CD44 Splice Variant v8-10 as a Marker of Serous Ovarian Cancer Prognosis (original) (raw)
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Gynecology Obstetrics and Reproductive Medicine, 2007
OBJECTIVE: Carcinogenesis and metastasis are multistep processes involving complex interactions between tumor cells and the environment. The main cause of tumor cell movement in invasive carcinomas may be the loss of the intercellular adherence junction. One adhesion receptor, CD44, binds to hyaluronan, an extracellular matrix component. This study investigated a series of benign, borderline, and malignant ovarian serous neoplasms to elucidate the role of CD44. STUDY DESIGN: Paraffin-embedded formalin-fixed blocks from benign serous tumors (n=11), benign mucinous tumors (n= 8), borderline serous tumors (n=6), borderline mucinous tumors (n=1), primary malignant ovarian serous tumors (n=9), and metastatic ovarian tumors (n=12) were stained immunohistochemically for CD44. The percentages of reactive tumor cells and stromal cells with CD44 were scored. The staining intensity was graded from 1+ to 3+. CD44 protein was preferentially expressed along the basolateral domain of the plasma me...
Clinical Significance of CD44 Expression in Serous Ovarian Cancer
Acta medica Medianae, 2020
Ovarian cancer is a devastating disease causing more than 180.000 deaths a year, with often insidious course, delayed clinical diagnosis, and limited response to therapy. The CD44 cell surface glycoprotein is involved in metastatic spread and progression in various types of cancer, including ovarian serous cancer. This study aimed to investigate the profile of CD44 immunohistochemical expression in ovarian serous cancer, and to determine its potential significance in prognosis of the disease. A total of 124 primary serous ovarian cancers were analyzed for the expression of CD44 by immunohistochemical method and assessed for possible relation with clinical and pathological parameters, as well as with patients' survival. High CD44 expression was observed in 67.7% of the investigated tumors. A positive family history of malignancies was associated with low expression CD44 in cancer cells (p = 0.004). Low expression of CD44 was more frequent in FIGO stage IV tumors than in other stages, as well as in high grade cancer compared to low grade, however these differences were not statistically significant. Mean survival was significantly longer in patients with high CD44 expression compared to those with absent or low expression (p = 0.009). The fatal outcome during the follow-up period occurred in 65% of patients with low CD44 expression, and in 42.86% of patients with high CD44 expression, with statistically significant difference between the groups (p = 0.035). In conclusion, the adverse clinical course of serous ovarian cancer was associated with the absence or low expression of CD44.
Immunohistochemical and serological evaluation of CD44 splice variants in human ovarian cancer
British Journal of Cancer, 1995
The surface glycoprotein CD44 is widely distributed in different tissues. In contrast to healthy tissue, tumour samples show a more complex pattern of CD44 expression, indicating a loss of splice control. Beside cell-surface expression, the measurement of soluble CD44 in serum of cancer patients could be useful in early diagnosis and assessment of disease status. We evaluated the surface expression of CD44 isoforms in 22 ovarian cancer patients by means of immunohistochemistry. Additionally, we investigated 134 serological samples of these patients for the occurrence of CD44 isoform expression. For CD44standard, CD44v5 and CF44v6 mean serum levels in patients with clinically detectable or non-detectable ovarian cancer were 422.4 ± 143.8 ng ml-and 547.4 ± 148.2 ng ml ', 12.3 ± 7.9 ng ml-' and 21.9 ± 12.2 ng ml-' and 105.5 + 37.9 ng ml-' and 144.9 ± 50.9 ng ml-' respectively (P-values not significant). CD44 surface proteins containing epitopes encoded by splice variants CD44v5, CD44v6 and CD44v7-8 were immunohistochemically detected in 9% (n = 2), 13% (n = 3) and 4% (n = 1) of the 22 tumour samples respectively. In the present study we showed that in ovarian cancer CD44 isoforms CD44v5 and CD44v6 are expressed in very low amounts by the tumours. In accordance with this, we found that the presence of tumour is not associated with higher serum levels of CD44standard, CD44v5 and CD44v6 in preoperative serum samples in ovarian cancer patients.
The prognostic value of CD44 isoform expression in endometrial cancer
British journal of cancer, 1998
Isoforms of the transmembrane glycoprotein CD44 have been implicated in tumour cell adhesion, tumour differentiation and metastatic spread in various human malignancies. We investigated the expression of CD44 isoforms containing variant exons v3, v5, v6 and v7-8 in 156 human endometrium cancer specimens by means of immunohistochemistry. CD44 isoforms CD44v3, CD44v5, CD44v6 and CD44v7-8 were detected in 26% (41 out of 156), 31% (48 out of 156), 22% (35 out of 156) and 15% (23 out of 156) of the tumour samples respectively. The expression of CD44 isoforms CD44v3, CD44v5 and CD44v7-8 showed no prognostic impact. In the univariate analysis, the expression of CD44v6 showed an association with shortened overall survival (log-rank test, P = 0.06). Multivariate analysis correcting for the confounding variable histological grading revealed CD44v6 not to be a prognostic factor in endometrial cancer (log-rank test, P = 0.06). Comparing the expression of CD44 isoforms CD44v3, CD44v5, CD44v6 and...
Expression and Function of CD44 in Epithelial Ovarian Carcinoma
Biomolecules, 2015
CD44, a cell surface glycoprotein, has been increasingly implicated in the pathogenesis and progression of epithelial ovarian cancer, the deadliest gynecologic malignancy in women. Here, we review recent reports on the expression and function of CD44 in epithelial ovarian carcinoma. Further functional data for CD44 in peritoneal adhesion and metastatic progression and its association with stem cells is highlighted. Recent studies utilizing CD44 for therapeutic targeting are also discussed.
Anticancer Research, 2004
Aim: To investigate the role of CD44s in the biological behavior of surface epithelial ovarian tumors and its correlation with clinicopathological parameters, prognosis, p53, steroid receptor status and proliferative indices (PCNA, MIB1). Materials and Methods: We analyzed a total of 83 patients with ovarian surface epithelial tumors, for the immunohistochemical expression of CD44s and the possible correlation with clinicopathological factors and patients' outcome. Results: A statistically significant correlation was found between the expression of CD44s, which was higher in cancer cases than in benign cystadenomas (p<0.0001) and, between cancer cases, which was lower in borderline tumors, (p=0.05). No statistical correlation was found between CD44s expression and the examined markers. In overall survival analysis we did not detect a statistically significant correlation with the expression of CD44s. Conclusion: The current study demonstrates that CD44s may be functionally involved in the pathogenesis of epithelial ovarian lesions.
Oncotarget, 2015
The clinical significance of Cluster of Differentiation 44 (CD44) remains controversial in human ovarian cancer. The aim of this study is to evaluate the clinical significance of CD44 expression by using a unique tissue microarray, and then to determine the biological functions of CD44 in ovarian cancer. In this study, a unique ovarian cancer tissue microarray (TMA) was constructed with paired primary, metastatic, and recurrent tumor tissues from 26 individual patients. CD44 expression in TMA was assessed by immunohistochemistry. Both the metastatic and recurrent ovarian cancer tissues expressed higher level of CD44 than the patient-matched primary tumor. A significant association has been shown between CD44 expression and both the disease free survival and overall survival. A strong increase of CD44 was found in the tumor recurrence of mouse model. Finally, when CD44 was knocked down, proliferation, migration/invasion activity, and spheroid formation were significantly suppressed, while drug sensitivity was enhanced. Thus, up-regulation of CD44 represents a crucial event in the development of metastasis, recurrence, and drug resistance to current treatments in ovarian cancer. Developing strategies to target CD44 may prevent metastasis, recurrence, and drug resistance in ovarian cancer.
OBSTETRICS & GYNECOLOGY, 2016
OBJECTIVE: To investigate the role of cancer stem cell marker CD44 variant 6 in the development of distant metastasis in patients with epithelial ovarian cancer. METHODS: Aretrospectivecohortstudywasperformed in 186 patients who underwent surgery for ovarian cancer from 2005 to 2013 at the Kumamoto University Hospital. The association between the expression of CD44 variant 6 and distant metastasis was evaluated based on a large-scale immunohistochemical analysis. Primary ovarian tumors that contained at least 10% CD44 variant 6–positive cancer cells were categorized as CD44v6-high (n553), and the tumors that contained less than 10% CD44 variant 6–positive cells were categorized as CD44v6-low (n5133). Distant metastasis–free survival was compared between the CD44v6-high and -low groups. Multivariate analysis was performed to estimate the influence of various clinicopathologic factors on the development of distant metastasis. RESULTS: At the time of ovarian cancer diagnosis, distant metastasis occurred in 13 of 53 patients (24.5%) in the CD44v6-high group and 17 of 133 patients (12.8%) in the CD44v6-low group (P5.049). The median metastasis-free survival after stage I–III ovarian cancer diagnosis was 19.5 months (range 11–55 months) in the CD44v6-high group (n540) and 39.5 months (range 22–57 months) in the CD44v6-low group (n5116) (P5.071). Multivariate analysis demonstrated that CD44 variant 6 expression was an independent risk factor for distant metastatic recurrence (hazard ratio 4.09, 95% confidence interval 1.29–12.98; P5.017). CONCLUSION: CD44 variant 6 represents an important predictor of distant metastasis and CD44 variant 6–positive ovarian cancer cells play a crucial role in the formation of distant metastases in patients with ovarian cancer.
Gynecologic Oncology, 1997
tion of adhesion molecules is thought to play an important CD44 is a cell-surface glycoprotein postulated to play a role in role in cell detachment from primary tumors [3], interactions tumor-cell metastasis. We have examined the expression of the with hematopoietic cells during circulation [4], and attachstandard CD44 (CD44s), and alternative spliced variants of CD44 ment to the endothelium in target organs [5]. containing variant exons v6, v9, and v10 (CD44v6, CD44v9, and CD44 is a widely expressed cell surface glycoprotein that CD44v10 respectively) in 9 samples of normal cervix, 6 samples serves as an adhesion molecule in cell-substrate and cellof cervical intraepithelial neoplasia (CIN), and 11 samples with cell interactions, including lymphocyte homing, hemopoieinvasive cervical carcinomas. RT/PCR demonstrated the presence sis, cell migration, and metastasis [6]. Genomically, CD44 of CD44s in all samples of normal cervix and those with invasive is constructed from a maximum of 20 exons [7]. Ten exons carcinomas. CD44v6 was also found in all normal cervical samples between exons 5 and 15 are called variant exons and are and in 9 tissue samples of invasive carcinomas. The results also alternatively spliced with various combinations. The smallsuggested that some tumor specimens had several higher molecular transcripts containing exon v6 compared to specimens of nor-est form of CD44 which does not contain the epitope enmal cervix. Immunohistochemistry detected the presence of CD44s coded by variant exons is called standard CD44 (hematopoiand the absence of CD44v10 in both epithelial and stromal cells etic form), whereas various types of CD44 which do contain in all specimens. In contrast, CD44v6 and CD44v9 were stained epitopes encoded by variant exons are called variant CD44. positive in epithelial cells but were absent in stromal cells. The One of the variants, CD44v6, was shown to confer highly intensity of CD44v6 and CD44v9 staining was strongest in normal metastatic properties to nonmetastatic rat pancreatic carcicervical epithelium followed by CIN, invasive squamous cell carcinoma cells [8]; it has since been shown to be expressed in noma, and adenocarcinoma. In the malignant samples, heterogea wide variety of metastatic tumors including colon [9], neity in staining intensity among different clusters of tumor cells gastric [10], breast [9, 11, 12], and brain cancer [13], and a was observed. Furthermore, poorly differentiated and undifferenticontributory role in metastasis has been suggested. Although ated carcinomas from patients having poor prognosis did not stain there have been several reports on the expression of CD44 at all. This study suggests that variant CD44 molecules may serve an important function in the cell contact of cervical epithelial and its variants in gynecological tissues such as specimens cells, and that cervical epithelium acquires heterogeneity in the of ovarian cancer [14, 15], endometrial cancer [16], and expression of CD44 adhesion molecules during carcinogenesis, uterine cervical cancer [17], very little is known about their which may be related to tumor metastasis.