Hedgehog signaling is activated in canine transitional cell carcinoma and contributes to cell proliferation and survival

Abstract

Transitional cell carcinoma (TCC) is the most commonly diagnosed tumor of the canine urinary system. Hedgehog (HH) signaling represents one possible novel therapeutic target, based on its recently identified central role in human urothelial carcinoma. The purpose of this study was to determine if HH mediators are expressed in canine TCC and the effect of inhibition of this pathway on cell growth and survival. HH pathway mediators were found to be expressed in five canine TCC cell lines. Indian HH was expressed in tumor cells in five canine bladder tumor tissues, but not in normal canine bladder tissue. Inhibition of HH signaling with cyclopamine and GANT61 led to significantly decreased cell proliferation but had a smaller effect on apoptosis. These results support future investigation of inhibitors of HH signaling in the treatment of canine TCC.

Melarsomine suppresses canine osteosarcoma cell survival via inhibition of Hedgehog-GLI signaling

“…Expression levels of GLI1, GLI2, and PTCH1 mRNA were quantified by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) using AMPIGENE qPCR Green Mix Lo-ROX with SYBR Green dye (Enzo Life Sciences, Farmingdale, NY, U.S.A.). The primer sequences used in this study were taken from a study by Gustafson et al [10] and are listed in Table 1. Data were analyzed using the ΔΔCt method, and relative expression levels of target mRNAs were normalized to those of HPRT1 (internal control).…”

“…(ATO) is an FDA-approved GLI inhibitor used to treat acute promyelocytic leukemia in humans and has been used in clinical trials for several other hematological and solid tumors [1,16,27,36]. Two recent studies have reported that Hh-GLI signaling is activated in canine OSA and transitional cell carcinoma and that the GLI inhibitor GANT61 decreases cell viability [10,28].…”

Expression of the hedgehog signalling pathway and the effect of inhibition at the level of smoothened in canine osteosarcoma cell lines

“…39 It was suspected that the high background level of apoptosis in canine TCC cell lines resulted from a high sensitivity to anoikis, a form of apoptosis or programmed cell death that occurs when anchorage-dependent cells are dislodged from the extracellular matrix. 18,40 The cell viability of Abrams appeared most sensitive by vismodegib treatment among three canine OSA cell lines including D17 and HMPOS but colony formation did not significantly decreased. 19 The variable effects of SMO antagonist on cell viability, colony formation, and apoptosis in the different cell lines indicate the need for more specific and personalized cancer treatment.…”

“…17 Similar results have been obtained for canine TCC cell lines; K9TCC cells were more sensitive to the inhibition of cyclopamine than K9TCC-sh, as the former cells express higher levels of IHH. 18 However, some studies have reported opposite effects; for example, SHEP1 human neuroblastoma cells are highly sensitive to cyclopamine, despite lower SHH signalling. 34 The differential drug susceptibilities in different cell lines might result from variable expression of various Hh components.…”

Characteristics and Applications of Canine In Vitro Models of Bladder Cancer in Veterinary Medicine: An Up-to-Date Mini Review

“…However, the overall median survival time for dogs that respond to NSAIDs and chemotherapy was still relatively short (up to a few months), which led to the search for novel therapeutic agents. In the past years, multiple studies including canine BC cell lines were conducted in order to evaluate the activity of novel anticancer agents ( Table 3 ) [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Although many of them were not transferred to in vivo studies, novel therapeutic agents that could improve survival of dog pets with bladder TCC were also found.…”