Molecular biology of transitional cell carcinoma
Introduction
An estimated 56,500 new cases of bladder carcinoma will be diagnosed in the USA in 2002, with 12,600 deaths attributable to this cancer [1]. Transitional cells are the origin of more than 90% of bladder carcinomas. About 75% of the neoplasms are superficial and papillary at first presentation. Although recurrences are frequent, only 10–15% of those will progress to a muscle invasive disease. In contrast, about 25% of bladder tumors are muscle invasive at initial presentation, and have a less favorable prognosis. Most muscle invasive tumors have no evidence of superficial precursor lesion, and are thought to develop via epithelial atypia and carcinoma in situ, representing an aggressive lesion with a high probability of progression (Fig. 1) [2], [3], [4]. The challenge is to identify that subset with the potential to evolve into muscle invasive, and subsequently metastatic disease. Currently, the most reliable prognostic factors for recurrence and progression are staging and grading [5], [6], [7]. The pattern of growth, papillary versus solid, is also important; with the papillary type being associated with better prognosis [7].
A better understanding of this pathology is expected from molecular genetics. The genetic events that characterize the transformation are just beginning to be understood, and a range of genetic changes had been noted in tumors, depending on the methodology used and the tumors selected for analysis. This review explores recent efforts to identify tumor markers that can potentially complement existing modalities and thus improve our understanding, diagnosis and management of bladder cancer.
Section snippets
Chromosomal abnormalities
Cytogenetic studies have identified many structural and numerical chromosomal changes in transitional cell tumors. Chromosomal aberrations could lead to fusion products or gene regulation changes (e.g. overexpression of certain genes) that have a direct impact on cellular proliferation, escape from cell-cycle arrest, or apoptosis. In the case of deletions, duplications, trisomies, and monosomies, a gene dosage effect can also be involved. According to the Knudson's hypothesis, genes whose
The cell cycle
During recent years many studies on factors controlling the cell cycle, cell proliferation, and apoptotic pathways have provided growing understanding of pathogenetic mechanisms leading to cancer. Such factors include, among many others, the p53 gene and the retinoblastoma (Rb) gene, which have been identified as tumor suppressor genes. P53 is found to play a role in the protection of the DNA integrity by preventing entry into the S-phase until DNA damage has been repaired and by directing
Telomerase activity
During normal cell division, telomere shortening leads to cell senescence and thus governs normal cell ‘mortality.’ Telomeres are maintained in normal stem cells by the enzyme telomerase. However, with abnormal expression of the enzyme in, for example, tumors, telomerase has been implicated in contributing to human cell immortalization and cancer cell pathogenesis. Telomerase is a ribonucleocomplex, and ectopic expression in tumors of its catalytic subunit, human telomerase reverse
Apoptosis
Unlike normal cells, tumors have acquired the ability to escape from programmed cell death (apoptosis), which usually occurs under adverse conditions such as DNA damage. In addition to p53 and bcl-2 (see detailed discussion above), other molecules of the complex apoptotic signaling pathways are abnormal in TCC. For example, Fas (CD95) and its ligand (FasL), which play key roles in the initiation of one apoptotic pathway, also have been implicated in TCC [89]. In this case, TCC expresses both
Angiogenesis
Angiogenesis is prerequisite to cancer growth and metastasis. It is regulated by the balance between various angiogenic and antiangiogenic factors released by cancer cells or nonmalignant cells that infiltrate the cancer [93], [94]. Increased micro-vascular (MVD) density has been shown to correlate with a higher incidence of metastasis and a worse prognosis in various cancers, including bladder carcinoma [95], [96]. Inoue et al. showed MVD, whether assessed in biopsy specimens or in residual
Invasion and metastasis
The expression of metastatic phenotype requires activation of additional effector genes or suppression of local inhibitors over and above those required for uncontrolled growth alone. Not all cells transformed by oncogene transfection aquire the ability to survive the multistep journey before distant metastases are established [107]. The initial events in cellular invasion are changes in cell adhesion. These changes consist of alteration in both cell–cell adhesion and interactions with the
Conclusion
Transitional cell carcinoma is a mixture of heterogeneous cell populations having different metastatic potentials. Despite the apparent de novo clinical presentation of invasive bladder tumors, cytogenetic and antigenic evidence supports the hypothesis that TCCs follow the general concept of multistep carcinogenesis and proceed through two distinct genetic pathways responsible for generating different TCC morphologies. These are the inactivation of cyclin-dependent kinase inhibitors in
Reviewers
Urs E. Studer, MD, Professor and Chairman, Department of Urology, University of Berne, Inselspital–Anna Seiler-Haus, CH-3010 Berne, Switzerland.
Cora N. Sternberg, MD, FACP, Chief, Department of Medical Oncology, San Camillo and Forlanini Hospitals, Pavilion Cesalpini, Circonvallazione Gianicolense 87, I-00152, Rome, Italy.
Sana Al-Sukhun, MD, MSc. Dr. Alsukhun is a senior fellow in the Division of Hematology/Oncology, Department of Internal Medicine, Wayne State University and the Barbara Ann Karmanos Cancer Institute in Detroit Michigan. Dr. Al-Sukhun has a Masters of Science major in cancer biology from Wayne State University.
References (124)
Mapping of the urinary bladder: its impact on the concepts of bladder cancer
Hum. Pathol.
(1979)- et al.
Chromosome 21q22 deletion. A specific chromosome change in a new bladder cancer subgroup
Cancer Genet. Cytogenet.
(1989) - et al.
Review of chromosome studies in urologic tumors, II. Cytoogenetic and molecular genetics of bladder cancer
J. Urol.
(1994) - et al.
Allelic deletion fingerprinting of urine cell sediments in bladder cancer
Mol. Diagn.
(2001) - et al.
Deletions of the INK4A gene in superficial bladder tumors. Association with recurrence
Am. J. Pathol.
(1999) - et al.
Frequent amplification of 11q13 DNA markers is associated with lymph node involvement in human head and neck squamous cell carcinomas
Eur. J. Cancer
(1994) - et al.
H-RAS, K-RAS and N-RAS gene activation in human bladder cancers
Cancer Genet. Cytogenet.
(2000) - et al.
Epidermal growth-factor receptors in human bladder cancer: comparison of invasive and superficial tumors
Lancet
(1985) - et al.
C-ERBB-2 gene amplification as a prognostic marker in human bladder cancer
Urology
(2000) - et al.
Patterns of chromosomal imbalances in advanced urinary bladder cancer detected by comparative genomic hybridization
Am. J. Pathol.
(1998)
Apoptosis, p53, bcl-2, and Ki-67 in invasive bladder carcinoma: possible predictors for response to radiochemotherapy and successful bladder preservation
Int. J. Radiat. Oncol. Biol. Phys.
Efficacy of radiochemotherapy with platin derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer
Int. J. Radiat. Oncol. Biol. Phys.
The p53 proto-oncogene can act as a suppressor of transformation
Cell
A genetic model for colorectal tumorgenesis
Cell
WAF1, a potential mediator of p53 tumor suppression
Cell
Loss of cell cycle regulators p27(Kip1) and cyclin E in transitional cell carcinoma of the bladder correlates with tumor grade and patient survival
Am. J. Pathol.
Angiogenesis assessed by platelet/endothelial cell adhesion molecule antibodies, as an indicator of node metastasis and survival in breast cancer
Lancet
Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer
J. Urol.
Angiogenesis
J. Biol. Chem.
Novel growth regulatory factors and tumor angiogenesis
Eur. J. Cancer
Cancer statistics 2001
CA Cancer J. Clin.
Longitudinal study of patients with bladder cancer: factors associated with disease recurrence and progression
Natural history and clinical behavior of in situ carcinoma of the human urinary bladder
Cancer
Pathology of bladder cancer: assessment of prognostic variables and response to therapy
Semin. Oncol.
The pathology of human bladder cancer
Cancer
Allelic losses of chromosomes 9, 11, and 17 in human bladder cancer
Cancer Res.
Characterization of chromosomal abnormalities in uroepithelial carcinomas by G-banding, spectral karyotyping and FISH analysis
Int. J. Cancer
Molecular genetic alterations in superficial and locally advanced human bladder cancer
Cancer Res.
Allelic loss of chromosome 17p distinguishes high grade from low grade transitional cell carcinomas of the bladder
Cancer Res.
Human genome studies expected to revolutionize cancer classification
J. Am. Med. Assoc.
Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade
J. Pathol.
Patterns of chromosomal imbalances in muscle invasive bladder cancer
Int. J. Oncol.
Molecular cytogenetic alterations associated with rapid tumor cell proliferation in advanced urinary bladder cancer
Int. J. Oncol.
Microsatellite instability in cancer of the proximal colon
Science
Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma
Cancer Res.
Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history
Cancer Res.
Microsatellite alterations in superficial and locally advanced transitional cell carcinoma of the bladder
Oncol. Rep.
Functional analysis of the mismatch repair system in bladder cancer
Br. J. Cancer
Microsatellite instability in transitional cell carcinoma of the urinary tract and its relationship to clinicopathological variables and smoking
Int. J. Cancer
Sensitive detection of transitional cell carcinoma of the bladder by microsatellite analysis of cells exfoliated in urine
Int. J. Cancer
Microsatellite alterations in urinary sediments from patients with cystitis and bladder cancer
Int. J. Cancer
Progressive increases in de novo methylation of CpG islands in bladder cancer
Cancer Res.
Aberrant promoter methylation profile of bladder cancer and its relationship to clinicopathological features
Cancer Res.
Role of the retinoblastoma protein in the pathogenesis of human cancer
J. Clin. Oncol.
Function of a human cyclin gene as an oncogene
Proc. Natl. Acad. Sci. USA
Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice
Nature
Accumulation of nuclear p53 and tumor progression in bladder cancer
N. Engl. J. Med.
Reduced expression of retinoblastoma (Rb) gene protein is related to cell proliferation and prognosis in transitional-cell bladder cancer
J. Cancer Res. Clin. Oncol.
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Sana Al-Sukhun, MD, MSc. Dr. Alsukhun is a senior fellow in the Division of Hematology/Oncology, Department of Internal Medicine, Wayne State University and the Barbara Ann Karmanos Cancer Institute in Detroit Michigan. Dr. Al-Sukhun has a Masters of Science major in cancer biology from Wayne State University.
Maha Hussain, MD, FACP. Dr. Hussain is a Professor of Medicine and Urology, Departments of Internal Medicine (Division of Hematology/Oncology) and Urology at the University of Michigan.