Comparative Pathobiology of Canine and Human Prostate Cancer: State of the Art and Future Directions

Abstract

First described in 1817, prostate cancer is considered a complex neoplastic entity, and one of the main causes of death in men in the western world. In dogs, prostatic carcinoma (PC) exhibits undifferentiated morphology with different phenotypes, is hormonally independent of aggressive character, and has high rates of metastasis to different organs. Although in humans, the risk factors for tumor development are known, in dogs, this scenario is still unclear, especially regarding castration. Therefore, with the advent of molecular biology, studies were and are carried out with the aim of identifying the main molecular mechanisms and signaling pathways involved in the carcinogenesis and progression of canine PC, aiming to identify potential biomarkers for diagnosis, prognosis, and targeted treatment. However, there are extensive gaps to be filled, especially when considering the dog as experimental model for the study of this neoplasm in humans. Thus, due to the complexity of the subject, the objective of this review is to present the main pathobiological aspects of canine PC from a comparative point of view to the same neoplasm in the human species, addressing the historical context and current understanding in the scientific field.

Keywords: Immunobiology; molecular biology; oncogenes; prostate carcinoma; tumor suppression.

Figure 1

Proliferative inflammatory atrophy in canine prostate, characterized by discrete proliferation of prostatic epithelium associated with mononuclear inflammatory infiltrate in the glandular interstitium. HE, 40×.

Figure 2

Histological patterns of canine PC. (A) Normal prostate. HE, 200×. (B) Solid/undifferentiated, showing pleomorphic cells with no specific growth pattern. HE, 200×. (C) Papillary, represented by neoplastic ductal epithelial cells exhibiting tubulopapillary projections. HE, 200×. (D) Small acinar streaky by dense fibrovascular stroma. HE, 50 µm. (E) Cribriform, characterized by neoplastic ductal cells forming irregular fenestrae with a central area of necrosis. HE, 50 µm. (F) Signet ring cells characterized by intracytoplasmic vacuolization with nuclear displacement to the periphery. HE, 200×.

Figure 3

Cellular origin and tumor initiation of the canine PC. The normal prostate of the dog has prominent acini with a smaller stromal component and a discontinuous basal cell layer (DLBC). Thus, canine PC can originate from luminal epithelium layer (LEL), with immunoexpression for low molecular weight cytokeratins (CK8/18) and AR; or originate from basal cells, with immunostaining for high molecular weight cytokeratins (CK5 and CK7), which is more frequent in tumors with a lower degree of cell differentiation, which may also have a continuous basement membrane. In addition to the basal and luminal cells of the prostatic acini, the canine PC may originate from urothelial cells present in the prostatic ducts that empty into the urethral canal, which express CK7 and UPIII. BML: Basement membrane layer.

Figure 4

Loss of cell adhesion and epithelial-mesenchymal transition of canine PC. Canine prostate tumor cells overexpress β-catenin, which is accumulated in the cell nucleus, binding to transcription factors to activate gene expression. Concomitantly, there is suppression of E-cadherin, resulting in important structural changes, such as loss of adhesion of neoplastic cells. Following this process, especially in tumors with a lower degree of cell differentiation, tumor cells undergo immunophenotypic changes, expressing mesenchymal markers (vimentin and snail). Such mechanisms significantly influence the process of invasion, migration and metastasis of neoplastic cells.