Cadherins as predictive markers of nodal metastasis in breast cancer.

Adhesion molecules, particularly cadherins play a pivotal role in cancer invasion and metastasis. Because the therapeutic management of tumors with and without nodal metastasis differs considerably, our idea was to identify tumors with metastatic potential. We studied the expression of E-cadherin and P-cadherin immunohistochemically in 51 cases of breast cancer that included 29 node-negative and 22 node-positive cases. Expression of the cadherins was mainly membranous, with cytoplasmic staining in a few lesions. Both E-cadherin and P-cadherin showed significant down-regulation of their expression in node-positive tumors in comparison to node-negative tumors. Logistic regression analysis revealed that the positive expression of E-cadherin and P-cadherin showed low odds ratios of 0.1 and 0.2, respectively, and were statistically significant. On multivariate analysis, both the cadherins were found to be of independent prognostic value. This suggests that cadherin expression could be a marker of nodal metastasis. An observation of interest was that the expression of E-cadherin and P-cadherin were highly correlated (correlation coefficient = 0.5873), which requires further evaluation for confirmation of a common regulatory pathway that could be activated in the early onset of nodal metastasis.     

The cadherin switch in ovarian high-grade serous carcinoma is associated with disease progression

Ovarian high-grade serous carcinoma (HGSC) often has a poor prognosis because of late presentation, lack of sensitivity and specificity of screening modalities and the development of chemoresistance. New targeted therapy is required if survival in these cases is to improve. The profile of E-, P- and N-cadherins in ovarian cancer and its association with survival remain poorly understood. Reduced expression of E-cadherin in prostate cancer associated with increase in the expression of N- and P-cadherins is described as cadherin switch. We hypothesised that there is a switch in the expression of cadherins that regulates the behaviour of HGSC and possibly its outcome. To identify the stages of the cadherin switch in HGSC, we studied the immunoexpression of E-, P- and N-cadherins in a cohort of 177 cases of HGSC. High expression of P-cadherin was associated with poor patient survival and was significantly higher in stage 2 disease when compared with stage 1 and stage 3 disease (P = 0.033). In contrast, loss of E-cadherin was observed in stage 3 HGSC when compared with other stages (P = 0.050). E-, P- and N- cadherin expressions were significantly associated with disease outcome when assessed individually and in various combinations with an interesting profile. Our results indicate that the cadherin switch alters through progression of HGSC. The profile of combined cadherin expressions in association with survival raises expectations in targeted therapy.     

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.     

Immunohistochemical observation of co-expression of E- and N-cadherins in rat organogenesis

Cadherins are a family of transmembrane glycoproteins that mediate cell-to-cell adhesion. Isoforms, including E- and N-cadherin, have been identified and shown to regulate morphogenesis through homophilic binding. In the ontogeny, the expressions of E- and N-cadherin change spatiotemporally, and the changes in cadherin isoforms, called cadherin switching, impact the mechanical adhesion of cells. Furthermore, cadherin functions as a receptor that transfers information from outside to inside cells, and in terms of switching, it affects cell phenotypes. To observe the expression patterns of E- and N-cadherins during embryogenesis and to identify cells that transiently coexpress both cadherins, we employed a recently developed immunohistochemical double staining technique in rat fetuses. At embryonic day 9, embryonic ectodermal cells more dominantly expressed E-cadherin, while mesodermal cells more dominantly expressed N-cadherin. At embryonic day 10, the expression pattern of E-cadherin in the surface ectoderm and endoderm and that of N-cadherin in the neuroectoderm were established. After embryonic day 10, unique co-expression of E- and N-cadherin was observed in primordia, such as the bulbus cordis, otic pit, notochord, and Rathke’s pouch. In the present study, it was possible to visualize the expression patterns of E- and N-cadherin during early fetal development, which enabled us to morphologically clarify cadherin switching.     

Epithelial (E-) and placentae (P-) cadherin cell adhesion molecule expression in breast carcinoma

Two members of the cadherin family of intercellular adhesion molecules are found in normal breast tissue: E- (epithelial) cadherin is present in both luminal and myoepithelial cells, whereas P- (placental) cadherin is confined to myoepithelium. There is experimental evidence that loss of E-cadherin is associated with increased invasiveness of malignant cells in vitro, which stimulated us to examine the presence and distribution of E- and P-cadherin in breast carcinomas by means of immunohistochemical staining. E-Cadherin was present in all in situ and invasive ductal carcinomas examined, although it had a patchy distribution and the staining was of variable intensity. However, in 83 per cent of invasive lobular carcinomas and all lobular carcinomas in situ there was complete loss of E-cauherin expression. In the remaining 17 per cent of invasive lobular tumours, E-cadherin appeared to have an abnormal distribution within the cytoplasm with variable expression on the cell membrane. P-Cadherin, by contrast, was absent from all benign breast luminal epithelium and 25 carcinomas of ductal and lobular type. It was found in only one carcinoma of lobular type. We suggest that loss of cell-cell adhesion mediated by E-cadherin plays a part in the characteristic morphology of lobular carcinomas.     

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.     

Anomalous expression of P-cadherin in breast carcinoma. Correlation with E-cadherin expression and pathological features.

Previous studies on the cell-cell adhesion molecules P- and E-cadherin have shown that P-cadherin is not expressed in breast cancer. In contrast, the expression of E-cadherin is a normal event in these tumors, but a reduction in the levels of this molecule in neoplastic cells is associated with the histological type, high histological grade, greater tumor size, and metastasis. The expression pattern of P- and E-cadherin were immunohistochemically studied in tissue sections from normal breast tissue, benign breast lesions, and 57 infiltrating breast carcinomas. Cadherin expression was analyzed in parallel with pathological features and the immunohistochemical expression of estrogen and progesterone receptors in breast carcinomas. P-cadherin was detected in the myoepithelial cells and E-cadherin in luminal epithelial cells from normal breast and benign breast lesions. P-cadherin expression was detected in 9 of 45 cases (20%) of infiltrating ductal carcinomas of no special type; none of the special histological types that were analyzed (7 infiltrating lobular carcinomas, 3 colloid carcinomas, and 2 infiltrating papillary carcinomas) expressed P-cadherin. In infiltrating ductal carcinomas, P-cadherin expression correlated significantly with a reduction in E-cadherin expression, histological grade (all cases were grade III tumors), and hormone receptor content (8 of 9 cases were estrogen and progesterone receptor negative). Although E-cadherin was not found in the 7 infiltrating lobular carcinomas, it was present in the remaining histological types and was preserved in 15 infiltrating ductal and 3 colloid and 2 papillary carcinomas and was reduced in 30 infiltrating ductal carcinomas. In addition, a reduction in E-cadherin expression was significantly associated with high histological grade and a lack of steroid hormone receptors in infiltrating ductal carcinomas. No apparent relationship was found between P- and E-cadherin expression and tumor size and axillary lymph node metastasis. The distinct patterns of P- and E-cadherin expression observed in this study strongly suggest a differential role for these cadherins in human breast carcinogenesis.     

Comparison of integrin,cadherin, and catenin expression in squamous cell carcinomas of the oral cavity

In addition to their role in maintenance of tissue integrity, cell adhesion molecules regulate the growth and differentiation of stratified squamous epithelia. Reduced expression of E-cadherin and the α₂β₁, α₃β₁ and α₆β₄ integrins is already reported to correlate with poor histological differentiation in oral squamous cell carcinomas. However, it is not clear how closely cadherin and integrin loss are related in any given tumour, nor whether cadherin loss is correlated with changes in expression of the cytoplasmic regulatory proteins known as catenins. Double-label immunofluorescence has been used to stain a panel of 22 oral squamous cell carcinomas with antibodies to ten proteins, including E- and P-cadherin, the major keratinocyte integrin subunits, and α-, β- and γ-catenin. Overall, E-cadherin expression and integrin expression correlated well with tumour grade, while P-cadherin staining was more variable. All tumours, regardless of differentiation status, showed reduced staining for at least two of the catenins, implying that the adhesive function of E- and P-cadherin could be impaired even when cadherin expression is normal. It is concluded that in all squamous cell carcinomas, regardless of degree of histological differentiation, there is some perturbed expression of cell adhesion molecules and that integrin and E-cadherin loss are closely related. © 1998 John Wiley & Sons, Ltd.     

Abnormalities of the E-cadherin/catenin adhesion complex in classical papillary thyroid carcinoma and in its diffuse sclerosing variant.

The cadherin/catenin complex regulates cellular adhesion and motility and is believed to function as an invasion suppressor system. Several studies have identified alterations in the expression profiles of those molecules in different histotypes of thyroid carcinoma. The diffuse sclerosing variant (DSV) of papillary thyroid carcinoma (PTC) is a rare, highly invasive variant of PTC in which an impairment of cell-cell adhesion may play a major role. In an attempt to progress in the understanding of the clinicopathological features of DSV, this study examined eight cases of DSV, 18 cases of classical PTC and a control group of normal thyroid by immunohistochemistry (E-, P- and N-cadherins and beta-, gamma- and alpha-catenins). The E-cadherin gene was also studied by polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) and methylation-specific PCR (MSP). In contrast to classical PTC, which showed heterogeneous loss of E-cadherin expression, in almost every case of DSV a pronounced reduction was observed in its membranous expression, accompanied by a relocation to the cytoplasm. Inactivation of the E-cadherin/catenin complex appears to occur in DSV via two different pathways: E-cadherin alteration either through mutation (one out of the eight cases) or through methylation of the E-cadherin gene promoter (three out of five cases); and beta- and/or gamma-catenin alterations (three of the eight cases). Methylation of the E-cadherin gene promoter, abnormalities of E-cadherin expression and alterations of gamma-catenin were also detected in classical PTC. In DSV, as in classical PTC, there is neo-expression of P-cadherin in areas of squamous metaplasia and no N-cadherin expression. In conclusion, abnormalities of the E-cadherin/catenin complex appear to be more pronounced in DSV than in classical PTC. It remains to be shown whether or not such differences are associated with the more aggressive behaviour of DSV compared with classical PTC.     

Mucoepidermoid carcinoma of the thyroid: a tumour histotype characterised by P-cadherin neoexpression and marked abnormalities of E-cadherin/catenins complex

The cadherin/catenins complex regulates cell-cell adhesion and motility and is believed to have an invasion suppressor role. Primary mucoepidermoid carcinoma of the thyroid (MECT) is a rare tumour characterised by a distinct morphological appearance and a questionable histogenesis. The coexistence of papillary thyroid carcinoma (PTC) foci in many patients with MECT suggests an association between the two tumour histotypes. In an attempt to clarify the putative relationship between MECT and PTC, we analysed tissue from 11 patients with MECT by immunohistochemistry (E-, P- and N-cadherins and alpha-, beta- and gamma-catenins). The E-cadherin gene was also analysed by polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP). The results were compared with a control group of normal thyroid, classical PTC and the diffuse sclerosing variant of PTC. Compared with normal thyroid and PTC, MECT displays marked abnormalities of the cadherin/catenin complex. Such abnormalities include the consistent neoexpression of P-cadherin and major alterations in the expression of E-cadherin and the three catenins. Our results point to the close relationship between the de novo expression of P-cadherin and the disruption of the cadherin/catenins complex with the squamoid phenotype of MECT.     

Expression of P-cadherin identifies prostate-specific-antigen-negative cells in epithelial tissues of male sexual accessory organs and in prostatic carcinomas. Implications for prostate cancer biology.

Cadherins constitute a family of calcium-dependent cell-cell adhesion molecules the individual members of which are essential for the sorting of cells into tissues during development. In this study, we examined the expression of E-cadherin, N-cadherin, and P-cadherin in tissues obtained from radical prostatectomies. Epithelial cells of prostatic glands, ejaculatory ducts, and seminal vesicles expressed E-cadherin but not N-cadherin. P-cadherin was expressed in epithelial cells of the seminal vesicles and ejaculatory ducts. In the prostate it was limited to the basal cells of prostatic acini, glands with basal cell hyperplasia, and atrophic glands denuded of the luminal cells. All P-cadherin-positive cells were negative for prostatic-specific antigen. Prostatic cancers were mostly P-cadherin negative, but some tumors had P-cadherin-positive areas frequently located close to ejaculatory ducts and negative for prostatic-specific antigen. The mutually exclusive expression of P-cadherin and prostatic-specific antigen suggests that these proteins are involved in differential mechanisms of cell regulation in prostate cancer. P-cadherin may become a useful marker in the diagnosis and management of patients with prostate cancer and low levels of prostatic-specific antigen.     

Expression of E- and N-cadherin and clinicopathology in hepatocellular carcinoma

Loss or reduced E-cadherin expression and aberrant expression of N-cadherin have been associated with invasiveness of human carcinoma cells and poor prognosis. The role of E- and N-cadherin, however, in hepatocellular carcinoma (HCC) has not yet been elucidated. The aim of the present study was to investigate the expression pattern of E- and N-cadherin in surgically resected HCC specimens according to their relationship with clinicopathological features. The expression patterns of E- and N-cadherin were evaluated on immunohistochemistry in 68 specimens of HCC and adjacent non-tumor tissue. The most different expression pattern between HCC and non-tumor tissue was the decreased staining intensity of E-cadherin (n = 37, 54%) and the dot-like discontinuous staining of N-cadherin (n = 35, 55%). Decreased intensity of E-cadherin and discontinuous staining of N-cadherin in HCC was correlated with advanced stage. The risk factors for expression patterns related to recurrence were loss of E-cadherin expression (odds ratio (OR) = 3.6; 95% confidence interval (CI): 1.1-12.4) and discontinuous staining of N-cadherin (OR = 1.6; 95% CI: 0.8-3.2). In conclusion, discontinuous staining of N-cadherin and loss of E-cadherin expression in HCC predicts a high risk of recurrence after surgical treatment.     

Cadherin switching dictates the biology of transitional cell carcinoma of the bladder: ex vivo and in vitro studies

Bladder cancer is the fifth most common malignancy in the UK. Clinically, the most important process in determining prognosis is the development of invasion, initially of the lamina propria and then beyond as these transitional cell carcinomas (TCCs) progress from stage pT1 to stages T2+. Cadherins and catenins are the main mediators of cell-cell interactions in epithelial tissues, and loss of membranous E-cadherin immunoreactivity is strongly correlated with high grade, advanced stage and poor prognosis in bladder cancer and other malignancies. However, the role of P-cadherin is yet to be fully elucidated in bladder TCC. The objectives of this study were to establish how the expression of cadherins and catenins determines clinical and in vitro behaviour in bladder TCC. Utilizing immunohistochemistry, immunofluorescence and western blotting, we demonstrated a significant reduction in the expression of E-cadherin and beta-catenin as grade and stage of bladder TCC progress, accompanied by a significant increase in P-cadherin expression (all p < 0.05, Pearson's chi2 test). Increased P-cadherin expression was also associated with a significantly worse bladder cancer-specific survival (log rank p = 0.008), with Cox regression showing P-cadherin to be an independent prognostic factor. Utilizing a variety of tissue culture models in a range of functional studies, we demonstrated that P-cadherin mediates defective cell-cell adhesion and enhances anchorage-independent growth. The results provide evidence that increased P-cadherin expression promotes a more malignant and invasive phenotype of bladder cancer, and appears to have a novel role late in the disease.     

Ectopic expression of PA2.26 antigen in epidermal keratinocytes leads to destabilization of adherens junctions and malignant progression

PA2.26 antigen is a small mucin-type transmembrane glycoprotein induced in mouse epidermal keratinocytes during carcinogenesis. It is located at plasma membrane projections, such as microvilli and ruffles, where it interacts with the actin cytoskeleton. Previous studies revealed that ectopic expression of PA2.26 in epidermal MCA3D keratinocytes induces cell surface extensions and increased motility. Here, we show that PA2.26-expressing MCA3D (3D2.26) cell transfectants undergo a phenotypic conversion linked to the acquisition of malignant characteristics. The 3D2.26 cells down-regulate basal keratin K14 and up-regulate vimentin and keratin K8 expression. Immunofluorescence analysis in 3D2.26 cell cultures showed loss of cortical actin filaments and destabilization of adherens junctions mediated by E- and P-cadherin, although both cadherin mRNAs were expressed in the transfectants. When the cadherin protein levels were analyzed in Western blots, no P-cadherin protein or smaller polypeptide E-cadherin forms were detected, suggesting that E- and P-cadherin synthesized in 3D2.26 cells was unstable and proteolytically degraded. Transplantation of 3D2.26 cells into athymic nude mice induced tumors, whereas MCA3D cells and control (3DN) transfectants were not tumorigenic after 72 days postinjection. The phenotype of the tumors was undifferentiated, with mixed regions exhibiting a glandular differentiation pattern in which the presence of numerous surface microvilli was observed at the ultrastructural level. Interestingly, PA2.26 antigen was highly expressed in these microvillous cell surfaces. Tumor cells were vimentin- and K8-positive and showed an aberrant pattern of E-cadherin protein expression in which large cytoplasmic aggregates were found close to the nucleus. Infiltration of tumor cells into lymphatic vessels and the presence of frequent regional lymph node metastases were also observed in the tumors. These results indicate that expression of PA2.26 antigen in premalignant keratinocytes induces a fully transformed and metastatic phenotype, and they suggest an involvement of PA2.26 in malignant progression.     

Expression of P-cadherin, but not E-cadherin or N-cadherin, relates to pathological and functional differentiation of breast carcinomas.

AIMS: To compare the expression of the cell adhesion molecules P-cadherin, N-cadherin, and E-cadherin in invasive and in situ breast carcinomas relative to clinicopathological features (size, node status, type, grade, and receptors) to determine whether expression patterns relate to specific tumour characteristics. METHODS: Using immunohistochemistry, 110 invasive and in situ breast carcinomas were examined for the presence, extent, and localisation of all three cadherins. Findings were related to tumour size, type, grade, node status, oestrogen (ER), progesterone, and epidermal growth factor receptor (EGFR) expression for invasive carcinomas and to grade and receptors for in situ carcinomas. RESULTS: P-cadherin was detected in 40% of invasive carcinomas, N-cadherin in 30%, and E-cadherin in 81%. For invasive carcinomas, the presence of P-cadherin significantly correlated with high grade, lack of ER and presence of EGFR, but not tumour size or node status. Carcinomas containing P-cadherin could be put into three categories dependent upon receptor and E-cadherin profile. There were no correlations between E/N-cadherin and size, grade, node status, or receptors. Three of 16 infiltrating lobular carcinomas expressed cytoplasmic but none membranous E-cadherin, and P-cadherin and N-cadherin were present in four carcinomas of this type. E-cadherin was found in all ductal carcinomas in situ, P-cadherin in a proportion of high grade tumours, and N-cadherin in a mixture of grades. CONCLUSION: P-cadherin but not E/N-cadherin expression in breast carcinomas shows a strong correlation with higher grade (poorer differentiation), lack of ERs, and presence of EGFR, and its expression may aid in the further subdivision of high grade carcinomas.     

Expression of cadherin adhesion molecules on human gametes

The presence of cadherins, Ca(2+)-dependent cell-cell adhesion molecules which may be involved in gamete interaction, was investigated in human gametes. Expression of cadherin molecules was demonstrated using an anti-pan-cadherin antibody and specific antibodies against the three classical cadherins: E- (epithelial), P- (placental) and N- (neural) cadherins. Samples of 48 h old unfertilized oocytes and spermatozoa from in-vitro fertilizing semen samples were lysed and separated by electrophoresis. Localization of cadherins was determined on intact, fixed, permeabilized spermatozoa and oocytes by immunocytochemisty assessed by confocal microscopy. Immunoblotting with the pan-cadherin antibody revealed a single band of approximately 120 kDa in spermatozoa (whether 'fresh', capacitated, or frozen-thawed) and oocyte extracts. Oocytes presented all three classical cadherins with the appropriate molecular weights of 120-130 kDa. In sperm lysate we demonstrated the presence of E-cadherin but not N-cadherin. The anti-P antibody detected a 90 kDa peptide as the only immunoreactive antigen. Following immunocytochemistry of human oocytes all cadherin molecules were allocated predominantly to the plasma membrane with only traces in the cytoplasm. In spermatozoa, several staining patterns were observed with each of the pan-cadherin, N-cadherin and E-cadherin antibodies mostly confined to different head regions. We conclude that cadherin molecules are present on plasma membranes of both human spermatozoa and oocytes and may play a role in the intricate recognition process preceding gamete fusion.     

P-cadherin expression is associated with high-grade ductal carcinoma in situ of the breast

Cadherins are calcium-dependent cell-cell adhesion glycoproteins, separated into several subclasses with distinct adhesive specificities and tissue distribution, which play an important role in many cellular events. We analyse the expression of E-, N- and P-cadherin in a series of ductal carcinoma in situ (DCIS) of the breast, since this disease represents a heterogeneous group, with different risks of progression to invasive breast carcinoma. We also studied the correlation between cadherin expression and DCIS classification systems, namely the Van Nuys and the Holland et al. classification, this latter based on cytonuclear differentiation and cell polarity. Our results showed that, regardless the classification applied, P-cadherin expression is strongly associated with high histological grade of DCIS (P=0.0047) and lack of estrogen receptors (P=0.0008). The use of Holland et al. classification showed a significant correlation between P-cadherin expression and decreased cell polarity (P=0.01). In conclusion, P-cadherin expression seems to be more relevant in DCIS pathogenesis than the altered expression of any other cadherin, including the decrease of E-cadherin expression.     

Spatio-temporal relation between cadherin switching and cytogenesis of hormone-producing cells in the developing rat adenohypophysis

Cadherins are a family of transmembrane glycoproteins that mediate cell-to-cell adhesion in solid tissues and have been reported to regulate not only morphogenesis but also cell motility, proliferation, and function by activating intracellular signaling pathways. We recently found that primordial cells in the developing rat adenohypophysis co-expressed E- and N-cadherins, but endocrine cells lost E-cadherin to possess only N-cadherin at certain embryonic stages. In the present study, we aimed to elucidate the temporal relationships between cadherin expression and cell proliferation as well as between cadherin expression and the onset of hormone production in embryonic adenohypophyses. Adenohypophyses and their primordia from embryonic and postnatal rats were fixed in Bouin’s fluid and paraffin sections were routinely prepared. Multiple fluorescence immunohistochemistry was performed for combinations of E-cadherin, N-cadherin, proliferating cell nuclear antigen (a marker of proliferating cells), cyclin D1, and pituitary hormones. In primordia from embryonic days 13 through 16, proliferative activities were seen in cells that co-expressed E- and N-cadherin. Cells arrested proliferation coincidentally when they lost E-cadherin after embryonic day 16. Possession of E-cadherin was closely related with expression of cyclin D1 at this stage. Moreover, hormone production was observed from embryonic day 16 only in cells that lost E-cadherin. In the developing adenohypophysis, proliferation and differentiation of hormone-producing cells have been reported to be regulated by a variety of external humoral factors. Our results raise the possibility that changes in cadherins are closely involved in these processes.