Expression of cadherin‐8 in renal cell carcinoma and fetal kidney

Abstract

Renal cell carcinomas (RCCs) represent 3% of all adult malignancies and are often associated with poor prognosis due to early metastasis and limited beneficial effects of current therapeutic modalities. 1 Most of these tumors originate from the proximal tubule. According to cell morphology and growth pattern, 3 main histologic tumor types can be distinguished, including clear cell carcinoma, papillary renal carcinoma and chromophobe RCC. 2 Several factors that may contribute to the process of malignant cell transformation in RCC have previously been characterized, including physical agents, chemical agents, habits, genetics (chromosomal rearrangement) and end-stage renal disease. 3 However, the pathogenic mechanisms that promote tumor progression, i.e., tumor invasion and metastasis, still have to be defined. There is accumulating evidence that cadherins may be involved in the pathogenesis of various human carcinomas by modulating celladhesive properties.The cadherin superfamily represents a group of cell-surface glycoproteins involved in cell recognition, cell signaling, cell communication, morphogenesis as well as angiogenesis and includes the groups of classic cadherins, desmosomal cadherins, protocadherins, 7TM-cadherins and T-cadherin. 4 The human classic cadherins are a group of cell-surface molecules mediating Ca 2ϩ -dependent cell adhesion by homo-or heterophilic interaction. These proteins, m.w. approximately 120 -130 kDa, are composed of an extracellular domain with 5 subdomains, each of which contains a cadherin-specific motif at the N-terminal site, a single transmembrane domain and a rather short and highly conserved cytoplasmic domain at the C-terminal site. The adhesive action of cadherins depends on the presence of Ca 2ϩ and on the function of the intracellular domain. 5 Cadherins are linked to the actin filament network through cytoplasmic interactions with catenins. These catenins regulate cadherin-mediated cell-cell adhesion. 6 In addition, these molecules may function as a downstream transcriptional activator. 7,8 More than 12 different molecules of the classic human cadherins have been identified so far by cDNA cloning. With respect to sequence homology and conservation of several amino acid residue motifs in the extracellular domain, Suzuki et al. 9 first proposed subdividing the classic human cadherins into 2 subgroups: type I (E-, N-and P-cadherins, cadherin-4) and type II (cadherins 5-15). Cadherin-8, a type II cadherin, was cloned by Tanihara et al. 10 and is characterized by strong sequence homology with the classical type I cadherins. 11 In mice, cadherin-8 expression is restricted to the developing CNS and thymus. 12,13 As has been demonstrated for type I cadherins, type II cadherins interact with ␣-and ␤-catenins. 14 Using an L-fibroblast cDNA transfection system and a long-term cell-aggregation assay, Shimoyama et al. 15 clearly demonstrated that all 8 type II cadherins exhibited cell-cell binding activity comparable to that of E-cadherin. Heterophilic interactions among the type I...

Expression of Ksp-cadherin during kidney development and in renal cell carcinoma

“…The relatively late appearance of Ksp-cadherin during renal development is in contrast to the expression pattern of other cadherins, such as cadherin-8, which can clearly be detected at the 6th week of gestation (Blaschke et al, 2002). Ecadherin, which colocalises with Ksp-cadherin in distal tubules of the adult kidney, appears earlier during renal development, directly after the mesenchymal -epithelial transition (Vestweber et al, 1985).…”

“…Three other RCC cell lines were established in the laboratory of Professor Gerhard Müller (University of Göttingen, Germany). All cell lines were grown in culture as described recently (Blaschke et al, 2002).…”

“…Cadherin-8 can only be detected on developing tubular structures (Blaschke et al, 2002). This rather complex pattern of cadherin expression in the normal adult kidney is mirrored by cadherin expression in RCC (Tani et al, 1995;Heicappell, 1999).…”

“…More than 70% of all RCCs are clear cell carcinomas that are thought to originate from proximal tubular epithelial cells. Therefore, most of the analysed RCC cell lines synthesised N-cadherin and cadherin-6 (Shimazui et al, 1996;Blaschke et al, 2002). Expression of cadherin-6 can serve as a prognostic marker for tumour progression (Shimazui et al, 2003(Shimazui et al, , 2004Paul et al, 2004).…”

“…Expression of cadherin-6 can serve as a prognostic marker for tumour progression (Shimazui et al, 2003(Shimazui et al, , 2004Paul et al, 2004). Some RCC cell lines also express E-cadherin and cadherin-8 (Shimazui et al, 1996;Blaschke et al, 2002), but since these cadherins are only found to be expressed on distal tubules or during development, respectively, their expression in the renal tumour cells must be regarded as an aberrant expression pattern.…”