Hernando Salazar

The differential expression of N-cadherin and E-cadherin distinguishes pleural mesotheliomas from lung adenocarcinomas

Malignant mesotheliomas are highly aggressive tumors that develop most frequently in the pleura of patients chronically exposed to asbestos. The distinction between malignant mesotheliomas and tumors of epithelial origin, particularly peripheral lung adenocarcinoma, can be difficult despite the use of immunocytochemical markers and other diagnostic tools. During embryonic development the cadherin cell-cell adhesion molecules participate in the segregation of cells into different tissues. As a result of complex mechanisms of tissue selectivity, N-cadherin is expressed by the developing pleural mesothelial cells and E-cadherin is expressed by the epithelial cells of the lung. Thus, we postulated that N-cadherin could be used as a marker of mesothelial cells and mesothelial tumors, in contrast to adenocarcinomas of the lung that are tumors of epithelial origin. We studied the expression of N-cadherin, E-cadherin and two cadherin-associated proteins, alpha-catenin and beta-catenin, in 19 pleural mesotheliomas, 16 lung adenocarcinomas and in 2 mesothelioma cell lines using specific monoclonal antibodies and immunohistochemical methods. Our results show that all mesotheliomas express high levels of N-cadherin, regardless of their histological type, in contrast to lung adenocarcinomas which expressed E-cadherin but no N-cadherin. The cadherin-associated proteins, alpha-catenin and beta-catenin, were present in both mesotheliomas and adenocarcinomas. Our results show that pleural mesotheliomas can be distinguished from lung adenocarcinomas based on the differential expression of N-cadherin and E-cadherin, using specific monoclonal antibodies and immunocytochemistry.

Expression of E-cadherin and N-cadherin in surface epithelial-stromal tumors of the ovary distinguishes mucinous from serous and endometrioid tumors

This study examines the expression of E-cadherin and N-cadherin in the most common epithelial tumors of the ovary. The homotypic interactions of distinctive members of the cadherin family of cell-cell adhesion molecules segregate cells into tissues during embryonic development, and their expression in tumors can be used to trace the histogenesis of tumor cells. Because the surface epithelium of the ovary is a modified mesothelium, we speculated that the expression of E (epithelial)-cadherin and N (neural, mesodermal)-cadherin may provide clues about the controversial origin of common epithelial ovarian tumors. Immunohistochemistry was performed in paraffin sections using well-characterized monoclonal antibodies to E- and N-cadherin and heat-induced antigen-retrieval methods. We found that serous and endometrioid tumors express both E- and N-cadherin. In contrast, mucinous tumors strongly express E-cadherin, but no N-cadherin. The presence of N-cadherin in serous and endometrioid tumors traces their origin to the mesoderm-derived ovarian surface epithelium. The absence of N-cadherin in mucinous tumors clearly distinguishes them from the former, suggesting histogenesis from a cell lineage other than the ovarian surface epithelium or aberrant differentiation mechanisms associated with neoplastic transformation.

Distinct cadherin profiles in special variant carcinomas and other tumors of the breast

The cadherins are homotypic adhesion proteins that are important in cell sorting during organogenesis. Classical cadherins include several different types that show tissue-specific expression. Cell lineage-specific expression of different cadherin subtypes can differentiate morphologically similar but histogenetically distinct tumors. We examined by immunohistochemistry in paraffin sections, the expression of E (epithelial), N- (neural), and P- (placental) cadherin in 36 unusual tumors of the breast (22 medullary carcinomas, 5 metaplastic carcinomas, 2 carcinosarcomas, 4 phyllodes tumors, and 3 periductal stromal tumors). All carcinomas stain with E-cadherin (22 of 22 medullary and 5 of 5 metaplastic). E-cadherin also stained the epithelial component but not the sarcomatous areas of 2 of 2 cases of carcinosarcomas. E-cadherin was not detected in the stromal tumors (phyllodes, periductal stromal tumor). N-cadherin was most frequently expressed in sarcomatoid metaplastic carcinomas (5 of 5), and variably in other tumors, including the sarcomatous area of carcinosarcoma (1 of 2), and 6 of 22 medullary carcinomas. P-cadherin was frequently identified in medullary carcinomas (20 of 22), in 5 of 5 metaplastic carcinomas, and in the proliferating stroma and benign epithelium of 3 of 3 periductal stromal, but not in phyllodes tumors (0 of 4). All sarcomatoid metaplastic carcinomas co-expressed all 3 classical cadherins. Our results show that these breast tumors have unique patterns of cadherin expression suggesting different histogenetic origin or lines of differentiation. The cadherin profiles in these tumors may be useful for classification and diagnosis.

Nuclear Localization of E-Cadherin Expression in Merkel Cell Carcinoma

CONTEXT Cadherins are cell-cell adhesion proteins that act as tumor suppressor genes and have a critical role in cell sorting and tissue formation during organogenesis. The pattern of cadherin expression constitutes a useful diagnostic and prognostic tool in the evaluation of tumors and for determining the histogenesis of tumor cells. We have previously characterized the cell types of several tumors based on the expression of individual cadherins. OBJECTIVE To investigate the expression of cadherins in Merkel cell carcinomas. DESIGN Paraffin immunohistochemical analysis of the 3 best-studied cadherins was performed on 35 cases of Merkel cell carcinoma. RESULTS E-cadherin was expressed in 34 (97%) of 35 Merkel cell carcinomas examined, N-cadherin was expressed in 22 (63%) of 35 cases, and P-cadherin was expressed in 15 (43%) of 35 cases. This frequency of cadherin expression was similar to a group of small cell and neuroendocrine tumors from other primary sites. Interestingly, the localization of E-cadherin expression was unique in Merkel cell carcinomas compared with other primary neuroendocrine tumors. Merkel cell carcinomas showed marked preference for nuclear versus membrane localization, whereas small cell tumors from other sites showed fewer cases of nuclear E-cadherin expression. The nuclear localization of E-cadherin did not correlate with cadherin-associated protein beta-catenin nuclear expression. CONCLUSIONS Our findings show that E-cadherin is the most frequently expressed cadherin in Merkel cell carcinoma, followed in frequency by N-cadherin then P-cadherin. The pattern of nuclear E-cadherin expression is more frequent for Merkel cell carcinoma than small cell tumors of other primary sites. These observations suggest that E-cadherin expression and function are altered in Merkel cell carcinoma, and this finding has potential use in the differential diagnosis of these tumors.

Loss of heterozygosity studies indicate that chromosome arm 1p harbors a tumor suppressor gene for renal oncocytomas

We carried out a complete genome scan for loss of heterozygosity (LOH) in four renal oncocytomas by using highly polymorphic CA repeat microsatellite loci. Three of the four tumors exhibited LOH for chromosome arm 1p, and the oncocytomas of both female patients lost Xq. Therefore, these chromosome arms may harbor tumor suppressor genes involved in the etiology of this disease. Although the genomes of oncocytomas are relatively stable, two different microsatellite loci in one tumor were mutated by ±2 nt. Similar alterations in CA repeats that are probably due to spontaneous mutation have been observed in renal cell carcinomas. Genes Chromosom Cancer 16:64–67 (1996).

Immunohistochemical analysis of β-tubulin isotypes in human prostate carcinoma and benign prostatic hypertrophy

β‐tubulin, the intracellular target of several antimicrotubule agents, is encoded by at least six genes and exists as multiple isotypes with tissue‐specific expression. Previous in vitro studies indicated that tubulin isotype composition may affect polymerization properties, dynamics, and sensitivity to drugs.