Chemo-angiogenic profile of bovine urinary bladder tumors distinguishes urothelial carcinomas from hemangiosarcomas

Angiogenesis and inflammation are two processes regulated by numerous common molecular mechanisms. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation; both mechanisms have been shown to be involved in carcinogenesis. With this study we sought to gain an understanding of the molecular mechanisms involved in tumor angiogenesis and inflammation in urinary bladder tumors. Tumor specimens were collected at slaughter from Friesian cows chronically exposed to bracken fern. Bracken chronic toxicity is characterized by the presence of multiple mixed tumors in the bladder, being reported throughout the world under the designation of bovine enzootic hematuria. We conducted molecular analyses of angiogenic factors and chemokine production by real-time RT-PCR, and also assessed microvessel density (MVD), microvessel pericyte coverage index (MPI) to reveal mature vessels, the extent of tumor-infiltrating leukocytes (TILk) and tumor cell apoptosis and proliferation in both epithelial and endothelial-derived bovine urinary bladder tumors. We defined a profile of chemokines/chemokine receptors (Mip1beta, CCR1) and angiogenesis-related factors (VEGF, VEGFR2) that allow distinguishing between urothelial carcinomas (epithelial origin) and hemangiosarcomas (endothelial origin). Taken together, our data reveals previously unrecognized paracrine and autocrine chemo-angiogenic loops in the context of bovine urinary bladder tumorigenesis.