[show abstract][hide abstract] ABSTRACT: BACKGROUND: Triple negative breast cancer (TNBC) in humans is defined by the absence of oestrogen receptor (ER), progesterone receptor (PR) and HER2 overexpression. Mammalian target of rapamycin (mTOR) is overexpressed in TNBC and it represents a potential target for the treatment of this aggressive tumour. Feline mammary carcinoma (FMC) is considered to be a model for hormone-independent human breast cancer. This study investigated mTOR and p-mTOR expression in FMC in relation to triple negative (TN) phenotype. RESULTS: The expression of mTOR, p-mTOR, ERalpha, PR and HER2 was evaluated in 58 FMCs by immunohistochemistry and in six FMC cell lines by Western blot analysis. 53.5% of FMC analyzed were ER, PR, HER2 negative (TN-FMC) while 56.9% and 55.2% of cases expressed mTOR and p-mTOR respectively. In this study we found that m-TOR and p-mTOR were more frequently detected in TN-FMC and in HER2 negative samples. CONCLUSIONS: In this study, we demonstrate that there is also a FMC subset defined as TN FMC, which is characterised by a statistically significant association with m-TOR and p-mTOR expression as demonstrated in human breast cancer.
BMC Veterinary Research 04/2013; 9(1):80. · 1.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: Platelet derived growth factor receptor (PDGFR)α and PDGFRβ are tyrosine kinase receptors that are overexpressed in 70-80% of human osteosarcomas (OSAs) and may be suitable therapeutic targets for specific kinase inhibitors (TKIs). Canine OSA shows histopathological and clinical features similar to human OSA, and is considered an excellent model in comparative oncology. This study investigated PDGF-A, PDGF-B, PDGFRα and PDGFRβ expression in 33 canine OSA samples by immunohistochemistry and in seven primary canine OSA cell lines by Western blot and quantitative PCR analysis. Immunohistochemical data showed that PDGF-A and PDGF-B are expressed in 42% and 60% of the OSAs analysed, respectively, while PDGFRα and PDGFRβ were expressed in 78% and 81% of cases, respectively. Quantitative PCR data showed that all canine OSA cell lines overexpressed PDGFRα, while 6/7 overexpressed PDGFRβ and PDGF-A relative to a normal osteoblastic cell line. Moreover, in vitro treatment with a specific PDGFR inhibitor, AG1296, caused a dose- and time-dependent decrease in AKT phosphorylation. Collectively, these data show that PDGFRs/PDGFs are co-expressed in canine osteosarcomas, which suggests that an autocrine and/or paracrine loop is involved and that they play an important role in the aetiology of OSA. PDGFRs may be suitable targets for the treatment of canine OSA with a specific TKI.
The Veterinary Journal 06/2012; · 2.42 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Osteosarcoma (OSA) represents the most common canine primary bone tumour. Despite several pathways have been investigated so far, few molecules have been identified as prognostic tools or potential therapeutic targets, and there is still the need to find out molecular pathways with specific influence over OSA progression to facilitate earlier prognosis and treatment.Aims of the present study were to evaluate the immunohistochemical pattern and levels of expression of a panel of molecules (survivin, beta-catenin, caspase 3 -inactive and active formsand p53) involved in cell cycle and apoptosis regulation in canine OSA samples, known to be of interest in the study also of human OSA, and to detect specific relations among them and with histological tumour grade, disease free interval (DFI) and overall survival (OS). RESULTS: Nuclear beta-catenin immunostaining was detected in normal osteoblasts adjacent to the tumour, and in 47% of the cases. Cytoplasmic and/or membranous immunostaining were also observed. Nuclear survivin and p53 positive cells were found in all cases. Moderate/high cytoplasmic beta-catenin expression ([greater than or equal to]10% positive cells) was significantly associated with the development of metastasis (P = 0.014); moderate/high nuclear p53 expression ([greater than or equal to]10% positive cells) was significantly associated with moderate/ high histological grade (P = 0.017) and shorter OS (P = 0.049). Moderate/high nuclear survivin expression ([greater than or equal to]15% positive cells) showed a tendency toward a longer OS (P = 0,088). CONCLUSIONS: The present results confirmed p53 as negative prognostic marker, while suggested survivin as a potential positive prognostic indicator, rather than indicative of a poor prognosis. The detection of nuclear beta-catenin immunostaining in normal osteoblasts and the absent/low expression in most of the OSAs, suggested that this pathway could not play a major role in oncogenic transformation of canine osteoblasts. Further studies are needed to confirm these hypotheses.
BMC Veterinary Research 06/2012; 8(1):78. · 1.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: Abnormal levels of heat shock proteins have been observed in a number of human neoplasms and demonstrate prognostic, predictive and therapeutic implications. Since osteosarcoma (OSA) in dogs provides an important model for the same disease in humans, the aim of this study was to evaluate the immunohistochemical expression of Hsp27, Hsp72, Hsp73 and Hsp90 in 18 samples of canine appendicular OSA, in relation to histological grade and overall survival (OS), in order to investigate their potential prognostic, predictive and/or therapeutic value. A semiquantitative method was used for the analysis of the results. Hsp27, Hsp73 and Hsp90 showed a variably intense, cytoplasmic and nuclear immunoreactivity that was not associated with histological type or grade. On the other hand, a high percentage of Hsp72 immunostaining was significantly associated with grade III (P < 0.01) and a lack of immunolabelling was significantly correlated to a longer OS (P = 0.006). Neoplastic emboli were occasionally positive for Hsp27, faintly immunoreactive for Hsp72 and intensely immunolabelled by Hsp73 and Hsp90. In conclusion, absence of Hsp72 immunosignal appears to be associated with a favourable prognosis whilst the widespread Hsp90 immunoreactivity detected in all tumour cases as well as in neoplastic emboli, suggests this protein could be targeted in the therapy of canine OSA, and likewise in its human counterpart.
Cell Stress and Chaperones 01/2012; 17(1):131-8. · 2.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chondroitin sulfate proteoglycan-4 (CSPG4), also known as high molecular weight-melanoma associated antigen (HMW-MAA), is a membrane-bound chondroitin sulfate proteoglycan highly expressed by human melanoma cells. This phylogenetically conserved tumour antigen plays an important biological role in human melanoma, where it is used as a marker to diagnose forms with unusual characteristics, such as desmoplastic melanoma, and to detect melanoma cells in lymph nodes and peripheral blood, and as a target for immunotherapy because of its restricted distribution in normal tissues. To identify suitable targets to develop novel approaches of treating canine melanoma, CSPG4 was studies to see whether it is expressed in canine malignant melanomas. Immunohistochemical staining of 65 canine malignant melanomas with an anti-human CSPG4-specific antibody detected CSPG4 in 37 cases (56.9%). Positive staining was more frequent, albeit not significantly, in amelanotic compared to melanotic tumours and was statistically associated with tumours having both melanin and the epithelioid histotype. The frequency of CSPG4 expression was similar to that of other melanoma antigens used as diagnostic markers for canine malignant melanoma, such as Melan A and the protein recognized by the PNL2 monoclonal antibody. The results suggest that CSPG4 constitutes a new potential immunohistochemical marker of canine malignant melanoma and may represent an immunotherapeutic target as in humans.
The Veterinary Journal 04/2011; 190(2):e26-30. · 2.42 Impact Factor