Review the S100 Proteins for Screening and Prognostic Grading
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Histol Histopathol (2007) 22: 1025-1032 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Review The S100 proteins for screening and prognostic grading of bladder cancer R. Yao1, D.D. Davidson2, A. Lopez-Beltran4, G.T. MacLennan5, R. Montironi6 and L. Cheng2,3 1Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA, 2Departments of Pathology and Laboratory Medicine, and 3Urology, Indiana University School of Medicine, Indianapolis, IN, USA, 4Department of Pathology, Cordoba University, Cordoba, Spain, 5Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA and 6Institute of Pathological Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy Summary. The S100 gene family, which is composed of Introduction at least 24 members carrying the Ca2+ binding EF-hand motif, has been implicated in both intracellular and The S100 protein family includes more than 20 extracellular functions, including enzyme activities, entities, all of which are identified only in vertebrates, immune responses, cytoskeleton dynamics, Ca2+ sharing a common structure carrying the Ca2+-binding homeostasis, cell growth and cell differentiation. Altered EF-hand motif (Marenholz et al., 2004, 2006). S100 S100 protein levels are associated with a broad range of proteins (SP) are low molecular weight, acidic peptides diseases, including cardiomyopathy, inflammatory and of 9-13 kDa with two distinct EF-hands. Interestingly, of immune disorders, neurodegenerative disorders and the 24 human SP, 19 family members are tightly cancer. Although the precise role of S100 protein in clustered at chromosome locus 1q21. The other five SP carcinogenesis is poorly understood, it seems that are found at chromosome 4p16 (S100P), 5q13 (S100Z), formation of homo- and hetero-dimers, binding of Ca2+ 7q22-q31 (S100A11P), 21q22 (S100B) and Xp22 and interaction with effector molecules are essential for (S100G) (Marenholz et al., 2006). Their gene structure is the development and progression of many cancers. highly conserved, generally comprising three exons and Several studies have suggested that S100 proteins two introns, with the first exon noncoding. The mouse promote cancer progression and metastasis through cell and rat have 17 and 14 proteins, respectively; with survival and apoptosis pathways. In animal models of clustering that is analogous to human SP. The mouse has bladder cancer, several S100 proteins are differentially a cluster of 13 SP family members in region F1-F2 of expressed in bladder tumors relative to normal mouse chromosome 3 (Marenholz et al., 2004). The rat urothelium. In human bladder cancer, overexpression of has 12 family members in region q34 of rat chromosome S100A4, S100A8 or S100A11 are associated with stage 2 (Table 1). Most SP show cell-specific expression progression, invasion, metastasis and poor survival. This patterns, suggesting that different SP have distinct review summarizes these findings and evaluates their organ-specific functions (Donato, 2003). Many SP can implications for human bladder cancer management. form homo- and heterodimers, which seem important for their functional diversification. The calcium-dependent Key words: Bladder, Urinary tract, Neoplasia, signaling roles of the SP are essential for each of their Transitional cell caricnoma, Urothelial carcinoma, S100 functions. The N-terminal EF-hand, sometimes referred proteins, Proteomics, Biomarkers as a ‘pseudo-canonical’ or ‘half’ EF-hand, binds calcium with a weak affinity (Kd≈ 200-500 mM) (Donato, 1986). The C-terminal EF-hand is the more conserved EF-hand domain and binds calcium with 100 times greater affinity (Kd≈ 10-50 mM) than the N-terminal EF-hand (Donato, 1986). Upon calcium binding, SP undergo a Offprint requests to: Dr. L. Cheng, Department of Pathology and conformational change and a hydrophobic cleft forms in Laboratory Medicine, Indiana University School of Medicine, 350 West each monomer. The hydrophobic cleft is important for 11th Street, Clarian Pathology Laboratory Room 4010, Indianapolis, IN calcium-dependent recognition of S100 target proteins 46202, USA. e-mail: [email protected] (Donato, 1999, 2003). In addition to calcium, many SP 1026 S100 proteins in bladder cancer bind Zn2+ and Cu2+ with high affinity. These divalent and Cheng, 2006; Jemal et al., 2006). Bladder tumors, cations may influence SP intra- and extracellular including some preinvasive lesions, carry a substantial functions (Marenholz et al., 2004). SP are multi- number of genetic alterations at the time of diagnosis. functional signaling proteins involved in numerous Losses of heterozygosity (LOH) at 1q, 3p, 4q, 6q, 8p, 9p, cellular functions, such as protein phosphorylation, 9q, 10q, 11p, 13q, 14q, 17p, 18q and 21q have been enzyme activation, interaction with cytoskeletal observed in human bladder cancers, implying the components, and calcium homeostasis (Donato, 2003). possible involvement of tumor suppressor genes Moreover, SP are regulators of many cellular processes harbored in those chromosomal regions (Kroft and such as cell growth, cell cycle progression, Oyasu, 1994; Knowles, 1995; Brandau and Bohle, 2001; differentiation, transcription and secretion (Donato, Mazzucchelli et al., 2005). Bladder tumorigenesis is 2003). The functions of SP in tumorigenesis and tumor associated with losses from chromosomes 9, 13 and 17, progression have not been clearly elucidated, but recent including inactivation of CDKN2 (p16) at 9p, of Rb at reports have suggested that SP regulation of the 13q14 and of p53 at 17p11. With recent advances in signaling pathways may promote tumor progression. molecular biology and novel technologies, several Bladder cancer is the sixth most common biomarkers have emerged as important adjuncts in the malignancy in developed countries. It ranks as the fourth diagnosis of lesions of the bladder. When used in and ninth most frequently diagnosed cancer in men and conjunction with careful histologic examination, women, respectively, in the United States. It is estimated immunohistochemistry can be a valuable aid in that about 61,420 cases will be newly diagnosed in the classifying tumors presenting in the bladder and USA and 13,060 patients will die from disseminated mesenchymal lesions of the bladder and in establishing urothelial carcinoma in 2006. Most bladder tumors are the urothelial origin of a metastatic tumor. In addition, a transitional cell carcinomas (TCCs). However, squamous number of biomarkers may prove to be important cell carcinoma is the predominant histologic type of indicators of prognosis or response to chemotherapy and bladder cancer in Middle Eastern countries (Davidson tumor progression and recurrence or progression (Bollito Table 1. S100 protein family members in human, mouse and rat and their expression and function in bladder tumors. Gene Chromsome Orthologous Chromsome Orthologous Chromsome Expression in bladder cancer name Location mouse gene location rat gene location S100A1 1q21 S100a1 3F1-F2 S100a1 2q34 underexpression in mouse and rat (unpublished data) S100A2 1q21 S100a2 (S100L) 3F1-F2 ----- S100A3 1q21 S100a3 3F1-F2 S100a3 2q34 overexpression in mouse (unpublished data) S100A4 1q21 S100a4 3F1-F2 S100a4 2q34 overexpression associated with stage progression, metastasis and poor survival in human (Davies et al., 2002) overexpression associated with metastasis in rat (Levett et al., 2002) overexpression in rat (unpublished data) S100A5 1q21 S100a5 3F1-F2 S100a5 2q34 underexpression in mouse (unpublished data) S100A6 1q21 S100a6 3F1-F2 S100a6 2q34 ----- S100A7 1q21 S100a7 3F1-F2 overexpression in human bladder SCC (Ostergaard et al., 1997, 1999) S100A7A 1q21 ----- S100A7L2 1q21 ----- S100A7P1 1q21 ----- S100A7P2 1q21 ----- S100A8 1q21 S100a8 3F1-F2 S100a8 2q34 overexpression associated with aggressive, invasive bladder tumors in human (Tolson et al., 2006). overexpression in mouse and rat (unpublished data) S100A9 1q21 S100a9 3F1-F2 S100a9 2q34 overexpression in mouse and rat (unpublished data) S100A10 1q21 S100a10 3F1-F2 S100a10 2q34 overexpression in mouse and rat (unpublished data) S100A11 1q21 S100a11 3E-F S100a11 2q34 underexpression associated with progression and poor survival in human (Memon et al., 2005). S100A11P 7q22-q31 ----- S100A12 1q21 ----- S100A13 1q21 S100a13 3F1-F2 S100a13 2q34 ----- S100A14 1q21 S100a14 3F2 LOC686203 2q34 ----- S100A16 1q21 S100a16 3F1-F2 S100a16 2q34 ----- S100B 21q22 S100b 10C1 S100b 20p12 ----- S100G Xp22 S100g XF4 S100g Xq21 overexpression in mouse and rat (unpublished data) S100P 4p16 ----- S100Z 5q13 S100z (predicted) 13D1 ----- 1027 S100 proteins in bladder cancer et al., 2005; Emerson and Cheng, 2005; Kyroudi- strongly correlated with the development of an Voulgari et al., 2005; Iczkowski and Butler, 2006). aggressively metastatic phenotype. Ebralidze et al. first Numerous markers have been identified that correlate to reported that the S100A4 mRNA expression level some extent with tumor stage and prognosis. However, correlates with the metastatic potential of several tumor the power of many of these markers in predicting the cell lines (Ebralidze et al., 1989). S100A4 expression clinical outcome of individual tumors is limited, and has been reported in several cancer types both in human alternative markers are still needed for detection and and animal models. Upregulated S100A4 mRNA is prognostic grading