Search

A 15‐year‐old spayed female Sumatran tiger (Panthera tigris sondaica) was presented with a short history of haematuria and dysuria, non‐responsive to antibiotics, and a gradual decline to inappetence over a period of 2–3 months. Ultrasound examination showed a thickened urinary bladder wall and the renal pelvis of right kidney was dilated and cystic. A presumptive diagnosis of renal failure was made, and the tigress was euthanised due to deteriorating quality of life and pronounced weight loss. Histopathology revealed extensive erosion of the urinary bladder wall and marked congestion of the submucosal vasculature, a potential cause of the haematuria observed clinically. Numerous foci of neoplastic cells were also observed throughout the lung parenchyma as well as within lymphatic vessels of the lung, the liver and the kidney. A diagnosis of a metastatic non‐papillary high‐grade urothelial carcinoma (UC) of the urinary bladder was made. Consistent with this diagnosis, immunohistochemistry revealed the neoplastic cells were negative for uroplakin III, as has been reported for a subset of high‐grade, infiltrative urinary bladder UCs of canines and humans. This is the first report of a primary tumour of the urinary bladder in a tiger and the first report of UC in a tiger. [ABSTRACT FROM AUTHOR]

Primary cutaneous and mucosal melanoma shows a wide histological spectrum. The correct diagnosis depends upon the demonstration of melanocytic differentiation by recognition of an associated in‐situ component or immunohistochemical evidence of a melanocytic phenotype using conventional melanocytic markers, such as S‐100, SOX10, Melan‐A and HMB‐45. Exceptionally, melanomas lose their melanocytic phenotype, at least focally, and show differentiation towards other lineages. Review of the literature shows that de‐ and trans‐differentiation in melanoma is rare but probably under‐recognised and under‐reported. These often large and frequently ulcerated tumours affect adults and show a wide anatomical distribution, including mucosal sites, although there is a predilection for sun‐damaged skin of the head and neck. Histologically, the tumours are biphasic and contain a pre‐existing conventional melanoma. The de‐differentiated component closely resembles atypical fibroxanthoma, both morphologically and immunohistochemically. Trans‐differentiated melanoma may show rhabdomyosarcomatous or spindle cell carcinomatous features. Undifferentiated melanomas are similar tumours in which the conventional melanoma component is absent. Their diagnosis depends entirely upon the clinical context and identification of a classical melanoma driver gene mutation, i.e. BRAF V600E. The diagnosis of these rare and unusual tumours is challenging, and requires thorough tumour sampling and recognition of the background of a pre‐existing but often focal conventional melanoma together with molecular analysis. [ABSTRACT FROM AUTHOR]

In contrast to other cancer types, melanoma incidence has been increasing over the last 50 years, and while it still represents less than 5% of all cutaneous malignancies, melanoma accounts for the majority of skin cancer deaths, due to its propensity to metastasise. Whilst melanoma most commonly affects the skin, it can also arise in mucosal surfaces, the eye, and the brain. For new therapies to be developed, a better understanding of the genetic landscape, signalling pathways, and tumour–microenvironmental interactions is needed. This is where animal models are of critical importance. The mouse is the foremost used model of human melanoma. Arguably this is due to its plethora of benefits as a laboratory animal; however, it is important to note that unlike humans, melanocytes are not present at the dermal–epidermal junction in mice and mice do not develop melanoma without genetic manipulation. In contrast, there are numerous reports of animals that spontaneously develop melanoma, ranging from sharks and parrots to hippos and monkeys. In addition, several domesticated and laboratory‐bred animals spontaneously develop melanoma or UV‐induced melanoma, specifically, fish, opossums, pigs, horses, cats, and dogs. In this review, we look at spontaneously occurring animal 'models' of melanoma and discuss their relevance to the different types of melanoma found in humans. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.. [ABSTRACT FROM AUTHOR]

Metastasis is the leading cause of death in cancer patients, and successful colonisation of a secondary organ by circulating tumour cells (CTCs) is the rate‐limiting step of this process. We used tail‐vein injection of B16‐F10 melanoma cells into mice to mimic the presence of CTCs and to allow for the assessment of host (microenvironmental) factors that regulate pulmonary metastatic colonisation. We found that mice deficient for the individual subunits of the NADPH oxidase of myeloid cells, NOX2 (encoded by Cyba, Cybb, Ncf1, Ncf2, and Ncf4), all showed decreased pulmonary metastatic colonisation. To understand the role of NOX2 in controlling tumour cell survival in the pulmonary microenvironment, we focused on Cyba‐deficient (Cybatm1a) mice, which showed the most significant decrease in metastatic colonisation. Interestingly, histological assessment of pulmonary metastatic colonisation was not possible in Cybatm1a mice, owing to the presence of large granulomas composed of galectin‐3 (Mac‐2)‐positive macrophages and eosinophilic deposits; granulomas of variable penetrance and severity were also found in Cybatm1a mice that were not injected with melanoma cells, and these contributed to their decreased survival. The decreased pulmonary metastatic colonisation of Cybatm1a mice was not due to any overt defects in vascular permeability, and bone marrow chimaeras confirmed a role for the haematological system in the reduced metastatic colonisation phenotype. Examination of the lymphocyte populations, which are known key regulators of metastatic colonisation, revealed an enhanced proportion of activated T and natural killer cells in the lungs of Cybatm1a mice, relative to controls. The reduced metastatic colonisation, presence of granulomas and altered immune cell populations observed in Cybatm1a lungs were mirrored in Ncf2‐deficient (Ncf2tm1a) mice. Thus, we show that NOX2 deficiency results in both granulomas and the accumulation of antitumoural immune cells in the lungs that probably mediate the decreased pulmonary metastatic colonisation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Metastasis is the leading cause of death in patients with advanced melanoma, yet the somatic alterations that aid tumour cell dissemination and colonisation are poorly understood. Here, we deploy comparative genomics to identify and validate clinically relevant drivers of melanoma metastasis. To do this, we identified a set of 976 genes whose expression level was associated with a poor outcome in patients from two large melanoma cohorts. Next, we characterised the genomes and transcriptomes of mouse melanoma cell lines defined as weakly metastatic, and their highly metastatic derivatives. By comparing expression data between species, we identified lunatic fringe (LFNG), among 28 genes whose expression level is predictive of poor prognosis and whose altered expression is associated with a prometastatic phenotype in mouse melanoma cells. CRISPR/Cas9‐mediated knockout of Lfng dramatically enhanced the capability of weakly metastatic melanoma cells to metastasise in vivo, a phenotype that could be rescued with the Lfng cDNA. Notably, genomic alterations disrupting LFNG are found exclusively in human metastatic melanomas sequenced as part of The Cancer Genome Atlas. Using comparative genomics, we show that LFNG expression plays a functional role in regulating melanoma metastasis. [ABSTRACT FROM AUTHOR]

The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 ( Acer1) in the skin. Acer1-deficient ( Acer1−/−) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1−/− mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1−/− skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1−/− mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Although transformation of melanocytes to melanoma is rare, the rapid growth, systemic spread, as well as the chemoresistance of melanoma present significant challenges for patient care. Here we review animal models of melanoma, including murine, canine, equine, and zebrafish models, and detail the immense contribution these models have made to our knowledge of human melanoma development, and to melanocyte biology. We also highlight the opportunities for cross-species comparative genomic studies of melanoma to identify the key molecular events that drive this complex disease. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

In this review we set out to celebrate the contribution that mouse models of human cancer have made to our understanding of the fundamental mechanisms driving tumourigenesis. We take the opportunity to look forward to how the mouse will be used to model cancer and the tools and technologies that will be applied, and indulge in looking back at the key advances the mouse has made possible. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Megaoesophagus, or oesophageal achalasia, is a neuromuscular disorder characterized by an absence of peristalsis and flaccid dilatation of the oesophagus, resulting in the retention of ingesta in the dilated segment. The aetiology and pathogenesis of idiopathic (or primary) megaoesophagus are still poorly understood and very little is known about the genetic causes of megaoesophagus in humans. Attempts to develop animal models of this condition have been largely unsuccessful and although the ICRC/HiCri strain of mice spontaneously develop megaoesophagus, the underlying genetic cause remains unknown. In this report, we show that aged Rassf1a-null mice have an enhanced susceptibility to megaoesophagus compared with wild-type littermates (∼20% vs. ∼2% incidence respectively; P = 0.01). Histological examination of the dilated oesophaguses shows a reduction in the numbers of nerve cells (both ganglia and nerve fibres) in the myenteric plexus of the dilated mid and lower oesophagus that was confirmed by S100 immunohistochemistry. There was also a chronic inflammatory infiltrate and subsequent fibrosis of the myenteric plexus and the muscle layers. These appearances closely mimic the gross and histopathological findings in human cases of megaoesophagus/achalasia, thus demonstrating that this is a representative mouse model of the disease. Thus, we have identified a genetic cause of the development of megaoesophagus/achalasia that could be screened for in patients, and may eventually facilitate the development of therapies that could prevent further progression of the disease once it is diagnosed at an early stage. [ABSTRACT FROM AUTHOR]