Description

Urothelial carcinoma (“UC”, also called transitional cell carcinoma) is the most common type of urinary bladder cancer in dogs and humans. UC comprises ~2% of all cancer in both species, and causes  >17,000 deaths in humans, and >40,000 deaths in dogs each year in the US. The majority of dogs with naturally-occurring UC have high grade invasive cancer that closely mimics muscle-invasive bladder cancer (MIBC) in humans. Although invasive UC can respond well to treatment, the cancer is lethal in approximately half of human patients, and in the majority of dogs. In addition to risk of urinary obstruction, invasive UC spreads to distant sites including lung, bones, and other sites in 50% of patients in both species. The canine model is serving an important role in testing and identifying new strategies for human trials. The very strong breed-associated risk, e.g. 20X higher risk in Scottish Terriers, enhances the value of the canine model in studying gene-environment risks.

Similarities in humans

Invasive UC in dogs closely resembles MIBC in humans in regards to: presenting symptoms / clinical signs, age at diagnosis, histopathologic and cellular features, molecular characteristics including signaling pathways and molecular subtypes, notable tumor heterogeneity, invasive and metastatic behavior, host immunocompetence, prognostic factors, and response to chemotherapy with platinum agents being most active in both species. Cyclooxygenase (COX)-2 is highly expressed in UC in both species, and COX inhibitors are commonly included in treatment protocols in dogs.  EGFR and HER2 are also overexpressed in UC in both species and are being targeted for therapy. A recent advance has been the identification of luminal and basal molecular subtypes in canine UC that mimic those in humans. This is an important finding because cancer behavior, response to treatment, and prognosis are affected by the subtype of the cancer in humans, and thus it is important to replicate those subtypes in the animal model.

Differences in humans

Human UC consists of low grade superficial cancer in two-thirds, and high grade invasive cancer in one-third of patients. Most dogs have high grade invasive UC. The male:female ratio is 2:1 in humans, and 0.5:1 in dogs. This difference may be partially due to occupational exposures in men over a long latency period. Also, most dogs with UC have been spayed or neutered at an early age. UC typically occurs in the bladder trigone in dogs, but is more evenly spread across different area of the bladder in humans. In another difference, >80% of canine UC harbors a BRAFV595E mutation, the canine homologue of BRAFV600E mutation in human cancer. It is intriguing that this mutation drives 8% of all human cancer across cancer types, and is especially important in metastatic melanoma, but it is uncommon in human UC. It is interesting that although BRAF mutations are common in canine UC, the cancer still takes on the features of the luminal and basal molecular subtypes of human UC.

Disease etiology

The most important risk factor for UC in humans is smoking, an important driver of the cancer in ~50% of cases. Exposure to aniline dyes, other chemicals, and cyclophosphamide also contribute to UC risk in humans. Key risk factors in dogs include exposure to older generation flea control products and lawn chemicals, along with obesity and female gender. Chronic inflammation and cyclophosphamide exposure are considered potential risk factors in both species. The strong breed-associated risk for UC in dogs includes a 20 fold increased risk in Scottish Terriers, and a 3-6 fold increased risk in West Highland White Terriers, Wirehair Fox Terriers, Shetland Sheepdogs and Beagles, compared to mixed breed dogs. Eskimo Dogs, Keeshonds, and Samoyeds have also been found to be at higher risk in some studies.

Clinical presentation

UC most commonly occurs in older individuals in both species. The most common presentation of UC in humans is unexplained hematuria in the absence of infection, stones, and other causes. The most common presenting clinical signs in dogs are hematuria, stranguria, increased frequency of urination, and inappropriate urination such as urinary accidents in the house. Distant metastases can be present in up to 20% of dogs at diagnosis. Although urinary signs predominate, rarely signs related to organ dysfunction due to metastases, or lameness associated with bone metastases or hypertrophic osteopathy can occur. UC can also be found incidentally during abdominal imaging performed to address other health concerns. The definitive diagnosis is made by histopathologic examination of tissues in both species.

Treatment

Human MIBC is typically treated with cystectomy and neoadjuvant or adjuvant chemotherapy. Radiation therapy is used in “bladder sparing” protocols. Chemotherapy and immune checkpoint inhibitors are used to treat metastases. Up to 50% of patients appear cured, but recurrence and new primary tumors remain a concern. Invasive UC in dogs can be controlled for months to over a year, but is rarely curable. Cystectomy is rarely performed in dogs. Further study of radiation therapy will define possible benefits. Most dogs with UC are treated with COX inhibitors, chemotherapy, and combinations of these. COX inhibitors induce remission in 18-20% and stable disease in >50% of dogs, and greatly enhance the activity of chemotherapy. Chemotherapy agents such as cisplatin, carboplatin, gemcitabine, vinblastine, and mitoxantrone have response rates similar to those in human UC. Ureteral and urethral stents can be placed to physically relieve urinary obstruction.    

Research sites

Multiple groups are involved in research related to UC although options for case enrollment have been limited by the COVID-19 pandemic. The Purdue Comparative Oncology Program has a focused effort in canine and translational UC research, and operates a canine bladder cancer clinic at the Purdue University Veterinary Teaching Hospital. More information can be found at: https://www.purdue.edu/vet/pcop/index.php.

Recent Publications

Knapp DW, Dhawan D, Ramos-Vara JA, Ratliff TL, Cresswell GM, Utturkar S, Sommer BC, Fulkerson CM, Hahn NM. Naturally-occurring invasive urothelial carcinoma in dogs, a unique model to drive advances in managing muscle invasive bladder cancer in humans. Front Oncol. 2020 Jan 21;9:1493. PMID: 32039002.

Jack S, Madhivanan K, Ramadesikan S, Subramanian S, Edwards DF 2nd, Elzey BD, Dhawan D, McCluskey A, Kischuk EM, Loftis AR, Truex N, Santos M, Lu M, Rabideau A, Pentelute B, Collier J, Kaimakliotis H, Koch M, Ratliff TL, Knapp DW, Aguilar RC. A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF-anthrax toxin chimera. Int J Cancer. 2020 Jan 15;146(2):449-460. PMID: 31584195.

Parker HG, Dhawan D, Harris AC, Ramos-Vara JA, Davis BW, Knapp DW, Ostrander EA. NAseq expression patterns of canine invasive urothelial carcinoma reveal two distinct tumor clusters and shared regions of dysregulation with human bladder tumors. BMC Cancer. 2020 Mar 24;20(1):251. PMID: 32209086.

Packeiser EM, Hewicker-Trautwein M, Thiemeyer H, Mohr A, Junginger J, Schille JT, Murua Escobar H, Nolte I. Characterization of six canine prostate adenocarcinoma and three transitional cell carcinoma cell lines derived from primary tumor tissues as well as metastasis. PLoS One. 2020 Mar 13;15(3):e0230272. PMID: 32168360.

Chand D, Dhawan D, Sankin A, Ren X, Lin J, Schoenberg M, Knapp DW, Zang X. Immune checkpoint B7x (B7-H4/B7S1/VTCN1) is over expressed in spontaneous canine bladder cancer: the first report and its implications in a preclinical model. Bladder Cancer. 2019 Jan 31;5(1):63-71. PMID: 30854414.

Gustafson TL, Biller B. Use of Toceranib phosphate in the treatment of canine bladder tumors: 37 cases. J Am Anim Hosp Assoc. 2019 Sep/Oct;55(5):243-248. PMID: 31433219.

Finotello R, Schiavo L, Ressel L, Frohmader A, Silvestrini P, Verin R. Lipoxygenase-5 expression in canine urinary bladder: normal urothelium, cystitis and transitional cell carcinoma. J Comp Pathol. 2019 Jul;170:1-9. PMID: 31375151.

Szigetvari NM, Dhawan D, Ramos-Vara JA, Leamon CP, Klein PJ, Ruple AA, Heng HG, Pugh MR, Rao S, Vlahov IR, Deshuillers PL, Low PS, Fourez LM, Cournoyer AM, Knapp DW. Phase I/II clinical trial of the targeted chemotherapeutic drug, folate-tubulysin, in dogs with naturally-occurring invasive urothelial carcinoma. Oncotarget. 2018 Dec 11;9(97):37042-37053. PMID: 30651934.

Elbadawy M, Usui T, Mori T, Tsunedomi R, Hazama S, Nabeta R, Uchide T, Fukushima R, Yoshida T, Shibutani M, Tanaka T, Masuda S, Okada R, Ichikawa R, Omatsu T, Mizutani T, Katayama Y, Noguchi S, Iwai S, Nakagawa T, Shinohara Y, Kaneda M, Yamawaki H, Sasaki K. Establishment of a novel experimental model for muscle-invasive bladder cancer using a dog bladder cancer organoid culture. Cancer Sci. 2019 Sep;110(9):2806-2821. PMID: 31254429.

Eto S, Saeki K, Yoshitake R, Yoshimoto S, Shinada M, Ikeda N, Kamoto S, Tanaka Y, Kato D, Maeda S, Tsuboi M, Chambers J, Uchida K, Nishimura R, Nakagawa T. Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells. PLoS One. 2019 Jun 17;14(6):e0218382. PMID:  31206526.

Maeda S, Murakami K, Inoue A, Yonezawa T, Matsuki N. CCR4 blockade depletes regulatory T cells and prolongs survival in a canine model of bladder cancer. Cancer Immunol Res. 2019 Jul;7(7):1175-1187. PMID: 31160277.

de Brot S, Grau-Roma L, Stirling-Stainsby C, Dettwiler M, Guscetti F, Meier D, Scase T, Robinson BD, Gardner D, Mongan NP. A fibromyxoid stromal response is associated with muscle invasion in canine urothelial carcinoma. J Comp Pathol. 2019 May;169:35-46. PMID: 31159949.

Cronise KE, Hernandez BG, Gustafson DL, Duval DL. Identifying the ErbB/MAPK signaling cascade as a therapeutic target in canine bladder cancer. Mol Pharmacol. 2019 Jul;96(1):36-46. PMID: 31048548.

Iwasaki R, Shimosato Y, Yoshikawa R, Goto S, Yoshida K, Murakami M, Kawabe M, Sakai H, Mori T. Survival analysis in dogs with urinary transitional cell carcinoma that underwent whole-body computed tomography at diagnosis. Vet Comp Oncol. 2019 Sep;17(3):385-393. PMID: 31012230.

Luethcke KR, Ekena J, Chun R, Trepanier LA. Glutathione S-transferase theta genotypes and environmental exposures in the risk of canine transitional cell carcinoma. J Vet Intern Med. 2019 May;33(3):1414-1422. PMID: 31008543.

Tsuboi M, Sakai K, Maeda S, Chambers JK, Yonezawa T, Matsuki N, Uchida K, Nakayama H. Assessment of HER2 expression in canine urothelial carcinoma of the urinary bladder. Vet Pathol. 2019 May;56(3):369-376. PMID: 30612533.

D'Hue CA, Dhawan D, Peat T, Ramos-Vara J, Jarmusch A, Knapp DW, Cooks RG. Fatty acid patterns detected by ambient ionization mass spectrometry in canine invasive urothelial carcinoma from dogs of different breeds. Bladder Cancer. 2018 Jul 30;4(3):283-291. PMID: 30112439.

Dhawan D, Hahn NM, Ramos-Vara JA, Knapp DW. Naturally-occurring canine invasive urothelial carcinoma harbors luminal and basal transcriptional subtypes found in human muscle invasive bladder cancer. PLoS Genet. 2018 Aug 8;14(8):e1007571. PMID: 30089113.

Sommer BC, Dhawan D, Ratliff TL, Knapp DW. Naturally-occurring canine invasive urothelial carcinoma: a model for emerging therapies. Bladder Cancer. 2018 Apr 26;4(2):149-159. PMID: 29732386.

Nagaya T, Okuyama S, Ogata F, Maruoka Y, Knapp DW, Karagiannis SN, Fazekas-Singer J, Choyke PL, LeBlanc AK, Jensen-Jarolim E, Kobayashi H. Near infrared photoimmunotherapy targeting bladder cancer with a canine anti-epidermal growth factor receptor (EGFR) antibody. Oncotarget. 2018 Apr 10;9(27):19026-19038. PMID: 29721181.

Aupperle-Lellbach H, Grassinger J, Hohloch C, Kehl A, Pantke P.  [Diagnostic value of the BRAF variant V595E in urine samples, smears and biopsies from canine transitional cell carcinoma]. Tierarztl Prax Ausg K Kleintiere Heimtiere. 2018 Oct;46(5):289-295. PMID: 30541168.

Leffler AJ, Hostnik ET, Warry EE, Habing GG, Auld DM, Green EM, Drost WT. Canine urinary bladder transitional cell carcinoma tumor volume is dependent on imaging modality and measurement technique. Vet Radiol Ultrasound. 2018 Nov;59(6):767-776. PMID: 29989254.

Maeda S, Tomiyasu H, Tsuboi M, Inoue A, Ishihara G, Uchikai T, Chambers JK, Uchida K, Yonezawa T, Matsuki N. Comprehensive gene expression analysis of canine invasive urothelial bladder carcinoma by RNA-Seq. BMC Cancer. 2018 Apr 27;18(1):472. PMID: 29699519.

Lin SJ, Kao CF, Wang FI, Jeng CR, Lee JJ, Wang LY, Chang HW, Chen YJ, Liu CH, Pang VF. Urothelial carcinomas of the urinary bladder with plasmacytoid or rhabdoid features and tendency of epithelial-mesenchymal transition in 3 dogs. Vet Pathol. 2018 Sep;55(5):673-677. PMID: 29661121.

Pallaoro A, Mirsafavi RY, Culp WTN, Braun GB, Meinhart CD, Moskovits M. Screening for canine transitional cell carcinoma (TCC) by SERS-based quantitative urine cytology. Nanomedicine. 2018 Jun;14(4):1279-1287. PMID: 29597048.

Macrì F, Di Pietro S, Mangano C, Pugliese M, Mazzullo G, Iannelli NM, Angileri V, Morabito S, De Majo M. Quantitative evaluation of canine urinary bladder transitional cell carcinoma using contrast-enhanced ultrasonography. BMC Vet Res. 2018 Mar 12;14(1):84. PMID: 29530040.

Henry CJ, Flesner BK, Bechtel SA, Bryan JN, Tate DJ, Selting KA, Lattimer JC, Bryan ME, Grubb L, Hausheer F. Clinical evaluation of tavocept to decrease diuresis time and volume in dogs with bladder cancer receiving cisplatin. J Vet Intern Med. 2018 Jan;32(1):370-376. PMID: 29080252.

Fulkerson CM, Dhawan D, Jones DR, Marquez VE, Jones PA, Wang Z, Wu Q, Klaunig JE, Fourez LM, Bonney PL, Knapp DW. Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs. Vet Comp Oncol. 2017 Mar;15(1):226-236. PMID: 26178438.

Honkisz SI, Naughton JF, Weng HY, Fourez LM, Knapp DW. Evaluation of two-dimensional ultrasonography and computed tomography in the mapping and measuring of canine urinary bladder tumors. Vet J. 2018 Feb;232:23-26. PMID: 29428087.

Millanta F, Impellizeri J, McSherry L, Rocchigiani G, Aurisicchio L, Lubas G. Overexpression of HER-2 via immunohistochemistry in canine urinary bladder transitional cell carcinoma - A marker of malignancy and possible therapeutic target. Vet Comp Oncol. 2018 Jun;16(2):297-300. PMID: 28871659.

Fulkerson CM, Dhawan D, Ratliff TL, Hahn NM, Knapp DW. Naturally occurring canine invasive urinary bladder cancer: a complementary animal model to improve the success rate in human clinical trials of new cancer drugs. Int J Genomics. 2017;2017:6589529. PMID: 28487862.

Kent MS, Zwingenberger A, Westropp JL, Barrett LE, Durbin-Johnson BP, Ghosh P, Vinall RL. MicroRNA profiling of dogs with transitional cell carcinoma of the bladder using blood and urine samples. BMC Vet Res. 2017 Nov 15;13(1):339. PMID: 29141625.

Ramsey SA. A Method for cross-species visualization and analysis of RNA-sequence data. Methods Mol Biol. 2018;1702:291-305. PMID: 29119511.

Walters L, Martin O, Price J, Sula MM. Expression of receptor tyrosine kinase targets PDGFR-β, VEGFR2 and KIT in canine transitional cell carcinoma. Vet Comp Oncol. 2018 Mar;16(1):E117-E122. PMID: 28884928.

Marvel SJ, Séguin B, Dailey DD, Thamm DH. Clinical outcome of partial cystectomy for transitional cell carcinoma of the canine bladder. Vet Comp Oncol. 2017 Dec;15(4):1417-1427. PMID: 28217972.

Ramsey SA, Xu T, Goodall C, Rhodes AC, Kashyap A, He J, Bracha S. Cross-species analysis of the canine and human bladder cancer transcriptome and exome. Genes Chromosomes Cancer. 2017 Apr;56(4):328-343. PMID: 28052524.

Pollard RE, Watson KD, Hu X, Ingham E, Ferrara KW. Feasibility of quantitative contrast ultrasound imaging of bladder tumors in dogs. Can Vet J. 2017 Jan;58(1):70-72. PMID: 28042158.

Inoue A, Maeda S, Kinoshita R, Tsuboi M, Yonezawa T, Matsuki N. Density of tumor-infiltrating granzyme B-positive cells predicts favorable prognosis in dogs with transitional cell carcinoma. Vet Immunol Immunopathol. 2017 Aug;190:53-56. PMID: 28778323.

Mochizuki H, Breen M. Sequence analysis of RAS and RAF mutation hot spots in canine carcinoma. Vet Comp Oncol. 2017 Dec;15(4):1598-1605. PMID: 27714944.

Charney VA, Miller MA, Heng HG, Weng HY, Knapp DW. Skeletal metastasis of canine urothelial carcinoma: pathologic and computed tomographic features. Vet Pathol. 2017 May;54(3):380-386. PMID: 27879443.

Knapp DW, Ruple-Czerniak A, Ramos-Vara JA, Naughton JF, Fulkerson CM, Honkisz SI. A nonselective cyclooxygenase inhibitor enhances the activity of vinblastine in a naturally-occurring canine model of invasive urothelial carcinoma. Bladder Cancer. 2016 Apr 27;2(2):241-250. PMID: 27376143.

Rippy SB, Gardner HL, Nguyen SM, Warry EE, Portela RA, Drost WT, Hostnik ET, Green EM, Chew DJ, Peng J, London CA. A pilot study of toceranib/vinblastine therapy for canine transitional cell carcinoma. BMC Vet Res. 2016 Nov 17;12(1):257. Erratum in: BMC Vet Res. 2016 Dec 30;12 (1):291. PMID: 27855679.

Mochizuki H, Shapiro SG, Breen M. Detection of BRAF mutation in urine DNA as a molecular diagnostic for canine urothelial and prostatic carcinoma. PLoS One. 2015 Dec 9;10(12):e0144170. PMID: 26649430.

Yoshikawa H, Nolan MW, Lewis DW, Larue SM. Retrospective evaluation of interfraction ureteral movement in dogs undergoing radiation therapy to elucidate appropriate setup margins. Vet Radiol Ultrasound. 2016 Mar-Apr;57(2):170-9. PMID: 26634416.

Mochizuki H, Shapiro SG, Breen M. Detection of copy number imbalance in canine urothelial carcinoma with droplet digital polymerase chain reaction. Vet Pathol. 2016 Jul;53(4):764-72. PMID: 26574558.

Choy K, Fidel J. Tolerability and tumor response of a novel low-dose palliative radiation therapy protocol in dogs with transitional cell carcinoma of the bladder and urethra. Vet Radiol Ultrasound. 2016 May;57(3):341-51. PMID: 26841125.

Shapiro SG, Knapp DW, Breen M. A cultured approach to canine urothelial carcinoma: molecular characterization of five cell lines. Canine Genet Epidemiol. 2015 Sep 17;2:15. PMID: 26401343.

Dhawan D, Paoloni M, Shukradas S, Choudhury DR, Craig BA, Ramos-Vara JA, Hahn N, Bonney PL, Khanna C, Knapp DW. Comparative gene expression analyses identify luminal and basal subtypes of canine invasive urothelial carcinoma that mimic patterns in human invasive bladder cancer. PLoS One. 2015 Sep 9;10(9):e0136688. PMID: 26352142.

Knapp DW, Dhawan D, Ostrander E. "Lassie," "Toto," and fellow pet dogs: poised to lead the way for advances in cancer prevention. Am Soc Clin Oncol Educ Book. 2015:e667-72.

Shapiro SG, Raghunath S, Williams C, Motsinger-Reif AA, Cullen JM, Liu T, Albertson D, Ruvolo M, Bergstrom Lucas A, Jin J, Knapp DW, Schiffman JD, Breen M. Canine urothelial carcinoma: genomically aberrant and comparatively relevant. Chromosome Res. 2015 Jun;23(2):311-31. PMID: 25783786.

Decker B, Parker HG, Dhawan D, Kwon EM, Karlins E, Davis BW, Ramos-Vara JA, Bonney PL, McNiel EA, Knapp DW, Ostrander EA. Homologous mutation to human BRAF V600E is common in naturally occurring canine bladder cancer--evidence for a relevant model system and urine-based diagnostic test. Mol Cancer Res. 2015 Jun;13(6):993-1002. PMID: 25767210.

Fulkerson CM, Knapp DW. Management of transitional cell carcinoma of the urinary bladder in dogs: a review. Vet J. 2015 Aug;205(2):217-25. PMID: 25747698.

Morgan M, Forman M.  Cystoscopy in dogs and cats. Vet Clin North Am Small Anim Pract. 2015 Jul;45(4):665-701. PMID: 26002795.

Hanazono K, Fukumoto S, Kawamura Y, Endo Y, Kadosawa T, Iwano H, Uchide T. Epidermal growth factor receptor expression in canine transitional cell carcinoma. J Vet Med Sci. 2015 Jan;77(1):1-6. PMID: 25223345.