Urologic Oncology: Seminars and Original Investigations
Original ArticleMolecular carcinogenesis in equine penile cancer: A potential animal model for human penile cancer
Introduction
Human penile cancer is a rare disease in developed countries with an incidence rate of around 1 per 100,000 [1]. In contrast, it is more common in developing countries accounting for up to 10% to 17% of cancer in males with an incidence that reaches 4 per 100,000 [1], [2]. Squamous cell carcinoma (SCC) is the predominant cancer type and accounts for over 95% of penile cancer cases [3], [4], [5]. The main treatment for advanced tumors is phalectomy and, when inguinal lymph node metastasis is present, bilateral inguinal lymphadenectomy is also performed. These procedures are associated with high psychological morbidity and negatively impact the quality of life of affected patients [4]. In the UK, it is reported that there has been an increase in incidence of approximately 25% since 1985 [6], [7]. The pathogenesis of human penile SCC (hPSCC) remains unclear; lack of circumcision, phimosis, cigarette-smoking and obesity have been widely discussed as potentially contributing to its development. The hypothesis of a bimodal pathogenesis of hPSCC is accepted, with human papillomavirus- (HPV) and non-HPV-related cases. HPV infection plays a role in hPSCC carcinogenesis and high-risk HPV-DNA is present in 12% to 72% of cancers [7].
As a result of its rarity, most treatment options are based on the results of small clinical trials. Experimental models for human diseases, including in vitro studies using cancer cell lines, and animal models using non-spontaneous/induced tumors or xenografts, are valuable resources in biomedical research when evaluating new potential therapies [8]. However, these models have limitations and often they do not resemble morphologically, or at the molecular level, the disease in humans. Currently, there is a lack of commercially available hPSCC cell lines and no reliable xenograft models have been produced [9].
In humans, a variety of proteins involved in hPSCC have been studied and associated with pathological features and prognosis. Overexpression of the enzyme COX-2 is associated with proliferation, angiogenesis, invasion and metastasis [10], [11]. Phosphatase and tensin homolog (PTEN), a tumor suppressor gene, is frequently mutated in many cancers, including hPSCC, leading to reduced production of its transcription product, PTEN protein, which holds important functions preventing cell proliferation [12]. E-cadherin and vimentin are proteins associated with the epithelial-mesenchymal transition (EMT) process, which have been associated with a poorer prognosis [13], [14]. Additionally, 14-3-3σ is an oncoprotein that promotes cell proliferation, survival, invasiveness, metastasis and chemoresistance by binding and modulating various molecular pathways in vulvar, cervical and head and neck SCC [15], [16], [17], [18].
Naturally occurring tumors in domestic animals represent a unique opportunity to study cancer in vivo. Yet, few studies have been done to establish a specific animal cancer as a model for its human counterpart [8]. SCC is the most common penile neoplasm in the horse and a novel type of equine papillomavirus (EcPV-2) is suggested to play a role as initiator in this cancer, acting in a similar way to high-risk HPV-16 in humans [19]. Currently, there is a significant paucity of knowledge on the molecular events leading to the initiation and progression of PSCC in the horse and, given the clinical and biological similarities with hPSCC, we hypothesize they could share similar protein aberrations and altered molecular mechanisms, particularly EMT. Equine PSCC (ePSCC) could therefore serve as a highly relevant spontaneous animal model in the context of translational research.
The objectives of this study were to analyze the expression of COX-2, 14-3-3σ, E-cadherin, vimentin and PTEN proteins in equine penile papilloma (ePP) and ePSCC and compare their expression with histopathological features and in comparison with hPSCC. Furthermore, we aimed to analyze the occurrence of EMT by examining E-cadherin and vimentin expression.
Section snippets
Cases and histological assessment
A search in the database of the Diagnostic Pathology Service of the Royal Veterinary College and the University of Bristol was performed using the following key words; ‘equine’, ‘papilloma’ and ‘squamous cell carcinoma’. A total of 58 cases were identified. Epithelial proliferative lesions from the skin, ocular or vulvar regions were excluded and finally a total of 45 cases of ePP or ePSCC were selected. Hematoxylin and eosin archived tissue sections were available and were re-examined by two
Epidemiological data
Clinical follow-up was available for 6/45 cases. Four horses, in which excisional biopsies or penile amputation were performed, were originally diagnosed as ePSCC. In this group, three horses were humanely euthanized due to tumor recurrence and tumor-related clinical disease (one had lymph node and pulmonary metastasis). The mean survival time for these 4 cases was 786 days (187–1178 days). A fifth case was originally diagnosed with ePP, recurred two times as ePSCC and died due to gastric colic
Discussion
Around 10% of all neoplasms in the horse affect the external genitalia and ePSCC is the most common with a reported incidence of 50-83% which greatly exceeds the incidence of this cancer in humans [22], [23], [24]. In both humans and horses, the disease produces severe discomfort, spreads to regional lymph nodes leading to distant metastases and death. In humans, its low incidence and the lack of a reliable inducible animal model has limited significant breakthroughs regarding pathogenesis and
Conclusions
In summary, our study is the first to recognize the histological and immunophenotypical similarities between ePSCC and hPSCC. Additionally, we have demonstrated that when the IF exhibits features of a poorly differentiated PSCC, EMT is a usual event. In light of these findings and in the era of the ‘one-pathology’ concept, we suggest that further research comparing equine and human PSCC could represent an outstanding opportunity to develop a preclinical animal model from which both species
Conflicts of interest
No conflicts of interest to declare.
Acknowledgments
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The main author (ASB) is supported by a Senior Clinical Training Scholarship (Residency) funded by the Horserace Betting Levy Board (HBLB) at the Royal Veterinary Collage.
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