Activating BRAF mutations are recognized as oncogenic drivers, and blockade of MAPK/ERK phosphorylation may be an effective therapeutic target against BRAF-mutated tumours. The aim of this study was to establish a novel cPCa cell line and to clarify the antitumor effects of MEK inhibitors on cPCa in vitro and in vivo. We established the novel CHP-2 cPCa cell line that was derived from the prostatic tissue of a cPCa patient. Sequencing of the canine BRAF gene in two cPCa cell lines revealed the presence of the BRAF V595E mutation. MEK inhibitors (trametinib, cobimetinib and mirdametinib) strongly suppressed cell proliferation in vitro, and trametinib showed the highest efficacy against cPCa cells with minimal cytotoxicity to non-cancer COPK cells. Furthermore, we orally administered 0.3 or 1.0 mg/kg trametinib to CHP-2 xenografted mice and examined its antitumor effects in vivo. Trametinib reduced tumour volume, decreased phosphorylated ERK levels, and lowered Ki-67 expression in xenografts in a dose-dependent manner. Although no clear adverse events were observed with administration, trametinib-treated xenografts showed osteogenesis that was independent of dosage. Our results indicate that trametinib induces cell cycle arrest by inhibiting ERK activation, resulting in cPCa tumour regression in a dose-dependent manner. MEK inhibitors, in addition to BRAF inhibitors, may be a targeted agent option for cPCa with the BRAF V595E mutation.
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Enfermedades de los Perros , Neoplasias de la Próstata , Masculino , Humanos , Animales , Perros , Ratones , Proteínas Proto-Oncogénicas B-raf/genética , Línea Celular Tumoral , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/genética , Inhibidores de Proteínas Quinasas , Quinasas de Proteína Quinasa Activadas por Mitógenos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/veterinaria , MutaciónRESUMEN
Magnetic resonance imaging (MRI) has been used to evaluate dogs with suspected prostatic neoplasia, however, published studies describing MRI characteristics of canine prostatic neoplasia are currently lacking. The aims of the current retrospective case series study were to describe MRI findings of the pelvic region in dogs with a histopathologic or cytologic diagnosis of prostatic neoplasia. Retrospective analysis of these images was then performed by a board-certified veterinary radiologist for shared imaging characteristics. The most consistent characteristics were heterogeneous hyperintensity of the tumor on T2-weighted images (10/10) and short tau inversion recovery images (10/10), prostatic capsular margin distortion by the tumor (10/10), cavitations (10/10), complete effacement of the prostatic architecture (9/10), neurovascular bundle (NVB) compression or invasion (9/10), heterogeneous isointensity of the tumor on T1-weighted images (9/10), and strong contrast enhancement of the tumor (8/10). Additional features included an overlying pattern of distorted radiating striations (7/10), regional lymphadenomegaly (5/10), mineralization within the mass (5/10), urinary bladder trigone involvement (6/10), and post-prostatic urethral involvement (7/10). These findings supported the use of MRI as an adjunct imaging modality for diagnosis and therapeutic planning of prostatic neoplasia and including prostatic neoplasia as a likely differential diagnosis for dogs with these MRI characteristics.
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Enfermedades de los Perros , Neoplasias de la Próstata , Masculino , Perros , Animales , Estudios Retrospectivos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/veterinaria , Próstata/patología , Imagen por Resonancia Magnética/veterinaria , Imagen por Resonancia Magnética/métodos , Vejiga Urinaria/patología , Enfermedades de los Perros/diagnóstico por imagen , Enfermedades de los Perros/patologíaRESUMEN
BACKGROUND: In male dogs, uroepithelial cancers include invasive urothelial carcinoma (iUC) and prostate carcinoma (PCA). The inability to distinguish iUC involving the prostate from PCA results in indiscriminate clinical management strategies that could be suboptimal as first-line chemotherapy for iUC (cisplatin) and PCA (docetaxel) differ in people. Prostate specific membrane antigen (PSMA) is a transmembrane protein, and its overexpression has been identified in human prostate carcinoma and neovasculature associated with solid tumor growth. This study investigates whether differential PSMA expression exists between presumptive canine iUC and PCA among cell lines and archived patient samples, which might allow for improved accuracy in disease-based stratification and optimal chemotherapy selection. Additionally, in vitro sensitivities of reported canine iUC and PCA cell lines to uroepithelial directed chemotherapeutic agents were characterized. RESULTS: Normalized PSMA gene and protein expressions were not significantly different between 5 iUC and 4 PCA cell lines. PSMA protein expression was uniformly observed in uroepithelial cancers regardless of anatomic origin from archived patient samples, further confirming that PSMA cannot differentiate iUC from PCA. In vitro sensitivity of cell lines to uroepithelial directed chemotherapeutics revealed that vinblastine exerted the broadest cytotoxic activity. CONCLUSIONS: Differential expression of PSMA was not identified between canine iUC and PCA cell lines or archived patient samples, and PSMA alone cannot be used for disease stratification. Nonetheless given its conserved overexpression, PSMA may be a targetable surface marker for both canine iUC and PCA. Lastly, in uroepithelial carcinomas, vinblastine might exert the broadest anticancer activity regardless of cellular origin.
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Carcinoma de Células Transicionales , Enfermedades de los Perros , Neoplasias de la Próstata , Neoplasias de la Vejiga Urinaria , Humanos , Masculino , Perros , Animales , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/veterinaria , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/veterinaria , Vinblastina/uso terapéutico , Antígenos de Superficie , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/veterinaria , Próstata/metabolismo , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/genéticaRESUMEN
OBJECTIVE: The purpose of this study was to determine whether prostatic aspirate culture is a superior method to detect infection compared to culture of urine collected by cystocentesis in dogs with prostatic neoplasia. MATERIALS AND METHODS: A prospective study was conducted and dogs with suspected or confirmed prostatic neoplasia were enrolled. Urinalysis was done and culture and antimicrobial susceptibility testing was performed on paired urine and prostatic aspirate samples collected at a single timepoint. RESULTS: Ten dogs with prostatic neoplasia were enrolled. All dogs had one or more clinical sign consistent with lower urinary tract disease. One dog (10%) had a positive urine culture, but negative prostatic aspirate culture, one dog (10%) had a positive prostatic aspirate culture, but negative urine culture, and one dog (10%) had both positive urine and prostatic aspirate cultures. Using prostatic aspirate culture as the reference standard, urine culture had a sensitivity for detecting infection of 87.5% (95% confidence interval 52.9 to 99.4) and specificity of 50% (92.6 to 97.4) in this population of dogs. CLINICAL SIGNIFICANCE: Positive cultures were uncommon with both culture collection methods. Study results did not identify prostatic aspirate culture to be a more sensitive method of detecting prostatic infection than urine culture collected by cystocentesis in these dogs with prostatic neoplasia.
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Infecciones Bacterianas , Enfermedades de los Perros , Neoplasias de la Próstata , Infecciones Urinarias , Masculino , Perros , Animales , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/veterinaria , Infecciones Urinarias/microbiología , Estudios Prospectivos , Enfermedades de los Perros/microbiología , Urinálisis/veterinaria , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/veterinaria , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/veterinariaRESUMEN
Canine prostate cancer is classified into adenocarcinoma, transitional cell carcinoma with prostatic involvement, and mixed forms. Early metastatic spread leads to poor prognosis and limited treatment options. Masitinib is approved for the treatment of canine mast cell tumours and inhibits tyrosine kinase c-Kit, tyrosine-protein kinase Lyn (Lyn), and platelet-derived growth factor receptors alpha and beta (PDGFR-α, PDGFR-ß), which are known to be expressed in canine prostate cancer. The aim of this study was to evaluate masitinib in an in vitro model consisting of cell lines from primary prostate adenocarcinoma, the associated lymph node metastasis of the same patient, and transitional cell carcinoma. To assess the suitability of the model system, the targets of masitinib were investigated by immunocytochemistry in the cell lines and by immunohistochemistry in the respective formalin-fixed, paraffin-embedded (FFPE) original neoplastic tissue. After exposure to masitinib, cell viability, cell count, apoptosis induction, and protein expression of c-Kit, Lyn, PDGFR-α, and PDGFR-ß were assessed. To hedge the efficacy, two application protocols of masitinib (single application or 12-h double-dose regimen) were compared. Immunocytochemical and immunohistochemical analysis revealed increased Lyn, PDGFR-α, and PDGFR-ß expression in cell lines and FFPE original neoplastic tissue compared to healthy prostate tissue. Masitinib exposure increased apoptosis, while the cell counts and cell viability decreased in a dose- and application interval-dependent manner, with increased impact in the 12-h double-dose regimen. These in vitro effects of masitinib in canine prostate cancer and associated metastasis support further in vivo research and modifications of the clinical treatment protocol in future studies.
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Adenocarcinoma , Carcinoma de Células Transicionales , Enfermedades de los Perros , Neoplasias de la Próstata , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/veterinaria , Animales , Benzamidas , Carcinoma de Células Transicionales/veterinaria , Línea Celular , Enfermedades de los Perros/tratamiento farmacológico , Perros , Masculino , Piperidinas , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/veterinaria , Proteínas Proto-Oncogénicas c-kit/metabolismo , Piridinas , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , TiazolesRESUMEN
BACKGROUND: Prostatic cancer is uncommon in dogs. Dogs with prostatic carcinoma have been reported to have a poor prognosis. Information regarding prognosis with various surgery options as well as prognosis with surgical vs. medical treatment is lacking. This retrospective study compares the outcomes of medical management to surgical treatment in dogs with prostatic adenocarcinoma and assesses the surgical outcomes of patients who underwent total prostatectomy (TP) and prostatocystectomy (TPC). The medical records of 41 dogs with prostatic adenocarcinoma, between February 2008 and June 2019, were reviewed for information on signalment, clinical signs in the initial evaluation, preoperative diagnostic imaging findings, treatment type (non-surgical or surgical), surgery type, postoperative complications, adjunctive medical therapy, and survival time. The dogs were divided into non-surgical (n = 12) or surgical (n = 29) groups. The surgical group was subdivided into the TP (n = 20) and TPC (n = 9) subgroups. RESULTS: Age was not significantly different between the surgical (median 13.1 years [8.4-15.4] years) and the non-surgical groups (median 10.8 [7.7-15.3] years). Body weight (BW) was also not significantly different between the surgical (median 6.8 kg [2.4-34.5 kg]) and non-surgical groups (median 6.4 kg [3.7-9.12 kg]). The overall median survival time (MST) from the initial evaluation was significantly longer in the surgical than in the non-surgical group (337 vs. 90.5 days). The postoperative MST was significantly longer in the TP group than in the TPC subgroup (510 vs. 83 days). As TPC was performed in cases of tumor progression, its postoperative complications were severe, resulting in a shorter MST. Ten (50%) and 6 patients (30%) in the TP subgroup postoperatively showed mild and severe urinary incontinence, respectively, whereas all patients in TPC subgroup did show severe incontinence. CONCLUSION: Results of the study suggest that surgical treatment of prostatic carcinoma results in longer survival times over medical management alone. In particular, TP might be recommended for improving survival time and quality of life in canine prostatic adenocarcinoma that does not infiltrate the bladder. Early detection is key for a survival advantage with surgical treatment.
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Adenocarcinoma , Enfermedades de los Perros , Neoplasias de la Próstata , Incontinencia Urinaria , Adenocarcinoma/cirugía , Adenocarcinoma/veterinaria , Animales , Enfermedades de los Perros/cirugía , Perros , Masculino , Complicaciones Posoperatorias/veterinaria , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/veterinaria , Calidad de Vida , Estudios Retrospectivos , Resultado del Tratamiento , Incontinencia Urinaria/veterinariaRESUMEN
A limited number of species, including men and dogs, spontaneously develop prostate cancer (PC). The histological and molecular relevance of canine PC as a model for the disease in men remains controversial. To address this challenge, this study aimed to assess the histomorphology and expression of basal cell, urothelial and neuroendocrine markers [p63, high molecular weight cytokeratin (HMWCK), Uroplakin 3 (UPIII), neuron-specific enolase (NSE)] in canine PC (n = 41). Based on histomorphology, 10/41 (24%), 21/41 (51%) and 9/41 (22%) were classified as adenocarcinoma (AC), urothelial carcinoma (UC), and mixed carcinoma, respectively. Tumour inflammation was common, frequently severe [20/41 (49%)], and associated with neutering (p < .02) and urothelial differentiation (p < .02). Most (36/40, 90%) cancers contained only rare cells with basal cell marker expression or were negative. The expression of UPIII was absent or weak in the majority (33/38, 87%) of tumours, with moderate to strong staining in the remaining cases. NSE expression in PC was rare and limited to 2/14 (14%) cases. Tumour extension into benign ducts and glands was a common finding with presence in 17/39 (44%) of carcinomas with and without urothelial differentiation. In conclusion, we confirm that canine PC is characterized by absent or weak expression of basal cell and urothelial markers. Although rare, NSE expression, potentially indicating neuroendocrine differentiation, is reported for the first time in canine PCa. Intraductal carcinoma of the prostate with concurrent invasive PCa (IDCP-inv) is a frequent, not previously described, finding in dogs with PC.
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Carcinoma Intraductal no Infiltrante , Carcinoma de Células Transicionales , Enfermedades de los Perros , Neoplasias de la Próstata , Neoplasias de la Vejiga Urinaria , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/veterinaria , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/veterinaria , Enfermedades de los Perros/patología , Perros , Inmunohistoquímica , Masculino , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/veterinaria , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/veterinariaRESUMEN
Claudin (CLDN) proteins are commonly expressed in cancers and targeted in novel therapeutic approaches. The C-terminal of Clostridium perfringens enterotoxin (C-CPE) efficiently binds several claudins. In this study, recombinant C-CPE conjugated to gold nanoparticles (AuNPs) has been used for prostate adenocarcinoma (PAC) and transitional cell carcinoma (TCC) cell killing in vitro using gold-nanoparticle-mediated laser perforation (GNOME-LP). A PAC and TCC cell lines, as well as red fluorescence variants, allowing deep tissue imaging, were used. CLDN-3, -4, and -7 expression was confirmed by qPCR and immunofluorescences. The binding of C-CPE-AuNPs complexes on the cell surface was examined by scanning electron microscopy (SEM). Further, transcriptome analysis was carried out to evaluate the effect of C-CPE binder on the biological response of treated cells. Directed C-CPE-AuNP binding verified the capability to target CLDN receptors. Transcriptome analysis showed that C-CPE binding may activate immune and inflammatory responses but does not directly affect cell survival. Cancer cells ablation was demonstrated using a combination of GNOME-LP and C-CPE-AuNPs treatment reducing tumor cell viability to less than 10% depending on cell line. The fluorescent cell lines and the verified proof of concept in vitro provide the basis for perspective xenograft studies in an animal model.
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Adenocarcinoma , Carcinoma de Células Transicionales , Enfermedades de los Perros , Enterotoxinas , Oro , Terapia por Láser , Nanopartículas del Metal , Neoplasias de la Próstata , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Adenocarcinoma/veterinaria , Animales , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/terapia , Carcinoma de Células Transicionales/veterinaria , Línea Celular Tumoral , Clostridium perfringens/química , Enfermedades de los Perros/metabolismo , Enfermedades de los Perros/terapia , Perros , Enterotoxinas/química , Enterotoxinas/farmacología , Oro/química , Oro/farmacología , Masculino , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/veterinariaRESUMEN
BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) and its receptor, VEGF receptor-2 (VEGFR-2), represent a complex family of angiogenic molecules consisting of different ligands and receptors. Due to the importance of VEGF-A/VEGFR-2 signaling in tumor proliferation and angiogenesis, this study aimed to evaluate the protein and gene expression levels of VEGF-A and VEGFR-2 in canine prostate cancer (PC). METHODS: We analyzed VEGF-A and VEGFR-2 expression in 87 PC samples by immunohistochemistry and quantitative-polymerase chain reaction. PC samples were graded according to the Gleason score and the immunohistochemical staining for VEGF-A and VEGFR-2 was quantified using a selected threshold from the ImageJ Software. Microvascular density was assessed by cluster of differentiation 31 staining and counting the number of positive vessels. Additionally, the homology of VEGF-A and VEGFR-2 between humans and dogs was assessed, followed by the construction of a protein structure homology model to compare the tertiary structures of these proteins in both species. RESULTS: Negative to weakly positive expression levels of VEGF-A and VEGFR-2 were observed in the epithelial cells of the normal prostate (NP) and prostatic hyperplasia samples. In contrast, the canine proliferative atrophy and PC samples exhibited higher VEGF-A (p < .0001) and VEGFR-2 (p < .0001) compared to NP. Moreover, positive correlations between the expression levels of VEGF-A and VEGFR-2 (Spearman's coefficient (r) = .68, p = .013) and the expression levels of VEGF-A and VEGFR-2 proteins (r = .8, p < .0001) were also observed in the NP samples. Additionally, the patients with PC exhibiting higher VEGFR-2 expression levels experienced a shorter survival period (p = .0372). Furthermore, we found an association between the microvascular density and overall survival. Dogs with a higher number of vessels showed a shorter survival time. We further demonstrated that the VEGF-A and VEGFR-2 exhibited high homology between humans and dogs, and identified their protein structures in both species. CONCLUSIONS: In conclusion, VEGFR-2 appears to be an independent prognostic factor in animals with PC. VEGF-A and VEGFR-2 are highly conserved between humans and dogs, which can be investigated further in future cross-species studies to explore their therapeutic applications.
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Enfermedades de los Perros/metabolismo , Neovascularización Patológica/veterinaria , Próstata/metabolismo , Neoplasias de la Próstata/veterinaria , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Enfermedades de los Perros/patología , Perros , Masculino , Clasificación del Tumor , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Pronóstico , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patologíaRESUMEN
Skeletal metastasis is a common finding in dogs with prostatic carcinoma and most frequently involves the lumbar vertebrae and pelvis. In the present report, we describe the case of a prostatic carcinoma in a 6-year-old Labrador retriever, who developed apparent oral sensitivity and pain within a week of initial diagnosis. Computed tomography of the skull revealed a mixed osteoproductive and osteolytic mass of the condylar process of the left mandible, and cytologic evaluation of the mass was consistent with metastatic prostatic carcinoma. To our knowledge, this is the first published report of mandibular metastasis of a prostatic carcinoma in a dog.
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Carcinoma , Enfermedades de los Perros , Neoplasias de la Próstata , Animales , Carcinoma/veterinaria , Enfermedades de los Perros/diagnóstico , Perros , Masculino , Mandíbula/diagnóstico por imagen , Mandíbula/patología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/veterinaria , Tomografía Computarizada por Rayos X/veterinariaRESUMEN
OBJECTIVE: To describe the surgical treatment and outcome of a large cohort of dogs with sterile prostatic cysts (PCs). STUDY DESIGN: Retrospective study. ANIMALS: Forty-four client-owned dogs. METHODS: Dogs with sterile PCs with at least 6 months of follow-up were included. Clinical variables, type of surgery, complications, recurrences, and outcomes (telephonic interviews or rechecks) were recorded. RESULTS: Extra- and intraparenchymal cysts were diagnosed in 29 and 11 dogs, respectively. Four dogs had both types. Extraparenchymal cysts were treated by partial resection and omentalization (n = 22) and complete resection (n = 7). Drainage and intracapsular omentalization were performed in all dogs with intraparenchymal cysts. The four dogs with both types of cyst were treated by omentalization. Resolution was documented in 39/44 dogs (88.6%). Intraoperative complications occurred in one dog (urethral tear). Major complications resulting in death occurred in three dogs (oliguric kidney injury, cardiac arrhythmia, and persisting urinary tract obstruction). Minor complications (n = 10) consisted of temporary urinary incontinence (n = 2), permanent urinary incontinence (n = 5), urinary retention (n = 2), and dysuria (n = 1). Recurrence occurred in two dogs with extraparenchymal cysts. Median long-term follow-up was 528 days (range, 250-730 days). Thirty-nine dogs had no signs associated with prostatic disease at long-term follow-up. CONCLUSION: Partial or complete resection and/or omentalization of sterile PCs led to resolution of clinical signs in most dogs, although postoperative urinary incontinence was frequent. IMPACT: This study is the largest case series relative to canine sterile PCs treated surgically and provides evidence on the prognosis and rate of complications.
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Quistes/veterinaria , Enfermedades de los Perros/cirugía , Enfermedades de la Próstata/veterinaria , Animales , Quistes/cirugía , Perros , Masculino , Recurrencia Local de Neoplasia/veterinaria , Complicaciones Posoperatorias/veterinaria , Pronóstico , Enfermedades de la Próstata/cirugía , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/veterinaria , Estudios Retrospectivos , Resultado del Tratamiento , Enfermedades Uretrales/veterinaria , Incontinencia Urinaria/veterinariaRESUMEN
Murine models of tumor development often require invasive procedures for tumor implantation, potentially causing pain or distress. However, analgesics are often withheld during implantation because of concerns that they may adversely affect tumor development. Previous studies examining the effects of analgesics on the development and metastasis of various tumor lines show that the effect of analgesics depends on the tumor line and analgesic used. A blanket statement that analgesics affect the general growth of tumors is not adequate scientific justification for withholding pain relief, and pilot studies or references are recommended for each specific tumor cell line and treatment combination. In this study, we evaluated the effects of 2 commonly used analgesics on tumor growth in 2 models of prostate cancer (PCa) bone metastasis. We hypothesized that a one-time injection of analgesics at the time of intratibial injection of tumor cells would not significantly impact tumor growth. Either C57BL/6 or SCID mice were injected subcutaneously with an analgesic (carprofen [5 mg/kg], or buprenorphine [0.1 mg/kg]) or vehicle (0.1 mL of saline) at the time of intratibial injection with a PCa cell line (RM1 or PC3, n = 10 to 11 per group). Tumor growth (measured by determination of tumor burden and the extent of bone involvement) and welfare (measured by nociception, locomotion, and weight) were monitored for 2 to 4 wk. Neither carprofen or buprenorphine administration consistently affected tumor growth or indices of animal welfare as compared with the saline control for either cell line. This study adds to the growing body of literature demonstrating that analgesia can be compatible with scientific objectives, and that a decision to withhold analgesics must be scientifically justified and evaluated on a model-specific basis.
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Neoplasias Óseas , Neoplasias de la Próstata , Analgésicos/uso terapéutico , Animales , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/veterinaria , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/veterinariaRESUMEN
Prostatic leiomyosarcoma is an uncommon tumor encountered in male dogs, with only 2 cases reported in the veterinary literature with no follow-up described. A 12-year-old male intact German Wirehaired Pointer presented for evaluation of straining to defecate and urinate. Whole body computed tomography (CT) examination identified a spherical multicavitary expansile mass arising from the prostate gland and severely obliterating the pelvic canal. Partial subcapsular prostatectomy was performed, and histological and immunohistochemical results were consistent with prostatic leiomyosarcoma. Metronomic cyclophosphamide and nonsteroidal anti-inflammatory drugs were administered as adjuvant chemotherapy. Follow-up CT 10 months later indicated no signs of recurrence or metastasis. To the best of our knowledge, this patient represents the first report of successful multidisciplinary treatment consisting of partial subcapsular prostatectomy and adjuvant chemotherapy for prostatic leiomyosarcoma in a dog. After 15 months of follow-up, the patient remained recurrence-free without metastasis.