Fig 6 - uploaded by Carlos Pinto
Content may be subject to copyright.
a^d. Transitional cell carcinoma of the urinary bladder. Di¡erent histological variants were identi¢ed, namely (a) micropapillary, (b) nested variant, and (c) microcystic. (d) Carcinoma in situ. Bovine bladder. HE. Bar, 150 mm (a, b, and c). Bar, 100 mm; inset bar, 20 mm (d).
Source publication
In cattle, bracken fern chronic toxicity is characterized by the presence of multiple tumours in the bladder (bovine enzootic haematuria). From October 1999 to March 2003, 433 urinary bladders with macroscopical lesions were collected in the slaughterhouse of São Miguel Island (Azores, Portugal), an endemic area where Pteridium aquilinum infestatio...
Similar publications
Inverted papilloma (IP) is an uncommon benign neoplasm of the urinary tract. Its multiplicity, recurrence, and association with transitional cell carcinoma (TCC) leads to conflicting clinical conclusions regarding its biological behavior, and hence, the need for rigorous follow-up protocols. In this study, we review all cases of urinary bladder IP...
Citations
... In some countries, there is a high prevalence of UBC in cattle associated with chronic ingestion of bracken fern (BF; Pteridium aquilinum (L.) Kuhn) [15], which contains several toxic components including the carcinogen ptaquiloside (PT) [16]. UC is the most common type of urinary bladder wall lesion in these cattle [17] and, thus, cattle that have consumed BF may represent an animal model of carcinogen-induced UC. Further relevance for this model comes from the fact that humans can be exposed to PT from spore inhalation, consumption of milk from BF-fed cattle [18,19], and the groundwater from regions where BF grows [20]. ...
... The carcinogenic effect of PT is based on its hydrolysis and the formation of a dienone intermediate (APT) that can produce DNA adducts (via alkylation), which are responsible for inducing carcinoma [51]). Cattle do not commonly develop UBC; however, those that have grazed on BF pastures can develop bovine enzootic hematuria due to chronic BF toxicity, which results in urinary bladder hemorrhages and the development of multiple lesions in the urinary bladder wall, most of which are UC (67%) [17]. DNA adducts have been detected in the ileum of calves that were fed BF [33], and in the upper gastrointestinal tissues of mice that were fed BF extract or spores [85], providing direct evidence for BF-induced carcinogenesis. ...
Background
In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC.
Results
Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside.
Conclusion
Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC.
... Several fern species can induce cancer due to the presence of ptaquiloside (Pt) (Niwa et al., 1983). Cattle grazing areas contaminated with these plants develop a condition known as Bovine Enzootic Hematuria (EBH), characterized by hematuria and generated by the presence of neoplastic and non-neoplastic lesions in the urinary bladder (Carvalho et al., 2006). In Argentina, Marin (2006) indicated that the disease had been linked to the consumption of Pteridium arachnoideum (Kaulf.) ...
... When the pH is alkaline Pt undergoes aromatization and deglycosylation forming pterosin B (Aranha et al.,2014), an unstable conjugated dienone with alkylating capacity on DNA molecules thus initiating carcinogenesis and the consequent formation of neoplasms (Rasmussen et al., 2008;Aranha et al., 2014). Thus, these changes affect tumor suppressor genes and proto-oncogenes that contribute to deregulating cell cycle control, apoptosis, and tissue differentiation (Bringuier et al., 1995) causing preneoplastic, benign neoplastic, and malignant neoplastic lesions (Carvalho et al.,2006). ...
... It is important to know about the toxicity of these fern species since some are associated with EBH. Moreover, in regions where EBH is endemic, it causes significant economic losses that are often underestimated (Marrero et al.,2001;Carvalho et al.,2006). A major aggravating factor is that surface or groundwater can be contaminated by Pt through a leaching process in regions with a high population density of Pteris, constituting a risk factor for urban or periurban populations (Alonso-Amelot and Avendaño 2002; Rasmussen et al., 2003). ...
The toxic effect of ferns of the genus of Pteris in bovines is caused by ptaquiloside, the main carcinogenic toxin. In this study, ten species of Pteris fern in different phenologic stages and plant conditions were collected in northwest Argentina. The phytochemical analysis showed the presence of Pt in the recent collected samples (adults and young plants) but not in the herbarium specimens. The results show a great variation of Pt concentration that depends on the phenologic stage, plant condition, and collection site. Pt was measured in 6-4326 μg/g concentration, with a mean concentration of 644 μg/g. No Pt was detected in eight species of Pteris collected from herbarium samples; such results may be a false negative. It is important to notice that analysis of herbarium samples for Pt may not be a reliable method to determine its presence. It is important to further understand the potential toxicity caused by these ferns because of their effect on animals, public health, and the environment.
... However, disease is very frequently seen in cattle and water buffaloes reared on pasturelands, where bracken fern (Pteridium spp.) grows abundantly. In these endemic areas, up to 90% of adult animals may be affected (Pamukcu, 1974;Pamukcu et al., 1976;Carvalho et al., 2006;Roperto et al., 2013). It is worth noting that the urinary bladder of these herbivores is a target for bracken genotoxins, such as ptaquiloside (PT) (Prakash et al., 1996). ...
Introduction:
Bladder tumors of cattle are very uncommon accounting from 0.1% to 0.01% of all bovine malignancies. Bladder tumors are common in cattle grazing on bracken fern-infested pasturelands. Bovine papillomaviruses have a crucial role in tumors of bovine urinary bladder.
Aim of the study:
To investigate the potential association of ovine papillomavirus (OaPV) infection with bladder carcinogenesis of cattle.
Methods:
Droplet digital PCR was used to detect and quantify the nucleic acids of OaPVs in bladder tumors of cattle that were collected at public and private slaughterhouses.
Results:
OaPV DNA and RNA were detected and quantified in 10 bladder tumors of cattle that were tested negative for bovine papillomaviruses. The most prevalent genotypes were OaPV1 and OaPV2. OaPV4 was rarely observed. Furthermore, we detected a significant overexpression and hyperphosphorylation of pRb and a significant overexpression and activation of the calpain-1 as well as a significant overexpression of E2F3 and of phosphorylated (activated) PDGFβR in neoplastic bladders in comparison with healthy bladders, which suggests that E2F3 and PDGFβR may play an important role in OaPV-mediated molecular pathways that lead to bladder carcinogenesis.
Conclusion:
In all tumors, OaPV RNA could explain the causality of the disease of the urinary bladder. Therefore, persistent infections by OaPVs could be involved in bladder carcinogenesis. Our data showed that there is a possible etiologic association of OaPVs with bladder tumors of cattle.
... In addition, histological variants of invasive urothelial carcinomas were classified according to the World Health Organization (WHO) Morphological Classification for human urothelial tumors (Lopez-Beltran et al. 2004, Cheng & Lopez-Beltran 2016, Humphrey et al. 2016) and the standards used for cattle with EH (França 2002, Peixoto et al. 2003, Roperto et al. 2010. Non-neoplastic lesions, when possible, were categorized according to the standards described by França (2002), Peixoto et al. (2003), Carvalho et al. (2006), Roperto et al. (2010), andMeuten (2017). Urothelial carcinomas were graded into four categories (grades 1 to 4), as proposed by Cheng et al. (2012) for humans, and adapted for domestic animals as low and high grades (Meuten 2017). ...
It is reported the occurrence of enzootic hematuria (EH) in buffaloes in Brazil after performing an epidemiological survey and clinicopathological analises. To date, EH caused by ingestion of Pteridium esculentum subsp. arachnoideum, a radiomimetic plant popularly known as “bracken fern”, has not been described in this species in Brazil. Bovine EH is responsible for high economic losses in Brazil’s Southeast Region not only because of the deaths it causes, but also owing to its negative effect on productivity. In São José do Barreiro County, São Paulo, some farmers in areas with a high incidence of bovine EH have been replacing cattle with buffaloes, based on the premise that the latter would be more resistant to poisoning by ingestion of Pteridium spp. However, even though initial observations indicated that buffaloes are indeed less sensitive than cattle to the toxic principle of Pteridium spp., cases of hematuria in this species have been reported. According to preliminary date, EH only occurs in buffaloes over six years of age. Macroscopic examination revealed a thickened urinary vesicle mucosa, along with multiple foci of ulcerated, exophytic, verrucous, and pedunculated lesions. In one of the buffaloes studied, the bladder wall was ruptured and exhibited marked secondary inflammation. Histologically, neoplastic and non-neoplastic changes similar to those described in cattle poisoned by Pteridium spp. were observed. The neoplasms found included papilloma, carcinoma in situ, urothelial carcinoma (low and high grade), inverted, microcystic, and trabecular variants, urothelial carcinoma with divergent differentiation (squamous and glandular), squamous cell carcinoma, lymphangioma, hemangioma, and hemangiosarcoma. There was also coexistence of epithelial and mesenchymal neoplasms. Bovine papillomavirus particles were not detected by polymerase chain reaction in the bladder samples analyzed.
... In cattle, the histological features of bladder tumours are quite different, with 51.2% of purely epithelial tumours, 17.4% of purely mesenchymal tumours and 31.4% of coexisting epithelial and mesenchymal tumours, and numerous benign tumours (papillomas, haemangiomas, etc.) [42]. Table 2. Classification of canine TCC subtypes based on growth pattern (adapted from Meuten and Meuten, 2016 [2]). ...
Cancer of the urinary bladder is a neoplasm with considerable importance in veterinary medicine, given its high incidence in several domestic animal species and its life-threatening character. Bladder cancer in companion animals shows a complex and still poorly understood biopathology, and this lack of knowledge has limited therapeutic progress over the years. Even so, important advances concerning the identification of tumour markers with clinical applications at the diagnosis, prognosis and therapeutic levels have recently been made, for example, the identification of pathological BRAF mutations. Those advances are now facilitating the introduction of targeted therapies. The present review will address such advances, focusing on small animal oncology and providing the reader with an update on this field. When appropriate, comparisons will be drawn with bladder cancer in human patients, as well as with experimental models of the disease.
... After prolonged ingestion of bracken, cattle and sheep can develop multiple mixed tumorous in the urinary bladder. Carvalho et al., (2006) divided bladder lesions into three main categories: inflammatory lesions, non-neoplastic epithelial abnormalities and tumorous and described in details. ...
Bracken (Pteridium aquilinum (L.) Kuhn) is cosmopolitan fern, found at varying altitudes on all continents except Antarctica. It is an aggressive colonizer and can appear in various plant communities, but an important characteristic is its ability to dominate in dense patches. Once establish, the deep-set rhizomes are nearly impossible to eradicate. In Croatia, bracken dominate on specific habitat type called “bujadnice” in Lika region, but can also be found in herbaceous layers in following forest communities: As. Betulo-Quercetum; As. Pteridio-Betuletum; As. Potentillo albae-Quercetum pubescentis; As. Castaneo sativae-Fagetum; As. Helleboro nigri-Piceetum. Bracken fern is significant problem for livestock-based extensive agriculture, because it causes a range of syndromes in farm animals including thiamine deficiency, acute hemorrhagic syndrome, bright blindness, enzootic hematuria and upper alimentary carcinoma. Man may consume the toxins of bracken either directly or indirectly. In terms of the economic loss and suffering caused by bracken, it is clearly that some steps must be taken to control distribution of this fern. Timing is important in any management treatment of bracken fern. The most effective time for bracken control is summer just after the new fronds have fully expanded and starch reserves in the rhizome are at their lowest level. Two or more annual treatments and combinations of cutting and herbicide are more effective than single treatments or even single annual treatments.
... Ingestion of bracken fern has been associated with enzootic hematuria of grazing cattle herds since the 1960s (111,112). Since then, the occurrence of bladder tumors in cattle grazing on bracken fern has been described by different teams in multiple continents (72,96,(113)(114)(115)(116). The morphology of bovine urinary bladder tumors is varied, includes multiple histological types of epithelial, mesenchymal and mixed lesions, and has been previously described in detail (114)(115)(116). ...
... Since then, the occurrence of bladder tumors in cattle grazing on bracken fern has been described by different teams in multiple continents (72,96,(113)(114)(115)(116). The morphology of bovine urinary bladder tumors is varied, includes multiple histological types of epithelial, mesenchymal and mixed lesions, and has been previously described in detail (114)(115)(116). The experimental administration of bracken fern to cows reproduced the urinary lesions in controlled conditions (117). ...
Bovine papillomavirus (BPV) are a cause for global concern due to their wide distribution and the wide range of benign and malignant diseases they are able to induce. Those lesions include cutaneous and upper digestive papillomas, multiple histological types of urinary bladder cancers—most often associated with BPV1 and BPV2—and squamous cell carcinomas of the upper digestive system, associated with BPV4. Clinical, epidemiological and experimental evidence shows that exposure to bracken fern (Pteridium spp.) and other related ferns plays an important role in allowing viral persistence and promoting the malignant transformation of early viral lesions. This carcinogenic potential has been attributed to bracken illudane glycoside compounds with immune suppressive and mutagenic properties, such as ptaquiloside. This review addresses the role of BPV in tumorigenesis and its interactions with bracken illudane glycosides. Current data indicates that inactivation of cytotoxic T lymphocytes and natural killer cells by bracken fern illudanes plays a significant role in allowing viral persistence and lesion progression, while BPV drives unchecked cell proliferation and allows the accumulation of genetic damage caused by chemical mutagens. Despite limited progress in controlling bracken infestation in pasturelands, bracken toxins remain a threat to animal health. The number of recognized BPV types has steadily increased over the years and now reaches 24 genotypes with different pathogenic properties. It remains essential to widen the available knowledge concerning BPV and its synergistic interactions with bracken chemical carcinogens, in order to achieve satisfactory control of the livestock losses they induce worldwide.
... Histopathological findings were consistent with inverted urothelial papilloma. 5,9,13,14,16 Formalin-fixed, paraffin-embedded tissue scroll of the samples was submitted for papillomavirus (PV) DNA amplification. Total DNA was extracted using the NucleoSpin DNA FFPE XS kit (Macherey Nagel), according to manufacturer's instructions. ...
... In veterinary pathology, inverted urothelial papilloma has only been described in cattle as a rare bladder neoplasm sharing histological features of urothelial papilloma, except for the endophytic pattern of growth of papillary projections. 5 In the case described here, cytological examination was not reliable for diagnosing IUP as it is possible that the cells observed on cytology were exfoliated from the normal urothelium covering the neoplasm; thus, histopathology was required to reach a definitive diagnosis. ...
... While the trabecular subtype arises from proliferation of the basal cell layers, the glandular subtype develops from cystitis cystica et glandularis, considered to be preneoplastic lesions in human pathology, with a high ratio of coexistence with bladder neoplasms. 5,6,10,15 Conclusively, although mitoses are usually rare to absent in IUPs in humans, 14,16 the neoplasm described here showed low mitotic activity. ...
A 12-year-old neutered female cat was referred with clinical signs referable to lower urinary tract disease. Clinical examination revealed a tense, painful urinary bladder, and proximal urethral thickening. Endoscopic studies showed a pedunculated mass with polypoid projections. Multiple full-thickness mucosal biopsies were obtained, and the mass was almost completely excised. The neoplasm was confined to the mucosa and consisted of epithelial cells arranged in anastomosing trabeculae and nests, growing downward into the lamina propria. Neoplastic cells showed minimal atypia and low mitotic activity. Histological findings were consistent with inverted urothelial papilloma. Feline papillomavirus DNA was not amplified from biopsies. One year later, the cat had no urological signs, and urinary bladder was normal at ultrasound. To the authors' knowledge, this is the first report of a case of inverted urothelial papilloma in a cat and is a differential diagnosis for low-grade urothelial carcinoma and other lesions with inverted growth pattern.
... Bovine δPVs play a central role in bovine and bubaline bladder carcinogenesis (6,7). Indeed urinary bladder tumors are common in adult cattle and water buffaloes reared fully or partially on hilly/mountain pasturelands rich in bracken fern (Pteridium spp.), as the urinary bladder of herbivores is the specific target for bracken genotoxins such as ptaquiloside (PT) (7)(8)(9)(10). Indeed PT is responsible for the alkylation of adenine of codon 61 of Hras gene, resulting in a glutamine 61 substitution that is essential for guanosine triphosphate (GTP) hydrolysis (11). ...
Blood samples from 260 unrelated cattle (132 animals affected by papillomavirus-associated bladder tumors and 128 healthy) were genotyped using the classic polymerase chain reaction/restriction fragment length polymorphism method to screen MHC class II bovine leukocyte antigen-DRB3. 2 polymorphism. The DRB3*22 allele was significantly (p ≤ 0.01) detected in healthy cattle, thus appearing to have a negative association (protective effect) with virus infection of the urinary bladder known to represent a bladder tumor risk for cattle living free at pasture. Considering the two sequence alleles identified in animals carrying DRB3*22, DRB3*011:01 allele from samples of animals harboring the unexpressed bovine papillomaviruses (BPV)-2 E5 gene was characterized by amino acid residues believed to have a protective effect against BPV infection such as arginine at position 71 (R⁷¹) in pocket 4, histidine at position 11 (H¹¹) in pocket 6, and both glutamine at position 9 (Q⁹) and serine at position 57 (S⁵⁷) in pocket 9 of the antigen-binding groove. The DRB3*011:02v allele from affected animals was characterized by amino acids believed to be susceptibility residues such as lysine (K⁷¹), tyrosine (Y¹¹), glutamic acid (E⁹), and aspartic acid (D⁵⁷) in these pockets. These results suggest that animals harboring the DRB3*011:01 allele may have a lower risk of BPV infection and, consequently, a reduced risk of bladder tumors.
... Besides the acute form, enzootic hematuria and upper alimentary tract carcinomas can result from long-term consumption of different ferns, such as the above-mentioned Pteridium spp. (D€ obereiner et al., 1967;Tokarnia et al., 1969;Carvalho et al., 2006;Souto et al., 2006;Lucena et al., 2011), Cheilanthes sieberi (McKenzie, 1978;Smith et al., 1989), Onychium contiguum (Dawra et al., 2001), Pteris deflexa and Pteris plumula (Micheloud et al., 2017). The active principle responsible for both acute and chronic Pteridium spp. ...
An outbreak of acute febrile syndrome associated with coagulopathy and severe pancytopenia occurred in cattle grazing in paddocks with high infestation by Adiantopsis chlorophylla. The administration of the plant to a calf reproduced the same signs and lesions seen in spontaneous cases. Similar syndromes are caused by ptaquiloside from bracken fern. Traces of the ptaquiloside-like molecule caudatoside were detected together with 0.03–0.24 mg/g of it's degradation product pterosin A, in dry fronds of the plant. In conclusion, A. chlorophylla is a cause of hemorrhagic diathesis in cattle.
