1. Introduction
Bladder cancer is one of the most common urinary neoplasms in industrialized countries, with more than 50,000 new cases diagnosed annually in Europe and North America [1,2]. In most countries of the Western world, transitional cell carcinomas (TCCs) account for 90% of the malignancies of this organ, while 5% are identified as squamous cell carcinomas and 2% as adenocarcinomas [3]. Approximately 80% of TCCs are low-grade tumors that are papillary, non-invasive and usually superficial, with stages Ta and Tis; the remaining 20% are high-grade papillary or non-papillary tumors that are often invasive or metastatic, with stages T1–T4. The five-year survival rate for TCC patients is 50%. The involvement of the bladder muscular wall signifies a worse prognosis and requires aggressive medical intervention such as radical cystectomy [4,5].
Occupational exposures in the textile and tire industries were the first factors implicated in the induction of bladder cancer. Currently, the prolonged use of phenacetin analgesics, exposure to cyclophosphamide, and smoking are the main risk factors associated with the etiology of transitional cell carcinoma [6]. Although men are 3-4 times more likely to develop bladder cancer, women present more often with advanced disease and have a lower probability of survival [7]. According to Shariat et al.[8], age is also considered a risk factor for urothelial carcinoma because the incidence of this cancer increases progressively with age; the incidence is higher after 60 years and peaks at 70 years, when the risk is 2% to 4% in men and 0.5% to 1% in women [9].
Clinically, the main problem associated with urothelial tumors is their highly unpredictable potential to progress to muscle-invasive disease, become multifocal and recur [5,10]. The recurrences might be
Two hypotheses have been proposed to explain the association between urothelial carcinogenesis, multifocality and recurrence. The first hypothesis suggests a monoclonal origin of the lesions. In other words, multifocal or recurrent tumors originate from a single transformed cell that proliferates and colonizes other parts of the bladder through intraepithelial migration or transportation by urine. The second hypothesis proposes a polyclonal origin, suggesting that urine carcinogens that are in contact with multiple sites lead to the development of independent multifocal tumors [14,15]. The understanding of the clonality of multifocal bladder tumors is important to establish therapeutic strategies because new therapies often target specific molecules in these tumors [10].
2. DNA mutation and bladder carcinogenesis
Tumors are made up of billions of cells that originate from an initial cell that eluded apoptosis, accumulated genetic alterations and multiplied clonally [16]. It is expected that both external and internal factors contribute to these genetic mutations. External factors include lifestyle, such as excessive alcohol consumption, an unhealthy diet, exposure to excessive sunlight and chemical carcinogens, lack of exercise and smoking [17]. Internal factors include gene mutations, changes in the hormonal and immune systems, and metabolic abnormalities. During cell division, spontaneous genetic errors occur at an estimated frequency of approximately 10−5 to 10−6 [18]. Therefore, the blockade of apoptosis can favor the accumulation of mutated cells, a critical event in cancer pathogenesis [19].
Carcinogenesis is a multistep process that involves initiation, promotion and progression. Initiation is characterized by the formation of a preneoplastic cell resulting from an irreversible genotoxic event (gene mutation) caused by chemical, physical or biological carcinogens. This mutation usually occurs in genes that control the cell cycle, cell differentiation, apoptosis and DNA repair, leading to the survival of cells with genetic alterations [20]. The promotion stage involves the selective clonal expansion of the initiated cell through an increase in cell growth or a decrease in apoptosis, leading to an accumulation of mutations and an increase in the level of genetic instability (genetic and epigenetic changes) [20]. The third step, progression, involves genetic events such as changes in ploidy and chromosome integrity and results in a change from the preneoplastic state to the neoplastic state, producing cells with a high degree of anaplasia, an imbalance between cell proliferation and apoptosis and self-sufficiency (e.g., growth and multiplication independent of stimuli - Figure 1) [20,21].
Urinary bladder carcinogenesis also occurs through multiple stages that are characterized by genetic changes that reflect the malignant transformation of an initiated normal cell [22]. These changes can occur in oncogenes/protooncogenes, tumor suppressor gene, regions of microsatellites, and cell cycle regulatory genes [23], which can trigger a framework of genetic instability characterized by a significant increase in the mutation rate (an early event in carcinogenesis). Genetic instability can be divided into two types: the first type comprises the insertions/deletions (basic single nucleotide changes) that result in read errors and are often observed in microsatellite regions (microsatellite instability), and the second type comprises the loss or gain of whole chromosomes or chromosome fragments (chromosomal changes), resulting in the loss or amplification of regions of DNA that contain genes crucial for neoplastic development [24].
Several studies have shown that many genetic and molecular alterations are involved in the initiation and progression stages of TCC, although the mechanisms responsible for the malignant phenotype are not completely understood. It is known that the accumulation of genetic changes, and not just a single mutation, determines the clinical behavior of TCC [25]. In fact, several studies have demonstrated the existence of numerous chromosomal changes in neoplastic and non-neoplasic urothelial cells from patients with a history of bladder cancer. The most frequent changes are polysomy of chromosomes 3, 7 and 17 and monosomy of chromosome 9 [26-30]. Furthermore, some authors have observed that 100% of patients with chromosome 17 loss exhibit recurrence [31]. Genetic analyses have also shown that the oncogenes
The
In normal cells, the p53 level is regulated by the interaction of the proteins mdm2, cop1, jnk and pirh2, which promote p53 degradation (ubiquitin/proteasome pathway) (Figure 2). After exposure to genotoxic or non-genotoxic stressors, the level of p53 is increased because the interaction with mdm2 and other regulators is inhibited. Then, several modulators (kinases, acetylases, etc) activate p53 transcriptional activity. The final result of p53 activation is either cell cycle arrest and DNA repair or apoptosis (Figure 3) [45].
Smoking is usually associated with the development of persistent clones of DNA-damaged cells in the urothelium and may partially explain the continuous occurrence of genetically aberrant cells in the mucosa. It is important to note that increased DNA damage has been detected in the transitional cells of smokers and ex-smokers who are free of neoplasia and have normal urinary bladder cell cytology [46]. Cytogenetic analyses have shown that bladder tumor recurrence is associated with high levels of DNA damage, which are still present in the normal-appearing urothelium of patients surgically treated for TCC [12]. Data suggest that part of this damage might occur through both clastogenic and aneugenic events, as detected by the micronucleus test (Figure 4) in TCC patients (J.P. Castro Marcondes personal communication, July 18, 2012). The increased level of DNA damage in cytologically “normal” cells from patients with a history of TCC has been shown to be related to the tumor histological grade, regardless of the length of time or clinical course since resection, suggesting these cells may be new TCC precursors or subclones of a previous TCC. Based on these data, it has been suggested that the primary tumor represents only the most obvious component of the disease, and several foci of secondary “reseeded” or “relocated” anomalous urothelium exist or may appear when the primary neoplasm is diagnosed [12]. Therefore, the genetic follow-up of patients after surgery must be a routine because elevated levels of DNA damage could predict recurrence.
Cystoscopy and cytology are considered standard procedures for monitoring patients with a history of TCC and individuals with bladder cancer symptoms (hematuria, pollakiuria and dysuria). However, these exams have a very limited ability to detect microscopic lesions and are subjective because they depend on the cytopathologist’s experience; therefore, these tests have very low sensitivity for low-grade lesions [47]. It has been shown that only 61% of patients with biopsies positive for TCC had a similar diagnosis based on the cytological analysis [48]. On the other hand, some authors have reported 100% agreement between biopsies and cytogenetic analysis results using probes for the centromeres of chromosomes 3, 7 and 17 and the 9p21 locus. Thus, the use of techniques that increase the sensitivity and specificity of early TCC detection, both in patients undergoing bladder tumor resection and in patients considered at risk for TCC, must be taken into consideration. In this context, biomarkers linked to the behavior of a particular biological entity (e.g., chromosome damage) might be used to assess cancer risk in different tissues.
3. Bladder cancer and chemotherapy
It is import to know the disease stage to effectively plan the treatment for bladder cancer. Different types of treatments are available, including surgery, biologic therapy, radiotherapy, and chemotherapy. TCC has been efficiently treated with radiotherapy and combinations of different antineoplastic compounds. Intravesical Bacillus Calmette Guérin (BCG) instillations have shown success as adjuvant treatment for patients with intermediate and high risk non-muscle-invasive bladder tumor [50]. BCG induces a massive influx of cytokines and inflammatory cells into the bladder wall and lumen [51]. Moreover, BCG therapy has been demonstrated to reduce the recurrence rate and the risk of progression to muscle invasive disease in patients with carcinoma in situ and superficial bladder tumors [52].
Combined chemotherapy protocols have been extensively studied with the goal of improving bladder cancer treatment and the overall survival rate [53]. The standard protocol includes the drugs methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) [54], but gemcitabine has also been successfully introduced [55]. The primary effect induced by these drugs is DNA damage with consequent cell cycle arrest and apoptosis. However, tumor cells have different levels of sensitivity to therapeutic agents, which may affect treatment success. Moreover, the genetic background of each tumor/patient must be taken into account to ensure treatment efficacy. In the context of developing chemotherapy protocols, the characterization of genes associated with a tumor’s sensitivity to antitumor agents plays a critical role in the selection of the optimal treatment [56].
In 2000, Von der Maase et al. [54] demonstrated that the gemcitabine/cisplatin regimen had an efficacy similar to that of the MVAC protocol but with superior safety and tolerability, thus providing a potential standard alternative to treat bladder cancer. Gemcitabine is a deoxycytidine analog, which is phosphorylated to yield an active dFdCTP metabolite (gemcitabine triphosphate) that is incorporated into DNA, causing DNA strand breaks and thereby eliciting a DNA damage response characterized by cell cycle arrest in the G1/S phase and replication blockage [57,58]. Gemcitabine can also be incorporated into RNA to inhibit RNA synthesis [59]. Because of its low molecular weight of 299 Da, (lower than the molecular weights of drugs commonly used in intravesical chemotherapy; e.g., mitomycin C and doxorubicin), gemcitabine is able to penetrate the bladder mucosa, which has beneficial effects on the treatment of invasive bladder cancers [60]. Cisplatin is one of the most potent antitumor agents, with the ability to induce DNA crosslinking and apoptosis [61,62]. A molecule of cisplatin consists of a central atom of platinum surrounded by two chlorine atoms and two ammonia groups. Cisplatin is activated by the reaction of water molecules with the chloride ions. This activated compound than reacts with DNA, RNA, proteins and phospholipid membranes [63]. Similar to other platinum compounds, cisplatin forms DNA adducts between adjacent guanines (65%) and between guanine and adenine (25%) and forms interstrand crosslinks (10%) that interfere with DNA replication and repair, contributing to its antitumor efficacy [64,65].
The
The
On the other hand, there are few data in the literature regarding the relationship between this biomarker and the response to gemcitabine or cisplatin [77-80]. With regard to cell cycle kinetics, gemcitabine or combined treatment with gemcitabine plus cisplatin induces G1 cell cycle arrest in TCC cell lines
In conclusion, while there is evidence implicating the role of
4. Actual scenario
Most cellular components exert their functions by interacting with other components located within the same cell, in different cells, or even in different organs. In humans, the complexity of the interaction networks (the human interactome) is impressive: there are approximately 25,000 protein-coding genes, approximately 1,000 metabolites and an indefinite number of distinct proteins and functional RNA molecules. Therefore, the number of cellular components capable of being regulatory interactome centers exceeds 100000 [95]. Moreover, the intra- and inter-cellular connectivity implies that the impact of genetic abnormality is not restricted to the activity of the gene product but can have effects on other genes and their products that might have no defect. Several authors have suggested that the disease phenotype is rarely a consequence of abnormalities in a single gene product but reflects various patho-biological processes that interact in a complex network [96]. Therefore, the effects of cell interconnection on disease progression can lead to the identification of genes and systems that offer better targets for drug development. Moreover, the potential use of microRNA in the future therapeutic interventions has also been discussed. For example, the effects of miR-100 on cell growth and clonogenic capacity in TCC cell lines emphasize a possible link between this miRNA and bladder carcinoma pathogenesis [97]. These new concepts may identify more accurate biomarkers for monitoring the functional integrity of networks and classifying diseases [96].
Changes in gene expression profiles may be immediate and more sensitive markers of drug toxicity than markers that are typically analyzed in toxicity tests (morphological changes, carcinogenicity and reproductive markers) [98]. Furthermore, some authors have shown that the implementation of proteomic platforms for the identification of novel targets of interest (membrane antigens, protein overexpression, etc.) is gaining widespread attention. The incorporation of biomarkers in clinical proteomics studies has also become important to define biologically effective therapeutic protocols for each patient and type of disease [99]. Thus, studies comparing gene and protein expression can confirm and emphasize the importance of using different technologies to understand and characterize complex biological systems.
5. Final conclusion
In this chapter, we presented data that demonstrate that high levels of DNA damage in normal-appearing urothelium are associated with tumor recurrence in patients treated for bladder TCC. Furthermore, the identification of genes associated with the sensitivity of tumors to chemotherapeutic drugs may play an important role in selecting the most efficient treatment protocol. Therefore, biomarker identification is relevant not only for diagnostic accuracy and prognosis but also for cancer therapy.
Currently, the ability of genomics and proteomics techniques to identify biomarkers and increase our understanding of complex cellular networks has been demonstrated. Thus, high-throughput methodologies help characterize diseases and increase our understanding of tumor progression mechanisms and the chemotherapy results. It is known that the primary effects of antineoplastic drugs are linked to DNA damage, leading to molecular events that may result in cell cycle arrest and apoptosis, which are essential responses for the maintenance of genetic integrity and cell viability [100]. Furthermore, it is known that early detection and treatment result in better survival rates for patients without clinical symptoms during the early stages of carcinogenesis [101].
Abbreviations
BCG – Baccillus Calmette Guérin
TCC – Transitional cell carcinoma
MVAC - Methotrexate, Vinblastine, Doxorubicin and Cisplatin
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