Chapter Introduction 1.1 Bladder cancer 1.1.1 Epidemiology of bladder cancer Overview Bladder cancer is the most common cancer of the urinary tract According to WHO statistics for 2000, bladder cancer is the seventh most commonly occurring cancer amongst men in the world In the US, it is the fourth most common cancer in men, after prostate, lung, and colorectal cancer and accounts for 6% of all malignancies In women, however, it is the 10th most common cancer The American Cancer Society estimates that in 2004 there will be about 60,240 new cases of bladder cancer (about 44,640 men and 15,600 women) and 12,710 deaths (about 8,780 men and 3,930 women) from bladder cancer in the United States (American Cancer Society 2004) In Singapore, bladder cancer is the ninth most common cancer amongst men (Chia et al., 1999) Geographic, racial and gender variation The highest incidence rates for bladder cancer are found in industrialized countries such as the United States, Canada, France, Denmark, Italy, and Spain Rates are lower in England, Scotland, and Eastern Europe The lowest rates are in Asia and South America, where the incidence is only about 30% as high as in the United States (Parkin et al., 1997) In the US, the highest rates are in white non-Hispanics (33.1 per 100,000) among men The rates for black men and Hispanic men are similar and are about one-half the white non-Hispanic rate The lowest rates are in the Asian populations (Miller et al., 1996) In all countries the incidence rates of bladder cancer are generally three to four times higher in men than in women According to a National Cancer Institute study, the incidence rates were 37.39 and 9.53 cases per 100,000 populations for men and women respectively during 1996-2000 in the US (National Cancer Institute, 2002) The lifetime risks of being diagnosed with bladder cancer were 3.52% and 1.13% for men and women respectively (Ries et al., 2002) Age-specific patterns The incidence of bladder cancer increases dramatically with age among men and women in all populations Rates in those aged 70 years and older are approximately two to three times higher than those aged 55-69 years, and about 15 to 20 times higher than those aged 30-54 years (Miller et al., 1996) The average age of diagnosis for transitional cell carcinoma (TCC) of the bladder is 69 years for men and 71 years for women (Kishi et al., 1981) Risk factors As with most cancers, the exact causes of bladder cancer are not yet known However, many risk factors are associated with this disease Chief among them are smoking and industrial chemicals Cigarette smoking is widely accepted as a major risk factor for bladder cancer and probably accounts for 50% of bladder cancer cases diagnosed in the United States It is estimated that smokers’ risk of bladder cancer may be up to three times that of non-smokers (Augustine et al., 1988; Clavel et al., 1989；Carpenter, 1989) Exposure to a group of chemicals known as arylamines also may increase risk of bladder cancer, as workers in the rubber and leather industries (Negri et al., 1989; Dolin et al., 1992), truck drivers (Hoar et al., 1985), painters (Guberan et al., 1989), hairstylists (Hartge et al., 1982) and aluminum workers (Theriault et al., 1984) have been reported to have elevated rates of the disease Coffee, alcohol, and artificial sweeteners have all been studied as risk factors for bladder cancer, but associations, if they exist, are weak (Jensen et al., 1986; La Vecchia et al., 1989) Other factors strongly associated with bladder cancer development include chronic infection of Schistosoma haematobium (Cheever, 1978), use of analgesic drugs containing phenacetin (Piper et al., 1985), and exposure to the cancer chemotherapeutic agent cyclophosphamide (Levine et al., 1989) Characteristics of drinking water, including high arsenic content in water (Chiou et al., 1995) and high levels of chlorination by-products (Cantor et al., 1998), also have been investigated as bladder cancer risk factors Bladder cancer has also been associated with radiation therapy to the pelvis for ovarian (Kaldor et al., 1995), cervical (Kleinerman et al., 1995), and prostatic carcinomas (Neugut et al., 1997) The mechanism is likely related to the generation of free radicals by radiation that causes direct DNA mutation of important regulatory genes Moreover, a few case-control studies have shown that family history of bladder cancer is also a risk factor for the disease, although most genetic changes that are associated with bladder cancer develop during a person's lifetime, rather than being inherited before birth Some people, however, seem to inherit a reduced ability to break down certain chemicals, such as aromatic amines, which makes them more sensitive to the cancer-causing effects (Mommsen et al., 1986；Yu et al., 1994; Kiemeney et al., 1996) 1.1.2 Pathology, staging and grading of bladder cancer More than 90% of cancers arising in the bladder are transitional cell carcinomas (TCCs) Some TCCs show a mixed pattern with squamous features or a glandular component (Martin et al., 1989) Less common pathologies are adenocarcinoma, squamous cell carcinoma, and small-cell carcinoma, which comprise approximately 6, 2, and less than 1% of bladder tumors, respectively Tumor grading (typically grades I – III) is based on the number of mitotic cells, presence of nuclear abnormalities, and cellular atypia Recently in an effort to reach a universally acceptable system and to avoid the overdiagnosis of cancer, two new classification systems for grading of urothelial neoplasms have been published The WHO/International Society of Urological Pathology (ISUP) consensus classification of 1998 (Epstein et al., 1998) distinguishes papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade carcinoma (LGC) and high-grade carcinomas (HGC), whereas the WHO 1999 system subdivides the high grade into grades II and III (WHO, 1999), and is otherwise identical Tumor staging is important because it can distinguish between patients requiring different therapeutic approaches It is based on the degree to which the tumor has invaded into or through the bladder wall (Fig 1.1) and adjacent organs The most widely accepted staging system in the Tumor-Node-Metastases (TNM) System 2002 (Sobin and Witteking, 2002) (Table 1.1) adopted by Union Internationale Contre le Cancer (UICC) The use of the TNM system is encouraged, as it corresponds best with the clinical outcome of the tumors (Epstein et al., 1998) Fig 1.1 Staging of bladder cancer Tumors T1 and TA are considered superficial, with tumors T2 or greater being invasive Table 1.1 2002 TNM Classification of Bladder Cancer Primary Tumor • TX = Primary tumor cannot be assessed • TO = No evidence of primary tumor • TiS = Carcinoma in situ • Ta =Noninvasive papillary carcinoma • T1 = Tumor invades lamina propria • T2= Tumor invades muscle • T2a = Tumor invades superficial detrusor muscle (inner half) T2b = Tumor invades deep muscle (outer half) T3 = Tumor invades perivesical fat • T3a = Microscopic invasion perivesical tissue T3b = Macroscopic invasion perivesical tissue T4 = Tumor invades prostate, uterus, vagina, pelvic wall or abdominal wall T4a = Tumor invades prostate, uterus, vagina T4b = Tumor invades pelvic or abdominal wall Lymph Node (N) • NX = Regional lymph nodes cannot be assessed • N0 = No regional lymph node metastasis • N1 = Metastasis in a single lymph node, cm or less in greatest dimension • N2 = Metastasis in a single lymph node, more than cm but not more than 5cm in greatest dimension, or multiple lymph nodes, none more than cm in greatest dimension • N3 = Metastasis in a lymph node more than cm in greatest dimension Distant Metastasis (M) • MX = Presence of distant metastasis cannot be assessed • M0 = No distant metastasis • M1 = Distant metastasis 1.1.3 Genetic alterations in bladder cancer With the advances in molecular biology in the last decade, our understanding of the biology of carcinogenesis and fundamental alterations in bladder cancer cells that lead to the malignant phenotype has also increased significantly Cytogenetic analysis of bladder tumors has demonstrated changes in multiple chromosomes and chromosome segments These abnormalities mostly affect chromosomes 9, 11, 17,18,8, and (Smeets et al., 1987; Tsai et al., 1990; Brewster et al., 1994; Sandberg et al., 1994) These molecular events may lead to activation of proto-oncogenes or to the inactivation of tumor-suppressor genes Chromosome 9: p16, p15, and p14ARF Abnormalities in chromosome have been seen commonly in bladder cancer Actually, deletions on chromosome 9, leading to a loss of heterozygosity (LOH) constitute the major event in carcinogenesis of TCC and affect more than 60% of all bladder cancers whatever the stages and grades (Tsai et al., 1990; Cairns et al., 1994; Knowles et al., 1994) Cytogenetic and molecular evidence has shown that it is often the only chromosomal aberration in early disease These facts suggest that chromosome alteration is an early event in bladder tumor carcinogenesis and progression More detailed cytogenetic analysis and deletion mapping have confirmed that the deleted areas are located at chromosome region 9p21 Recent studies have identified p16, p15, and p14ARF genes in this region (Nobori et al., 1994; Cairns et al., 1994; Chin et al., 1998) P16 functions as an inhibitor of cyclin-dependent kinase and prevents the phosphorylation of retinoblastoma protein (Rb), thereby maintains an active Rb and blocks the exit from the G1 phase of the cell cycle Loss of function of p16, by permitting Rb phosphorylation, results in unregulated cell growth as the cell is able to escape into S phase (Fig 1.2) Homozygous deletions seem to be the common mechanism of inactivation of this genetic locus in bladder cancer (Orlow et al., 1995; Packenham et al., 1995; Balazs et al., 1997) Another potential mechanism by which p16 function is lost in bladder cancer is by gene silencing via methylation of the promoter region of p16 (Dominguez et al., 2003) PO4 CYCLIN D PO4 PO4 pRB CDK4/6 PO4 pRB PO4 PO4 + E2F E2F Transcription activation and cell cycle progression CYCLIN D pRB pRB E2F E2F p16 CDK4/6 Cell cycle arrest p16 Fig 1.2 Mechanism of action of p16 p16 binds to and inhibits the function of cdk4 and cdk6 In the absence of p16, these two kinases bind to cyclin D and phosphorylate a number of regulatory proteins, including pRB pRB no longer binds E2F in its phosphorylated form, and as a result this transcription factor can stimulate expression of genes critical for cell cycle progression 10 Mommsen S, Aagaard J Susceptibility in urinary bladder cancer: acetyltransferase phenotype and related risk factors Cancer Lett 1986; 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270:18997-9007 Zhou, JH, Rosser, CJ, Tanaka, M, Yang, M, Baranov, E, Hoffman, RM, Benedict, WF Visualizing superficial human bladder cancer cell growth in vivo by green fluorescent protein expression Cancer Gene Ther 2002; 9:681-6 Zou Y, Zong G, Ling YH, Hao MM, Lozano G, Hong WK, Perez-Soler R Effective treatment of early endobronchial cancer with regional administration of liposome-p53 complexes J Natl Cancer Inst 1998; 90:1130-7 180 ...1.1 Bladder cancer 1.1.1 Epidemiology of bladder cancer Overview Bladder cancer is the most common cancer of the urinary tract According to WHO statistics for 2000, bladder cancer is the... for bladder cancer and probably accounts for 50% of bladder cancer cases diagnosed in the United States It is estimated that smokers’ risk of bladder cancer may be up to three times that of non-smokers... promising approach in the case of bladder cancer, as bladder cancer is proven to respond well to immunotherapy The detailed potential use of this method in treating bladder cancer will be further discussed