Expression Of V6 Research Articles

Importance of different CD44v6 expression in human gastric intestinal and diffuse type cancers for metastatic lymphogenic spreading

In 42 human gastric adenocarcinomas of intestinal (n = 25) and diffuse types (n = 17) the expression of CD44v6 splice variants was investigated immunohistochemically and compared with the pattern of lymphogenic tumor spreading. Distinct differences were observed between the two cancer types: 92% of intestinal-type tumors expressed CD44v6 as in the intestinal metaplasia in chronic atrophic gastritis, while v6 expression occurred in only 17% of diffuse-type cancers. The analysis of RNA expression confirmed the immunohistochemical data. Intestinal-type cancers yielded a much more complex pattern of amplification products hybridizing to exon v6 than did normal mucosa, whereas diffuse-type tumors did not express exon v6. Also the pattern of lymphogenic spreading was quite different between the two cancer types: in diffuse-type tumors only a sinus carcinosis without CD44v6 expression was observed in a significantly higher number of lymph nodes than in intestinal-type cancers, which showed in particular infiltrative lymph node metastases always with CD44v6 expression as in the primary tumors. When infiltrative lymph node invasion occurred in v6-negative diffuse-type cancers, v6 neoexpression was also demonstrable in the lymph node metastases. Additionally, the number of infiltrative lymphogenic metastases increased with more extensive v6 expression in primary gastric cancers of both types. These data suggest that the expression of CD44v6 isoform is important for the infiltrative spreading of tumor cells into lymph nodes. Additionally, the phenotypic similarities in v6 expression between intestinal metaplasia and intestinal-type cancers, but not of tumors of diffuse type, may support the Correa hypothesis.

CD44 in colon cancer.

Alternative splicing of ten different variant exons (v1-v10) is responsible for the creation of a large number of different CD44 surface proteins. Some of these proteins play decisive roles in the metastatic spread of rat tumours. Also in human cancers, CD44 splice variants are frequently expressed in advanced states of tumorigenesis. In breast cancer and in non-Hodgkin's lymphomas expression of exon v6 is correlated with poor prognosis of patient survival. In colorectal carcinogenesis, expression of exon v5 is an early tumour marker since it is already detectable on small dysplastic polyps (but not on normal colon epithelium). In contrast, exon v6 expression occurred with increased frequency with tumour progression, and its expression on colorectal tumours indicated reduced survival probability. Most likely, tumours carrying the CD44 v6 epitope acquire selective advantage during tumour progression and metastasis formation. This could be a proliferative advantage since mice transgenic for the CD44 isoform CD44v4-v7 on T lymphocytes show an accelerated T-dependent immune response as compared with non-transgenic siblings.

Splice Variants of CD44 in Human Cervical Cancer Stage IB to IIB

Aberrant expression of the cell adhesion molecule CD44 has been detected in human tumors and the expression of specific CD44 isoforms (splice variants) has been shown to be associated with metastasis and poor prognosis in human malignancies. We used three different variant exon sequence-specific murine monoclonal antibodies to epitopes encoded by exon v5, exon v6, or exon v7-v8 of human variant CD44 to study the expression of CD44 splice variants by immunohistochemistry in human cervical cancer. One-hundred five patients with surgically treated squamous cell carcinomas of the cervix stages IB to IIB were included in the study. CD44 splice variants CD44v5, CD44v6, and CD44v7-8 were detected in 70, 67, and 26%, respectively. Tumors expressing exon v6 had significantly more often metastasized to the pelvic nodes (58 vs 79%, P = 0.04). Expression of exon v6 was significantly correlated with a greater probability of vascular space invasion (73 vs 50%, P = 0.04) and a significantly lower rate of inflammatory stromal reaction (48 vs 78%, P = 0.004). Patients suffering from tumors expressing splice variant CD44v6 showed poorer overall survival (P = 0.03). In cases with negative pelvic lymph nodes we found a poorer prognosis when tumors expressed CD44v6 (P = 0.01) or CD44v7-8 (P = 0.02). Among the investigated CD44 splice variants expression of exon v6 is the most promising prognostic marker in surgically treated cervical cancer.

Ulcerative colitis is differentiated from other colonic inflammatory by CD44 v3 and v6 expression: [formula omitted], C. Prince, L. Kaklamanis, D. Jackson, D.L.I. Simmons, D.P. Jewell, R.W. Chapman, J. M. Trowell and J.I. Bell. Nuffield Depts. of Clinical Medicine and Pathology, Oxford, England

Ulcerative colitis is differentiated from other colonic inflammatory by CD44 v3 and v6 expression: [formula omitted], C. Prince, L. Kaklamanis, D. Jackson, D.L.I. Simmons, D.P. Jewell, R.W. Chapman, J. M. Trowell and J.I. Bell. Nuffield Depts. of Clinical Medicine and Pathology, Oxford, England

Differential expression of the human metastasis adhesion molecule CD44V in normal and carcinomatous stomach mucosa of Chinese subjects.

CD44 is a cell surface adhesion molecule involved in cell-cell and cell-matrix interactions. Tumor cells transfected to overexpress the isoform CD44V readily gain access to lymph nodes and form distant metastases. Monoclonal antibodies directed at epitopes common to known CD44 isoforms were used to investigate CD44V expression in 30 normal gastric mucosa tissues, 64 different gastric adenocarcinomas, 20 metastatic adenocarcinoma lymph nodes and 4 established gastric carcinoma cell lines. In addition, CD44V gene expression in six gastric adenocarcinoma tissues and four gastric cancer cell lines were investigated by northern blotting. Immunohistochemistry screening of 30 subjects with normal gastric mucosa did not reveal expression of CD44 variants. Areas of intestinal metaplasia, a precancerous lesion, were stained with antibodies against either V5- or V6-containing isoforms of CD44. Tubular and signet-ring cell types of adenocarcinoma were strongly positive for epitopes encoded by CD44 variants containing exons V5 (41/49 and 10/10, respectively). Some tubular type adenocarcinomas (15/49) also expressed CD44 variants containing the V6 epitope. Tumor differentiation was closely related to CD44 V5 expression (P < 0.001). In addition, 18 of 20 gastric adenocarcinomas metastatic to lymph nodes expressed the V5 epitope of CD44 and 4 of 20 expressed the V6 epitope. Analysis of four established gastric adenocarcinoma cell lines revealed that two had moderate to strong expression of exons V5 and V6 of CD44. An antibody directed against CD44 variants containing exons V8 to V10 strongly stained all gastric adenocarcinoma cell lines. Northern blotting demonstrated that all four tumor cell lines and six gastric carcinoma mucosa tissues expressed CD44V. Generation of CD44 splice variants may be closely linked with gastric carcinoma tumorigenesis and differentiation. In addition, expression of CD44 variants containing exons V5 and V6 may be used as an indicator of evolving gastric cancer.

CD44-Splice-Varianten als Prognosefaktoren beim invasiven Zervixkarzinom

Aberrant expression of specific isoforms of the cell adhesion molecule CD44 has been detected in various malignant human tumors. We wanted to verify whether the expression of these splice variants was associated with a higher incidence of metastasis and poor prognosis. We studied the expression of CD44 splice variants v5, v6 and v7-8 by immunohistochemistry in human cervical cancer. 105 surgically treated patients with cervical cancer of stages IB-IIB were included in the study. Tumors expressing exon v6 had significantly more often metastasized to the pelvic nodes (p = 0.04), and patients suffering from tumors expressing CD44v6 showed poorer overall survival. Even in cases with negative pelvic lymph nodes, we found a significantly poorer prognosis when tumors expressed CD44v6. Among the investigated CD44 splice variants, expression of exons v6 and v7-8 is the most promising prognostic marker in cervical cancer. They can possibly identify patients with an increased risk earlier than morphologic prognostic parameters.

Expression of mutant p53 protein and CD44 variant proteins in colorectal tumorigenesis.

Colorectal tumorigenesis evolves through a series of molecular genetic changes, providing putative markers for tumour progression. This study investigated the relation between expression of the tumour suppressor gene p53 and splice variants v5 and v6 of the cell adhesion molecule CD44 by immunohistochemistry on tissue samples of early adenomas (n = 12), late adneomas (n = 12), Dukes's A and B carcinomas (n = 21), and Dukes's C and D carcinomas (n = 22) and compared these results with expression of these proteins in normal colonic mucosa (n = 17). A statistically significant trend of increasing expression was seen for both p53 (p < 0.005) and CD44 variant exon v6 (p < 0.0005) in subsequent stages of this tumour progression model. High expression of CD44 v5 was seen in most colorectal neoplasms (83%-96%), independent of stage. A statistically significant correlation was present between p53 expression and expression of variant v6 of CD44 (p < 0.01). Both p53 expression and CD44 v6 expression in adenomas increased with the degree of dysplasia (p < 0.05). The results of this study show that mutant p53 protein and variant v6 of the CD44 glycoprotein are markers of tumour progression in colorectal cancer.