Efficacy of metformin in canine mammary carcinoma: in vitro and in vivo activity on cancer stem cells

In recent years comparative oncology acquired a relevant role in cancer research highlighting the relevance of naturally developing cancers in animals as models for human disease and pharmacological research, although it is stili an underutilized resource in translational oncology research. The present study focuses on spontaneous Canine Mammary Carcinoma (CMC) as experimental model for the study of anticancer activity of innovative drugs. The first step of our work was the isolation and characterization of Cancer Stem Cells (CSCs) derived from CMC post-surgical tissues. CSCs represent the tumorigenic celi subpopulation found within different human tumor types, able to generate tumors through the stem celi processes of self-renewal and chemo-and radio-resistance, causing relapse and metastasis. Therefore, development of specific therapies targeted to CSCs holds hope for improvement of treatment efficacy in cancer patients. In CMC-derived CSCs we evaluated the effects of metformin, a drug widely used in patients with type 2 diabetes, that has been associated with a lower cancer risk in epidemiologic studies. The stem phenotype of CSC cultures, has been investigated in vitro (by stem cell marker expression, self-renewal, proliferative potential) and in vivo (tumorigenicity in nude mice). Metformin is able to inhibit the proliferation of canine CMCs both in vitro and in vivo in xenograft tumors. On these bases a study on dogs bearing CMC treated with metformin before surgery has been planned. Preliminary results on 7 animals showed a significant block or decrease oftumor volume after metformin treatrnent. The ongoing research is aimed at increasing the number of dogs, to obtain reliable results that support the efficacy of metformin in targeting CSC of CMC, as potenti al neo-adjuvant agent in combination with current chemotherapeutic regirnens and future translation into veterinary and human oncology