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1.
Tumour Biol ; 42(1): 1010428319901052, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31959092

RESUMEN

Feline invasive mammary carcinomas are characterized by their high clinical aggressiveness, rare expression of hormone receptors, and pathological resemblance to human breast cancer, especially triple-negative breast cancer (negative to estrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2). Recent gene expression studies of triple-negative breast cancers have highlighted their heterogeneity and the importance of immune responses in their biology and prognostic assessment. Indeed, regulatory T cells may play a crucial role in producing an immune-suppressed microenvironment, notably in triple-negative breast cancers. Feline invasive mammary carcinomas arise spontaneously in immune-competent animals, in which we hypothesized that the immune tumor microenvironment also plays a role. The aims of this study were to determine the quantity and prognostic value of forkhead box protein P3-positive peritumoral and intratumoral regulatory T cells in feline invasive mammary carcinomas, and to identify an immune-suppressed subgroup of triple-negative basal-like feline invasive mammary carcinomas. One hundred and eighty female cats with feline invasive mammary carcinomas, treated by surgery only, with 2-year follow-up post-mastectomy, were included in this study. Forkhead box protein P3, estrogen receptor, progesterone receptor, Ki-67, epidermal growth factor receptor type 2, and cytokeratin 14 expression were assessed by automated immunohistochemistry. Peritumoral regulatory T cells were over 300 times more abundant than intratumoral regulatory T cells in feline invasive mammary carcinomas. Peritumoral and intratumoral regulatory T cells were associated with shorter disease-free interval and overall survival in both triple-negative (ER-, PR-, HER2-, N = 123 out of 180) and luminal (ER+ and/or PR+, N = 57) feline invasive mammary carcinomas. In feline triple-negative basal-like (CK14+) mammary carcinomas, a regulatory T-cell-enriched subgroup was associated with significantly poorer disease-free interval, overall survival, and cancer-specific survival than regulatory T-cell-poor triple-negative basal-like feline invasive mammary carcinomas. High regulatory T-cell numbers had strong and negative prognostic value in feline invasive mammary carcinomas, especially in the triple-negative basal-like subgroup, which might contain a "basal-like immune-suppressed" subtype, as described in triple-negative breast cancer. Cats with feline invasive mammary carcinomas may thus be interesting spontaneous animal models to investigate new strategies of cancer immunotherapy in an immune-suppressed tumor microenvironment.


Asunto(s)
Neoplasias Mamarias Animales/patología , Neoplasias de la Mama Triple Negativas/patología , Animales , Gatos , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunohistoquímica/métodos , Inmunosupresión/métodos , Neoplasias Mamarias Animales/metabolismo , Pronóstico , Receptores Estrogénicos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Microambiente Tumoral/fisiología
2.
Anticancer Res ; 39(10): 5483-5494, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31570442

RESUMEN

BACKGROUND/AIM: Canine mammary gland tumors (CMGTs) are the most common tumors in female dogs. Rivoceranib (also known as apatinib) is a novel anti-angiogenic tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor-2 (VEGFR2). The aim of this study was to disclose the antitumor effects of rivoceranib on CMGT cell lines. MATERIALS AND METHODS: The direct effects of rivoceranib on CMGT cells in vitro were analyzed by cell proliferation and migration assays. Cell-cycle distribution and apoptotic ratio were analyzed by flow cytometry. Expression levels of phosphorylated VEGFR2 were evaluated by western blot analysis. RESULTS: Rivoceranib treatment significantly reduced the proliferation and migration of CMGT cells in a dose-dependent manner. Flow cytometry results revealed significant increases in G0/G1 phase arrest and apoptosis proportional to the drug concentration used. Rivoceranib reduced the level of phosphorylated VEGFR2. CONCLUSION: We confirm that rivoceranib exerts antitumor effects on CMGT cells by inhibiting biological functions.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Mamarias Animales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Perros , Femenino , Fase G1/efectos de los fármacos , Neoplasias Mamarias Animales/metabolismo , Fosforilación/efectos de los fármacos , Fase de Descanso del Ciclo Celular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo
3.
Int J Mol Sci ; 20(18)2019 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-31505876

RESUMEN

: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment contribute to all stages of tumorigenesis and are usually considered to be tumor-promoting cells. CAFs show a remarkable degree of heterogeneity, which is attributed to developmental origin or to local environmental niches, resulting in distinct CAF subsets within individual tumors. While CAF heterogeneity is frequently investigated in late-stage tumors, data on longitudinal CAF development in tumors are lacking. To this end, we used the transgenic polyoma middle T oncogene-induced mouse mammary carcinoma model and performed whole transcriptome analysis in FACS-sorted fibroblasts from early- and late-stage tumors. We observed a shift in fibroblast populations over time towards a subset previously shown to negatively correlate with patient survival, which was confirmed by multispectral immunofluorescence analysis. Moreover, we identified a transcriptomic signature distinguishing CAFs from early- and late-stage tumors. Importantly, the signature of early-stage CAFs correlated well with tumor stage and survival in human mammary carcinoma patients. A random forest analysis suggested predictive value of the complete set of differentially expressed genes between early- and late-stage CAFs on bulk tumor patient samples, supporting the clinical relevance of our findings. In conclusion, our data show transcriptome alterations in CAFs during tumorigenesis in the mammary gland, which suggest that CAFs are educated by the tumor over time to promote tumor development. Moreover, we show that murine CAF gene signatures can harbor predictive value for human cancer.


Asunto(s)
Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica , Glándulas Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/metabolismo , Transcripción Genética , Animales , Femenino , Fibroblastos/patología , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Ratones , Ratones Transgénicos
4.
BMC Vet Res ; 15(1): 325, 2019 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-31506083

RESUMEN

BACKGROUND: Estrogens are essential for the development and proper function of several hormone-dependent organs. There are, however, several lines of evidence associating estrogens with mammary carcinogenesis. A marked individual genetic variability concerning estrogens biosynthesis, metabolism and mechanism of action was recognized and associated with human breast cancer susceptibility, clinical features and progression. Although some genetic variations in canine ESR1 gene were reported, their influence in clinicopathological features and progression of canine mammary tumors has not been fully evaluated. This study aims to assess the influence of SNPs in ESR1 gene (rs397512133, rs397510462, rs851327560, rs397510612, rs852887655, rs852684753 and rs852398698) in canine mammary tumors characteristics and progression. A group of 155 non-neutered bitches with mammary tumors was included in the study. Follow-up information was assessed 24 months after surgery. RESULTS: Genetic profiles associated with a later onset of mammary tumors and less aggressive clinicopathological features, namely smaller tumor size (≤ 3 cm) with extensive tubular differentiation and low canine-adapted prognostic index (vet-NPI), were identified in this study. CONCLUSIONS: Our data suggest that the ESR1 genetic profile may help on the decision regarding the selection of individual tailored preventive measures against canine mammary tumors development, such as early neutering.


Asunto(s)
Enfermedades de los Perros/genética , Neoplasias Mamarias Animales/genética , Receptores Estrogénicos/genética , Animales , Perros , Femenino , Genotipo , Neoplasias Mamarias Animales/metabolismo , Polimorfismo de Nucleótido Simple
5.
Nat Commun ; 10(1): 4131, 2019 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-31511510

RESUMEN

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA (5,6-dimethylxanthenone-4-acetic acid) can induce strong production of IFNα/ß and rejection of transplanted primary tumors. In the present study, we address whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFNα/ß production. Mechanistically, we identify TGFß, which is abundant in spontaneous tumors, as a key molecule limiting this IFN-induced tumor regression by DMXAA. Finally, blocking TGFß restores the production of IFNα by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGFß.


Asunto(s)
Interferón-alfa/metabolismo , Interferón beta/metabolismo , Neoplasias Mamarias Animales/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Femenino , Factor 3 Regulador del Interferón/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Virus del Tumor Mamario del Ratón/metabolismo , Ratones , Fosforilación/efectos de los fármacos , Xantonas/farmacología
6.
J Comp Pathol ; 170: 26-33, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31375156

RESUMEN

The aims of the present study were: (1) to investigate the presence of oxytocin receptors in benign and malignant canine mammary tumours (CMTs) and to evaluate the possible association between oxytocin receptor (OTR) expression and the expression of oestrogen receptor (OR) α and ORß, and (2) to examine associations between receptor expression and tumour size, clinical stage, histological subtype, tumour grading and lymph node status. Forty-three canine mammary tumour samples (19 benign, 24 malignant) were examined by immunohistochemistry to detect OTR, ORα and ORß expression. Results were expressed as total score for each receptor, calculated as the sum of the percentage of positive cells and the intensity of immunolabelling. In all of the evaluated mammary tumour samples, OTRs were identified and their expression tended to be higher in benign tumours than malignant tumours. Among the malignant tumours, the expression of OTR was significantly higher in grade I and II lesions than in grade III lesions. ORα-positive tumours had a tendency towards a higher OTR total score than ORα-negative tumours. These results report for the first time that CMTs express OTRs and their expression is associated with the presence of ORα. An interaction between oxytocin and the OTR might play a role in the development and progression of this type of neoplasia.


Asunto(s)
Enfermedades de los Perros/metabolismo , Enfermedades de los Perros/patología , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Receptores de Oxitocina/biosíntesis , Animales , Biomarcadores de Tumor/análisis , Perros , Receptor alfa de Estrógeno/biosíntesis , Femenino
7.
Breast Cancer Res ; 21(1): 85, 2019 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-31366361

RESUMEN

BACKGROUND: Claudin-low breast cancer is a molecular subtype associated with poor prognosis and without targeted treatment options. The claudin-low subtype is defined by certain biological characteristics, some of which may be clinically actionable, such as high immunogenicity. In mice, the medroxyprogesterone acetate (MPA) and 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumor model yields a heterogeneous set of tumors, a subset of which display claudin-low features. Neither the genomic characteristics of MPA/DMBA-induced claudin-low tumors nor those of human claudin-low breast tumors have been thoroughly explored. METHODS: The transcriptomic characteristics and subtypes of MPA/DMBA-induced mouse mammary tumors were determined using gene expression microarrays. Somatic mutations and copy number aberrations in MPA/DMBA-induced tumors were identified from whole exome sequencing data. A publicly available dataset was queried to explore the genomic characteristics of human claudin-low breast cancer and to validate findings in the murine tumors. RESULTS: Half of MPA/DMBA-induced tumors showed a claudin-low-like subtype. All tumors carried mutations in known driver genes. While the specific genes carrying mutations varied between tumors, there was a consistent mutational signature with an overweight of T>A transversions in TG dinucleotides. Most tumors carried copy number aberrations with a potential oncogenic driver effect. Overall, several genomic events were observed recurrently; however, none accurately delineated claudin-low-like tumors. Human claudin-low breast cancers carried a distinct set of genomic characteristics, in particular a relatively low burden of mutations and copy number aberrations. The gene expression characteristics of claudin-low-like MPA/DMBA-induced tumors accurately reflected those of human claudin-low tumors, including epithelial-mesenchymal transition phenotype, high level of immune activation, and low degree of differentiation. There was an elevated expression of the immunosuppressive genes PTGS2 (encoding COX-2) and CD274 (encoding PD-L1) in human and murine claudin-low tumors. CONCLUSIONS: Our findings show that the claudin-low breast cancer subtype is not demarcated by specific genomic aberrations, but carries potentially targetable characteristics warranting further research.


Asunto(s)
Claudinas/metabolismo , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/metabolismo , Oncogenes , Transcriptoma , Animales , Biopsia , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Mamarias Animales/patología , Ratones , Ratones Transgénicos , Mutación
8.
J Vet Med Sci ; 81(9): 1238-1248, 2019 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-31308293

RESUMEN

Cancer consists of heterogeneous cells that contain a small population of cells that possess stem cell properties; these cells, referred to as cancer stem cells (CSCs) or tumor-initiating cells, are involved in tumor progression and metastasis. Using a sphere-forming assay, canine mammary CSCs were found to be similar to human breast CSCs. Metabolic reprogramming has been recognized as a hallmark of various cancers. However, the significance of cellular metabolism in CSCs remains unclear. The aim of this study was to define the metabolic characteristics of CSCs derived from canine mammary tumors and gain an understanding of the maintenance of stemness. We identified metabolite profiles of canine mammary adenocarcinoma cell lines using gas chromatography-mass spectrometry. Metabolites were extracted from both adherent and sphere-forming cells derived from three cell lines. Sphere-forming cells were separated from adherent cells using an orthogonal, partial least-squares discriminant analysis. Sphere-forming cells were found to contain high levels of the amino acids alanine, glycine and proline compared with adherent cells. They also had high levels of palmitoleate, palmitate and dihomo-gamma-linolenic acid compared with adherent cells. In a sphere-forming assay, palmitate increased the number of spheres for all cell lines. These results indicate that the sphere-forming cells derived from canine mammary adenocarcinoma cell lines have specific metabolic profiles that may be useful for the development of CSC-specific therapies targeting metabolic pathways and potential stemness biomarkers; these results also clarify the maintenance of stemness in canine mammary CSCs.


Asunto(s)
Adenocarcinoma/veterinaria , Neoplasias Mamarias Animales/metabolismo , Células Madre Neoplásicas/metabolismo , Esferoides Celulares/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Aminoácidos/metabolismo , Animales , Línea Celular Tumoral , Perros , Ácidos Grasos/metabolismo , Femenino , Cromatografía de Gases y Espectrometría de Masas , Neoplasias Mamarias Animales/patología , Células Madre Neoplásicas/efectos de los fármacos , Palmitatos/farmacología
9.
Oncol Rep ; 42(3): 1149-1160, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31322257

RESUMEN

While erythropoietin (EPO) regulates erythropoiesis, the erythropoietin receptor (EPOR) has been identified in many non­hematopoietic cells, including cancer. Our previous study demonstrated that overexpression of EPOR altered the cell growth and the sensitivity of RAMA 37 breast cancer cells to tamoxifen. Indeed, results of the present study uncovered the role of EPOR in the resistance of EPOR­overexpressing RAMA 37­28 cells to paclitaxel chemotherapy. In this regard, EPOR silencing in the presence of paclitaxel therapy decreased RAMA 37­28 cell proliferation, confirming its role in the sensitivity or resistance of RAMA 37­28 cells to paclitaxel. Notably, compared to parental RAMA 37 cells, RAMA 37­28 cells also showed a lower rate of apoptosis induced by paclitaxel, as monitored by caspase 3/7 activation and Annexin V by IncuCyte ZOOM system. Moreover, enhanced activation of signaling pathways mediated by pERK1/2 in RAMA 37­28 cells as detected by western blot analysis was demonstrated to be essential for paclitaxel resistance.


Asunto(s)
Adenocarcinoma/patología , Antineoplásicos Fitogénicos/farmacología , Resistencia a Antineoplásicos , Eritropoyetina/metabolismo , Neoplasias Mamarias Animales/patología , Paclitaxel/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animales , Apoptosis , Proliferación Celular , Eritropoyetina/genética , Femenino , Humanos , Neoplasias Mamarias Animales/tratamiento farmacológico , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/metabolismo , Ratas , Células Tumorales Cultivadas
10.
Nat Commun ; 10(1): 2450, 2019 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-31164648

RESUMEN

Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8+ T cells and immune-stimulatory myeloid subsets. Tumor-associated macrophages (TAMs) isolated from Camkk2-/- mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2-/- macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT. Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8+ T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment. These data, credential CaMKK2 as a myeloid-selective checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.


Asunto(s)
Neoplasias de la Mama/inmunología , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/inmunología , Carcinoma/inmunología , Neoplasias Mamarias Animales/inmunología , Células Mieloides/inmunología , Escape del Tumor/inmunología , Microambiente Tumoral/inmunología , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Linfocitos T CD8-positivos/inmunología , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/antagonistas & inhibidores , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Proliferación Celular , Quimiocinas/inmunología , Femenino , Humanos , Inmunohistoquímica , Técnicas In Vitro , Macrófagos/inmunología , Macrófagos/metabolismo , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Células Mieloides/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/metabolismo , Escape del Tumor/genética
11.
Vet Comp Oncol ; 17(3): 427-438, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31050171

RESUMEN

Neutrophil gelatinase-associated lipocalin (NGAL) is a new biomarker for renal injury. It is also involved in tumorigenesis of different human cancer types. The oncogenic role of NGAL is related to its molecular forms, and heterodimer formation with matrix metalloproteinase 9 (MMP9) promotes human breast cancer (HBC) invasion and metastasis. To date, the levels of NGAL and NGAL/MMP9 complex have not yet been explored in canine mammary tumours (CMTs). Hence, this study aimed to investigate whether NGAL and its molecular forms could be the biomarker for CMT diagnosis. To this end, expression profile of NGAL and MMP9 in mammary epithelial cells as well as in urine samples were detected. By immunohistochemistry staining, NGAL was expressed at variable levels. Unlike HBC, a significant reduction in NGAL expression was demonstrated in benign and malignant CMTs as compared with normal controls. Additionally, NGAL expression was significantly reduced in dogs with metastatic CMTs. By contrast, the mean score of MMP9 expression in ascending order was normal groups, benign, and malignant CMTs. Interestingly, analysis of the molecular form revealed the NGAL/MMP9 complex presents in most mammary tissues and urine of dogs with benign or malignant CMTs, whereas the complex was absent in samples from dogs without CMTs. In conclusion, NGAL and MMP9 are ubiquitously expressed in canine mammary epithelial cells in normal and cancerous status. However, the NGAL/MMP9 complex exclusively presents in mammary tissues and urine of dogs with tumours.


Asunto(s)
Enfermedades de los Perros/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Lipocalina 2/metabolismo , Neoplasias Mamarias Animales/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Animales , Perros , Femenino , Lipocalina 2/genética , Neoplasias Mamarias Animales/genética , Metaloproteinasa 9 de la Matriz/genética
12.
Vet Comp Oncol ; 17(3): 413-426, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31069942

RESUMEN

Human epidermal growth factor 2 (HER2) overexpression leads to aggressive mammary tumour growth. Although the prognosis of HER2+ tumours in humans is greatly improved using biologicals, therapy resistance, which may be caused by increased phosphatidyl-3-kinase (PI3K), rous sarcoma proto-oncogene (cSRC) or wingless-type MMTV integration site family (Wnt) activity, is a major concern. A recent analysis of 12 canine mammary cell lines showed an association between HER2/3 overexpression and phosphatase and tensin homologue (PTEN) deletion with elevated Wnt-signalling. Wnt-activity appeared to be insensitive to phosphatidyl-3-kinase (PI3K) inhibitors but sensitive to Src-I1. We hypothesized that Wnt activation, was caused by HER2/3-activated cSRC activation. The role of HER2/3 on Wnt signalling was investigated by silencing HER2/3 expression using specific small interfering RNA (siRNAs). Next, the effect of an epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor on Wnt activity and migration was investigated and compared to other tyrosine kinase inhibitors (TKIs) of related signalling pathways. Finally, two TKIs, a cSRC and a PI3K inhibitor, were investigated in a zebrafish xenograft model. Silencing of HER1-3 did not inhibit the intrinsic high Wnt activity, whereas the HER kinase inhibitor afatinib showed enhanced Wnt activity. The strongest inhibition of Wnt activity and cell viability and migration was shown by cSRC inhibitors, which also showed strong inhibition of cell viability and metastasis in a zebrafish xenograft model. HER2/3 overexpression or HER2/3-induced cSRC activation is not the cause of enhanced Wnt activity. However, inhibition of cSRC resulted in a strong inhibition of Wnt activity and cell migration and metastasis. Further studies are needed to unravel the mechanism of cSRC activation and cSRC inhibition to restore sensitivity to HER-inhibitors in HER2/3-positive breast cancer.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Dasatinib/farmacología , Genes erbB-2/fisiología , Neoplasias Mamarias Animales/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Animales , Proliferación Celular , Supervivencia Celular , Enfermedades de los Perros/metabolismo , Perros , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias Experimentales , Proteínas Proto-Oncogénicas pp60(c-src)/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Proteínas Wnt , Pez Cebra
13.
Discov Med ; 27(148): 163-166, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-31095925

RESUMEN

Breast cancer is the most common form of cancer in women. The cause of sporadic cases is usually difficult to ascertain. Viruses that might be related to breast cancer are human papillomaviruses and herpes viruses. Mouse mammary tumor virus (MMTV) has also been a suspect. MMTV is a milk-transmitted beta retrovirus, a form of single-stranded positive-sense RNA virus that inserts a copy of its genome into the DNA of a host cell, thus altering the cell's genome. MMTV DNA sequences have been found in 36% of human breast tumor samples and 24% of non-cancerous breast tissue. The sequences were 98% similar to the MMTV envelope (env) gene. But a search for MMTV sequences within the human genome found no env sequences, although there were sequences from the MMTV GAGdUTPase and POL genes. Therefore, env sequences from breast tumors and normal breast tissue identified in other studies may have come from an MMTV infection. Humans apparently acquire MMTV infection from one species of mice, Mus domesticus. MMTV transmission from mice to humans may explain the relationship of breast cancer to high socioeconomic status. Many infectious diseases are associated with low income and poverty. The association is usually detrimental, but not always. During the 20th century, improved sanitation delayed exposure to the poliovirus and onset of infection in middle and upper class children. These children contracted paralytic polio, while children from low-income families living in poor neighborhoods and substandard housing, infected in infancy, were spared. Humoral immunity passively transferred from the mother protected them from paralytic polio, and they remained immune for life. A similar relationship may exist with MMTV. High income and affluence are linked to increasedbreastcancer incidence. Girls of high socioeconomic status living in affluent, clean homes would have delayed exposure to Mus domesticus and MMTV. When infection finally occurred they would be vulnerable to MMTV-induced breast cancer in later life. Impoverished girls living in substandard, mouse-infested housing would be exposed to mice and MMTV in early life. Humoral MMTV immunity passively transferred from the mother would protect them and render them immune to MMTV-induced breast cancer in later life.


Asunto(s)
Neoplasias de la Mama , Neoplasias Mamarias Animales , Virus Oncogénicos/metabolismo , Infecciones Tumorales por Virus , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/virología , Bovinos , Femenino , Genoma Humano , Humanos , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Neoplasias Mamarias Animales/virología , Ratones , Infecciones Tumorales por Virus/metabolismo , Infecciones Tumorales por Virus/patología , Infecciones Tumorales por Virus/virología
14.
BMC Vet Res ; 15(1): 155, 2019 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-31101115

RESUMEN

BACKGROUND: Sphingosine kinase 1 (SPHK1) is an enzyme that converts pro-apoptotic ceramide and sphingosine into anti-apoptotic sphingosine-1-phosphate. There is growing evidence that SPHK1 activation promotes oncogenic transformation, tumor growth, chemotherapy resistance, and metastatic spread. High SPHK1 expression has been associated with a poor prognosis in several human cancers. RESULTS: In the present study, the expression level of SPHK1 was examined in feline mammary tumor (FMT) specimens, and the IHC expression level of SPHK1 was associated with the histological grade of FMTs. IHC analysis of 88 FMT cases revealed that the expression level of SPHK1 was upregulated in 53 tumor tissues (60.2%) compared to adjacent mammary tissues. SPHK1 expression in FMTs was significantly associated with histological grade, presence of lymphovascular invasion, and estrogen receptor negativity. Treatment of primary FMT cells with SPHK1 inhibitors reduced cell viability, indicating that SPHK1 acts to promote FMT cell survival. These results indicate that SPHK1 may play an important role in FMTs and may be a therapeutic target in cats with FMT. CONCLUSIONS: SPHK1 over-expression in breast cancer tissues is associated with a poor prognosis in humans. SPHK1 over-expression in more aggressive FMTs provides support for a potential role of SPHK1 inhibitors for the treatment of FMTs. Targeting SPHK1 has potent cytotoxic effects in primary FMT cells. These findings suggest that further examination of the role SPHK1 plays in FMTs will pave the way for the investigation of SPHK1 inhibitors in future clinical applications.


Asunto(s)
Enfermedades de los Gatos/patología , Neoplasias Mamarias Animales/enzimología , Neoplasias Mamarias Animales/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Animales , Vasos Sanguíneos/patología , Enfermedades de los Gatos/enzimología , Gatos , Femenino , Regulación Neoplásica de la Expresión Génica , Sistema Linfático/patología , Glándulas Mamarias Animales/enzimología , Glándulas Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/metabolismo , Invasividad Neoplásica , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Receptores Estrogénicos/genética , Receptores Estrogénicos/metabolismo
15.
Pol J Vet Sci ; 22(1): 133-141, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30997777

RESUMEN

Characterisation of copy number variation (CNV) and loss of heterozygosity (LOH) has pro- vided evidence for the relationship of this type of genetic variation with the occurrence of a broad spectrum of diseases, including cancer lesions. The role of CNVs and germinal or somatic LOHs in canine mammary tumours is still unknown. Therefore, the aim of this study was to identify CNVs and LOHs in canine mammary tumours. Forty-eight samples obtained from normal (n=24) and tumour (n=24) tissues of dogs were analysed. In the study, we used CanineHD BeadChip assay (Illumina) and OncoSNP software to identify copy number alternations in genomes of dif- ferent dog breeds and in different mammary cancer types occurring in this species. The analyses revealed that, in the case of CNV, the amplification-type variants were longer and more frequent than deletions. Based on the analysis of the frequency of different types of aberrations in the in- dividual parts of the genome, regions that are particularly susceptible to structural aberrations were indicated. The fraction of genes identified within these regions was associated with major processes of neoplastic transformation. Association analysis of such traits as tumour grading as well as the size and age of dogs demonstrated that structural aberrations were more frequent in dogs diagnosed with tumour malignancy grade II and III, in dogs with a larger body size, and in large dogs aged 7-8. The promising results of these pioneering investigations prompt continuation thereof to analyse other types of cancer.


Asunto(s)
Enfermedades de los Perros/genética , Variación Estructural del Genoma , Neoplasias Mamarias Animales/metabolismo , Polimorfismo de Nucleótido Simple , Animales , Perros , Femenino , Regulación Neoplásica de la Expresión Génica , Pérdida de Heterocigocidad , Neoplasias Mamarias Animales/genética
16.
Vet Comp Oncol ; 17(3): 394-406, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31025532

RESUMEN

Acute phase proteins (APP) and biomarkers of oxidative status change in human and canine mammary tumours, however, they have not been studied in feline mammary tumours. The aims of this study were to investigate the APP and antioxidant responses in feline malignant mammary tumours, to evaluate their relation with tumour features, and to assess their prognostic value. Serum amyloid A (SAA), haptoglobin (Hp), albumin, butyrylcholinesterase (BChE), insulin-like growth factor1 (IGF1), paraoxonase1 (PON1), total serum thiols (Thiol), glutathione peroxidase (GPox) and total antioxidant capacity determined by different assays, including trolox equivalent antioxidant capacity assessed by two different methodologies (TEAC1/2), ferric reducing ability of plasma (FRAP), and cupric reducing antioxidant capacity (CUPRAC), were determined in serum of 50 queens with spontaneous mammary carcinomas and of 12 healthy female cats. At diagnosis, diseased queens presented significantly higher SAA and Hp, and lower albumin, BChE, GPox, TEAC1, TEAC2 and CUPRAC than controls. Different tumour features influenced concentrations of APP and antioxidants. Increases in serum Hp, and decreases in albumin, Thiol and FRAP were significantly associated with neoplastic vascular emboli, metastasis in regional lymph nodes and/or in distant organs. Distant metastasis development during the course of the disease was associated with increases in SAA and TEAC1. At diagnosis, decreased albumin was associated with a longer survival, and BChE <1.15 µmoL/mL.minute was associated with a shorter survival time on multivariate analysis. Feline malignant mammary tumours are associated with an APP response and oxidative stress, and different tumour features influence the inflammatory response and the oxidative damage. Furthermore, some of these analytes proved to have prognostic value.


Asunto(s)
Proteínas de Fase Aguda/metabolismo , Enfermedades de los Gatos/metabolismo , Neoplasias Mamarias Animales/metabolismo , Animales , Biomarcadores de Tumor , Gatos , Femenino , Neoplasias Mamarias Animales/patología , Estrés Oxidativo , Tasa de Supervivencia
17.
Anticancer Res ; 39(4): 2077-2083, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30952752

RESUMEN

BACKGROUND/AIM: IL-35 has a prominent immunosuppressive role and its overexpression has been reported in human breast cancer. However, the impact of IL-35 in canine mammary carcinogenesis has not been addressed yet. The present study determined the clinicopathological significance of IL-35 immunoexpression and its correlation with overall survival (OS) in 72 malignant canine mammary tumor (CMT) patients. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded malignant CMT samples (n=72) were submitted to immunohistochemical staining to detect IL-35 expression. Survival curves were obtained by the Kaplan-Meier method and the log-rank test was used for the survival estimates. Cox proportional hazard model for multivariate analysis was also performed. RESULTS: IL-35 overexpression was associated with: skin ulceration, tumor necrosis, mitotic index, nuclear pleomorphism, tumor differentiation, histological grade of malignancy (HGM), neoplastic intravascular emboli and lymph node metastasis. Additionally, IL-35 was also correlated with a worse overall survival in multivariate analysis, arising as an independent predictor of poor prognosis. CONCLUSION: IL-35 is associated with carcinogenesis and worse prognosis of CMT.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Enfermedades de los Perros/metabolismo , Interleucinas/metabolismo , Neoplasias Mamarias Animales/metabolismo , Animales , Perros , Femenino , Estimación de Kaplan-Meier , Pronóstico
18.
Cell Biochem Funct ; 37(2): 72-83, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30773657

RESUMEN

Cancer cell progression and proliferation increase cell density, resulting in changes to the tumour site, including the microenvironment. What is not known is if increased cell density influences the aggressiveness of cancer cells, especially their proliferation, migration, and invasion capabilities. In this study, we found that dense cell culture enhances the aggressiveness of the metastatic cancer cell lines, 4T1 and ZR-75-30, by increasing their proliferation, migration, and invasion capabilities. However, a less metastatic cell line, MCF-7, did not show an increase in aggressiveness, following dense cell culture conditions. We conducted a differential proteomic analysis on 4T1 cells cultured under dense or sparse conditions and identified an increase in expression for proteins involved in migration, including focal adhesion, cytoskeletal reorganization, and transendothelial migration. In contrast, 4T1 cells grown under sparse conditions had higher expression levels for proteins involved in metabolism, including lipid and phospholipid binding, lipid and cholesterol transporter activity, and protein binding. These results suggest that the high-density tumour microenvironment can cause a change in cellular behaviour, leading towards more aggressive cancers. SIGNIFICANCE OF THE STUDY: Metastasis of cancer cells is an obstacle to the clinical treatment of cancer. We found that dense cultures made metastatic cancer cells more potent in terms of proliferation, migration, and invasion. The proteomic and bioinformatic analyses provided some valuable clues for further intensive studies about the effects of cell density on cancer cell aggressiveness, which were associated with events such as pre-mRNA splicing and RNA transport, focal adhesion and cytoskeleton reorganization, ribosome biogenesis, and transendothelial migration, or associated with proteins, such as JAM-1 and S100A11. This investigation gives us new perspectives to investigate the metastasis mechanisms related to the microenvironment of tumour sites.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias Mamarias Animales/metabolismo , Proteínas de Neoplasias/metabolismo , Proteómica , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Ratones , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética
19.
Nano Lett ; 19(2): 997-1008, 2019 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-30676760

RESUMEN

Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor ( S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.


Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Colágeno/metabolismo , Doxorrubicina/administración & dosificación , Neoplasias Mamarias Animales/tratamiento farmacológico , Donantes de Óxido Nítrico/administración & dosificación , S-Nitrosotioles/administración & dosificación , Animales , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos/métodos , Femenino , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/ultraestructura , Donantes de Óxido Nítrico/farmacología , Proteolisis/efectos de los fármacos , S-Nitrosotioles/farmacología , Dióxido de Silicio/química , Microambiente Tumoral/efectos de los fármacos
20.
J Vet Med Sci ; 81(3): 397-400, 2019 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-30674742

RESUMEN

We previously showed that the promoter region of the human epidermal growth factor receptor (hEGFR) gene elicits high transduction efficiency, with transgene expression restricted to canine breast tumor cells. However, it was unclear whether this promoter induces tumor cell-specific transgene expression in canine urothelial carcinoma cells. Furthermore, compared with studies in human cancer cells, the utility of the telomerase reverse transcriptase (TERT) gene promoter for therapeutic transgene expression in canine cancer cells has not been evaluated thus far. Here, we compared the activity of these promoters in canine mammary tumor and urothelial carcinoma cells. Our results showed that compared with the TERT promoter, the hEGFR promoter was more useful as a tumor-specific promoter to induce efficient transgene expression in canine tumor cells.


Asunto(s)
Carcinoma/veterinaria , Enfermedades de los Perros/metabolismo , Receptores ErbB/metabolismo , Neoplasias Mamarias Animales/metabolismo , Telomerasa/metabolismo , Neoplasias de la Vejiga Urinaria/veterinaria , Animales , Carcinoma/metabolismo , Línea Celular Tumoral , Perros , Receptores ErbB/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Regiones Promotoras Genéticas , Telomerasa/genética , Transgenes
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