ABSTRACT
The heterogeneous nature of human breast cancer (HBC) can still lead to therapy inefficacy and high lethality, and new therapeutics as well as new spontaneous animal models are needed to benefit translational HBC research. Dogs are primarily investigated since they spontaneously develop tumors that share many features with human cancers. In recent years, different natural phytochemicals including berberine, a plant alkaloid, have been reported to have antiproliferative activity in vitro in human cancers and rodent animal models. In this study, we report the antiproliferative activity and mechanism of action of berberine, its active metabolite berberrubine, and eight analogs, on a canine mammary carcinoma cell line and in transgenic zebrafish models. We demonstrate both in vitro and in vivo the significant effects of specific analogs on cell viability via the induction of apoptosis, also identifying their role in inhibiting the Wnt/ß-catenin pathway and activating the Hippo signals with a downstream reduction in CTGF expression. In particular, the berberine analogs NAX035 and NAX057 show the highest therapeutic efficacy, deserving further analyses to elucidate their mechanism of action more in detail, and in vivo studies on spontaneous neoplastic diseases are needed, aiming at improving veterinary treatments of cancer as well as translational cancer research.
ABSTRACT
Tumour-associated macrophages (TAMs) are an important part of the tumour microenvironment but knowledge of their distribution in canine soft tissue sarcomas (STSs) is limited to absent. We analysed 38 STSs retrieved from the veterinary pathology archive; oral and visceral STSs, synovial cell sarcoma, tumours of histiocytic origin, haemangiosarcoma, carcinosarcomas, and undifferentiated tumours were excluded. Iba-1 positive, non-neoplastic tumour infiltrating cells (morphologically indicative of macrophages) were classified as TAMs and were counted in 10 consecutive tumours areas, where no necrosis or other inflammatory cells could be identified. Associations between numbers of TAMs and mitoses, differentiation, and necrosis scores or grade were investigated. TAMs were evident in all STSs and ranged between 6% to 62% of the cells in the microscopic field. The number of TAMs positively correlated with the STSs' histologic grade. When the components of the grade were analysed separately, TAMs were statistically correlated with mitoses, but not with differentiation or necrosis score. The present findings suggest that TAMs are present in higher numbers when STS proliferation is the predominant feature that drives tumour grade. The abundant presence of TAMs in high-grade STSs may also increase the likelihood of a pathologist misdiagnosing STS for histiocytic sarcoma.
