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Recently, several candidate molecular biomarkers have humans. The carcinogens can be delivered systemically,
been discovered and could be used to subdivide urinary by gavage or in the drinking water, or locally, by injection
bladder tumors in clinically relevant subsets, aiding the or via instillation. The tumor subtype and the time needed
prognosis, and treatment selection for patients. Further for tumorigenesis depend on the carcinogen used, animal
[3]
analytical and clinical validation is required to integrate species and strains and the treatment regimen. Because
these markers into the clinical practice. these models use immunocompetent animals and are highly
reproducible, they can be used to study the mechanisms
Several risk factors and genetic pathways have been involved in pathogenesis of bladder cancer and are suitable
implicated in the development of UBC. Low grade, non- for studies on interactions between host immune system
invasive tumors are associated with fibroblast growth factor and the tumor. In addition, several rodent bladder cancer
receptor 3 (FGFR3) and Harvey rat sarcoma viral oncogene cell lines derived from carcinogen-induced bladder tumors
homolog (HRAS) overexpression and/or mutations whereas were established and made available for in vitro and in vivo
carcinoma in situ (CIS) and high-grade/invasive UBC are studies. These include rat bladder tumor cell lines such as
associated with tumor protein p53 (TP53), retinoblastoma Nara bladder tumor II and AY-27 derived from BBN-induced
1 (RB1), and phosphatase and tensin homolog (PTEN) bladder tumors in Wistar rats, and Fischer 344 rats exposed
mutations and/or loss. Chemical and environmental to FANFT, respectively. The murine bladder tumor-2 murine
[4]
exposure including aromatic amides, aniline dyes, nitrites bladder cancer cell line, derived from an FANFT-induced
and nitrates, and tobacco smoking as well as frequent bladder tumor in C3H mice, has also been widely used. [8-10]
cystitis and Schistosoma haematobium infections are also Rodents are exceptionally suited for these types of studies
associated with UBC etiology. [5] because rats and mice do not develop spontaneous urinary
bladder tumors under normal conditions. The occurrence
[11]
Malignant UBC consists of heterogeneous mass of of non-neoplastic urothelial lesions, such as inflammation
interconnected cells containing tumor cells in different and hyperplasia, is also uncommon in these species. [12]
phases of the cell cycle, cancer stem cells subpopulations,
supporting stromal cells and vasculature. Several tumor In our studies, C3H/He mice were exposed to BBN, a
models have been used in basic science studies and complete genotoxic carcinogen metabolically derived
clinical trials to increase our understanding of molecular from a compound found in tobacco smoke. Exposure to
mechanisms underlying tumor initiation, progression, BBN in the drinking water induced the development
metastasis and chemoresistance; yet none of these models of hyperplasia, dysplasia, low and high-grade papillary
can adequately mimic the clonal origin, histopathology, UBC, CIS, and MIBC in the urothelium of exposed
progression, and clinical behavior of human tumors. rodents. The grade of cell atypia and extent of tumor
[13]
Therefore, a combinatorial approach based on multiple invasion increased with increasing doses of carcinogen
model systems studying specific aspects of this highly and extended period of exposure. Similar exposure
[12]
complex disease is required. Several models have
been used in the study of UBC, ranging from cell lines to BBN resulted in papillary tumors in Fischer 344
[13]
(including cancer cell lines from human or non-human rats. The broad spectrum of lesions mimics the major
origin, immortalized and transformed cells, and grown pathogenic mechanisms found in human urinary bladder
in monolayer or three-dimensional systems) to animal carcinogenesis: pre-neoplastic lesions occur before in situ
models (including carcinogen-induced tumor models, and muscle-invasive tumors, following different genetic
xenografts, and genetically engineered mice). Here, we pathways. These lesions are characterized by 3 different
discuss the translational potential and applications of these variables with recognized relationship to the natural
models with particular emphasis on chemically induced history of UBC and patient outcome as DNA content,
UBC models, patient-derived xenografts (PDXs) models, p53 alterations, and proliferative index measured by
and human bladder cancer cell lines. Ki-67 protein expression. DNA ploidy was evaluated by
calculating the 5c exceeding rate, defined as the percentage
CHEMICALLY INDUCED UBC of cells with values above 5 n. Alterations in these
markers were detected even in non-malignant histological
Chemically induced bladder cancer models induced lesions but were more frequent in urothelial tumors with
by organo-specific bladder carcinogens were initially higher malignant and aggressive potential namely CIS,
explored in the 1960s and were of the first models high-grade papillary and muscle-invasive tumors as shown
used to evaluate chemotherapy for UBC. [6,7] In these in Figure 1. This abnormal biological profile represents a
[13]
models, carcinogenesis of the urothelium occurs after high level of genetic instability underlying the urothelium
repeated exposure to carcinogens such as N-butyl-N- carcinogenesis process. This phenomenon is well known
(4-hydroxybutyl) nitrosamine (BBN), N-[4-(5-nitro-2- in human UBC, especially when CIS is present. The CIS
furyl)-2-thiazolyl]-formamide (FANFT), and N-methyl- surrounding normal-appearing urothelium shows a high
N-nitrosourea mimicking the environmental exposure frequency of abnormal DNA content, p53 mutated protein
known to be the leading cause of bladder cancer in expression, and a high proliferative status. [11,14]

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 2 ¦ February 29, 2016 ¦