Establishment of a dog primary prostate cancer organoid using the urine cancer stem cells

Abstract

Dog spontaneously develops prostate cancer (PC) like human. Since most dogs with PC have poor prognosis, they are expected to become a translational model for human advanced PC. Stem cell-derived 3D organoid culture could recapitulate organ structures and physiology. Using patient tissues, human PC organoid culture system was established. Recent study showed that urine cells also possess the characteristic of stem cells. However, the urine cell-derived PC organoids have never been produced. We therefore generated PC organoids using the dog urine samples. Urine organoids from each PC dog were successfully generated. Each organoid showed cystic structures and resembled the epithelial structures of original tissues. Expression of an epithelial cell marker, E-cadherin and a myofibloblast marker, α-SMA was observed in the urine organoids. The organoids also expressed a basal cell marker, CK5 and a luminal cell marker, CK8. CD49f-sorted basal cell organoids rapidly grew compared with CD24-sorted luminal cell ones. The population of CD44-positive cells was the highest in both organoids and the original urine cells. Injection of the organoids into immunodeficiency mice successfully formed tumor, which exhibited the features of the organoids. Treatment with a microtubule inhibitor, docetaxel but not a cyclooxygenase inhibitor, piroxicam and an mTOR inhibitor, rapamycin decreased the cell viability of organoids. Treatment with a Hedgehog signal inhibitor, GANT61 increased the radiosensitivity in the organoids. These findings revealed that PC organoids using urine might become a useful tool to investigate the mechanisms of pathogenesis and treatment of dog PC.

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