Overexpression of CD44 Variant 6 in Human Endometrial Cancer and Its Prognostic Significance

doi:10.1006/gyno.2000.6014

Gynecologic Oncology

Volume 80, Issue 3, March 2001, Pages 355-358

https://doi.org/10.1006/gyno.2000.6014 Get rights and content

Abstract

Objective. We evaluated the prognostic significance of CD44 isoform CD44 V6 in endometrial cancer.

Method. Immunohistochemistry was used to determine the expression of CD44 V6 in 78 randomly selected endometrial cancer specimens.

Results. CD44 V6 was detected in 53% (41/78) of the tumor samples. Clinicopathological evaluation revealed an inverse correlation with CD44 V6 expression and conventional poor prognosticators such as lower segment involvement, nuclear and structural grade, myometrial invasion, serosal involvement, lymph-vascular space invasion, and adnexal metastasis. Furthermore, the CD44 V6-negative group was found to be associated have a higher recurrence rate and a shorter disease-free survival.

Conclusion. These findings indicate that absence of CD44 V6 expression in cases of endometrial cancer might be coupled with a more aggressive course.

References (20)

AH Wolfson et al.
The prognostic significance of surgical staging for carcinoma of the endometrium
Gynecol Oncol
(1992)
TO Wilson et al.
Evaluation of unfavourable subtypes in endometrial adenocarcinoma
Am J Obstet Gynecol
(1990)
PJ Disaia et al.
Risk factors and recurrent patterns in stage I endometrial cancer
Am J Obstet Gynecol
(1985)
CP Morrow et al.
Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium a Gynecologic Oncology Group study
Gynecol Oncol
(1991)
M Katsura et al.
Overexpression of CD44 variants 6 and 7 in human endometrial cancer
Gynecol Oncol
(1998)
K Tokumo et al.
CD44 exon V6 is not implicated in the progression and metastasis of endometrial cancer
Cancer Lett
(1998)
C Kainz et al.
Splice variants of CD44 in human cervical cancer stage IB to IIB
Gynecol Oncol
(1995)
N Yaegashi et al.
Menstrual cycle dependent expression of CD44 in normal human endometrium
Hum Pathol
(1995)
SL Parker et al.
Cancer statistics, 1996
CA Cancer J Clin
(1996)

There are more references available in the full text version of this article.

Cited by (37)

Cell adhesion molecules in endometrial cancer – A systematic review
2019, Advances in Medical Sciences
Citation Excerpt :
They suggest that the lack of CD44v6 expression in endometrial cancer can be correlated with a more aggressive course. Also, Ayhan et al. [57] revealed an inverse correlation of CD44v6 expression with tumor size, lower uterine segment invasion, nuclear and structural grade, infiltration of the myometrium and serous membrane, invasion of lymphatic spaces and metastases to the appendages. Moreover, they found that patients with negative expression of CD44v6 in cancer cells showed a higher percentage of recurrences and shorter disease-free survival time.
Adhesive molecules are responsible for the cell-cell interaction and the surrounding intercellular environment creating normal tissue architecture. The role of adhesion proteins in cancer refers to angiogenesis, loss of tissue continuity, and deprivation of intercellular contact with the extracellular matrix, promoting the spread of cancer through the formation of metastases. The integrity of the epithelium is disturbed – with disturbances in the whole mechanism of cell connections, thanks to which cancer cells infiltrate surrounding tissues, and move to lymphatic and blood vessels. Adhesive molecules are divided into five main families: cadherin, catenins, integrins, the immunoglobulin superfamily and non-classical adhesion molecules. In the present review we describe the role of all five families of adhesive molecules in endometrial cancer.
Immunohistochemical expression of cancer stem cell related markers CD44 and CD133 in endometrial cancer
2016, Pathology Research and Practice
Citation Excerpt :
In the relevant literature, the correlation between CD44 and LVSI also varies. Many reported that loss of CD44, particularly CD44v6, is of interest in advanced-stage disease, which is similar to our findings [26,31–33]. Leblanc et al. [34] and Yorishima et al. [35] found positive relationships between LVSI and CD44v6 expression, which implies that molecules affect local invasion.
The goal of this study was to detect the presence of cancer stem cell markers CD44 and CD133 in immunohistochemically stained samples of endometrial cancer and correlate their expression with clinicopathological variables to identify the impact of CD44 or CD133 expression on tumor behavior and endometrial carcinogenesis. Marker expression was analyzed in 62 endometrial cancer samples (57 endometrioid carcinoma and 5 carcinosarcoma) and 15 proliferative endometrium samples. We detected CD133 and CD44 expression in 87.09% and 79.03% respectively of the studied endometrial cancers, and the expression was significantly different from the normal group. CD44 expression decreased with myometrial invasive depth and lymph-vascular space invasion (LVSI), and these inverse relationships were significant (p = 0.034, p = 0.019, respectively). CD133 was more expressed by early stage tumor (FIGO I-II) compared with those having FIGO III to IV stage disease (p = 0.021). The most notable conclusion of the present study is that CD44 and CD133 might participate in early-stage endometrial cancer carcinogenesis, and their overexpression may facilitate the early diagnosis of endometrial cancers. Analysis of our results supports the hypothesis that CD44 expression tends to decrease as the disease becomes invasive and progressive. So, we concluded that CD44 down-regulation might warn of a more aggressive course and may have a link with poorly prognosis carcinosarcomas. Further examination of the expression and function of CD44 and CD133 with a greater number of carcinosarcomas is warranted.
Advances and advantages of nanomedicine in the pharmacological targeting of hyaluronan-CD44 interactions and signaling in cancer
2014, Advances in Cancer Research
Citation Excerpt :
Hyaluronan induces intracellular signaling when it binds to “constitutively activated” CD44 variants during cell dynamic processes, but does not do so under conditions of adult tissue homeostasis, which generally involve the standard form of CD44 (CD44s). Overexpression of variant, high molecular weight (HMW) isoforms CD44v4-v7 and CD44v6-v9 in various cancers (Ayhan, Tok, Bildirici, & Ayhan, 2001; Foekens et al., 1999; Gunthert et al., 1991; Ishida, 2000) as well as downregulation of the standard CD44s isoform in colon cancer is postulated to result in increased tumorigenicity (Choi, Takahashi, Eto, Yoon, & Tanabe, 2000), emphasizing the potential importance of CD44 splice variants in cancer (Misra et al., 2011). A puzzling aspect of many studies of hyaluronan-induced oncogenic signaling is their basis in experiments in which exogenous hyaluronan is added to cultured tumor cells.
Extensive experimental evidence in cell and animal tumor models show that hyaluronan–CD44 interactions are crucial in both malignancy and resistance to cancer therapy. Because of the intimate relationship between the hyaluronan–CD44 system and tumor cell survival and growth, it is an increasingly investigated area for applications to anticancer chemotherapeutics. Interference with the hyaluronan–CD44 interaction by targeting drugs to CD44, targeting drugs to the hyaluronan matrix, or interfering with hyaluronan matrix/tumor cell-associated CD44 interactions is a viable strategy for cancer treatment. Many of these methods can decrease tumor burden in animal models but have yet to show significant clinical utility. Recent advances in nanomedicine have offered new valuable tools for cancer detection, prevention, and treatment. The enhanced permeability and retention effect has served as key rationale for using nanoparticles to treat solid tumors. However, the targeted and uniform delivery of these particles to all regions of tumors in sufficient quantities requires optimization. An ideal nanocarrier should be equipped with selective ligands that are highly or exclusively expressed on target cells and thus endow the carriers with specific targeting capabilities. In this review, we describe how the hyaluronan–CD44 system may provide such an alternative in tumors expressing specific CD44 variants.
Cadherins, catenins and cell cycle regulators: Impact on survival in a Gynecologic Oncology Group phase II endometrial cancer trial
2011, Gynecologic Oncology
Citation Excerpt :
A significant relationship was not observed between the expression of CD44 and PFS or OS. While our analysis focused on standard CD44, the subject of many has been the splice variants (isoforms), especially CD44 v6 and has yielded contradictory trends, but falling short of statistical significance [37–41]. The sample size is a limitation that should be addressed in future investigations.
We evaluated the clinical relevance of catenins, cadherins and cell cycle regulators in stage IV or recurrent endometrial carcinoma in a multi-center phase II trial (GOG protocol #119).
Tissue microarrays of metastatic or recurrent (n = 42) tumor were developed and immunohistochemistry was performed. Average expression (percent staining x intensity) was assessed in tumor epithelium (^E) and stroma (^S) and categorized into tertiles (T1, T2, T3) for E-cadherin^E, N-cadherin^E, alpha-catenin^E, beta-catenin^E, gamma-catenin^E, p120-catenin^E and Ki-67^E; as negative, below median or above median for p16^E, p27^E and CD44^S; or as negative or positive for p53^E, Ki-67^S and APC^S (adenomatous polyposis coli). End points included response and survival.
E-cadherin^E, p16^E, and p53^E varied by race (p = 0.003, p = 0.024, p = 0.002,) and N-cadherin^E, Ki-67^E, p16^E and p27^E by tumor type (p = 0.015, p = 0.011, p = 0.005, p = 0.021). Correlations were observed among E-cadherin^E with p120^E (r = 0.66), p53^E (r = − 0.32), alpha-catenin^E (r = 0.52), beta-catenin^E (r = 0.58), and gamma-catenin^E (r = 0.58). High E-cadherin^E (T2 or T3) versus low (T1) expression was associated with better survival in unadjusted (hazard ratio [HR] = 0.14, 95% confidence interval [CI] = 0.06–0.37 or HR = 0.17, 95% CI = 0.07–0.42) and adjusted models (HR = 0.18, 95% CI = 0.05–0.59 or HR = 0.22, 95% CI = 0.07–0.70). High p16^E versus negative expression was associated with worse survival in unadjusted (HR = 3.87, 95% CI = 1.74-8.61) and adjusted (HR = 4.18, 95% CI = 1.28–13.6) models. Positive versus negative expression of p53^E was associated with worse survival in unadjusted (HR = 2.31, 95% CI = 1.16–4.60) but not adjusted models.
E-cadherin^E and p16^E appear to be clinically relevant, independent prognostic factors in stage IV or recurrent endometrial cancers treated with Tamoxifen and Medroxyprogesterone acetate, and merit further study.
Delivery of CD44 shRNA/nanoparticles within cancer cells. Perturbation of hyaluronan/CD44v6 interactions and reduction in adenoma growth in Apc Min/+mice
2009, Journal of Biological Chemistry
Our studies have shown that constitutive interactions between hyaluronan and CD44 on tumor cells induces various anti-apoptotic cell survival pathways through the formation of a multimeric signaling complex that contains activated receptor tyrosine kinases. Inhibition of the hyaluronan-CD44 interactions on tumor cells by hyaluronan-CD44 interaction antagonists suppresses these activities by disassembling the complex. Although the anti-tumor activity of hyaluronan-oligosaccharides, a hyaluronan-CD44 interaction antagonist, is effective in sensitizing tumor cells to chemotherapeutic agents and reducing tumor growth in xenografts, hyaluronan-oligosaccharide alone was not effective in reducing tumor progression in Apc Min/+ mice. We now show in vitro and in vivo that targeted inhibition of the expression of CD44v6 depletes the ability of the colon tumor cells to signal through hyaluronan-CD44v6 interactions. First, we cloned oligonucleotides coding CD44v6 shRNA into a conditionally silenced pSico vector. Second, using pSico-CD44v6 shRNA and a colon-specific Fabpl promoter-driven Cre recombinase expression vector packaged into transferrin-coated nanoparticles, we successfully delivered the CD44v6 shRNA within pre-neoplastic and neoplastic colon malignant cells. Third, using the Apc Min/+ mice model, we demonstrated that inhibition of the CD44v6 expression reduces the signaling through a hyaluronan/CD44v6-pErbB2-Cox-2 interaction pathway and reduced adenoma number and growth. Together, these data provide insight into the novel therapeutic strategies of short hairpin RNA/nanoparticle technology and its potential for silencing genes associated with colon tumor cells.
CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas
2004, Modern Pathology
The natural course of pheochromocytomas (PCC) cannot be predicted for certain on the basis of primary histology, their malignant character can only be confirmed by the occurrence of metastases during follow-up. Based on the recently proposed PASS score for evaluation we examined 37 adrenal (36 sporadic and one familial) and six sporadic extra-adrenal paragangliomas (all designated as pheochromocytomas) with a ‘malignant histology’ to find additional predictive factors. Drawing upon the follow-up (18 months to 12 years, mean 5.8 years) metastasized (n=20) and nonmetastasized (n=23) courses could be distinguished. Metastasized PCC revealed significantly (P=0.03) more copy number changes on comparative genomic hybridization (CGH) (mean 8.3) than nonmetastasized tumors (mean: 4.3). The most frequent chromosomal alterations were losses on 1p (75.6%) and 3q (44%). Both were detected with identical frequency in metastasized and nonmetastasized PCC. A gain on 17q (P=0.025) was significantly predominant in malignant courses and suggests similarities in the genetic origin and progression of PCC and neuroblastomas. The proliferative activity (MIB-1 score) of metastasized PCC (n=20) was found to be significantly higher in metastasized tumors (mean 12.8% vs mean 3.5%). In contrast, the semiquantitatively scored membrane-bound staining of CD 44-S was stronger in tumors without metastases (mean 2.1 vs mean: 0.25) during the follow-up period (P<0.01). Although the results correspond to the established weight differences the tumor weight does not appear to be an independent prognostic factor. Our study suggests that CD 44-S and MIB-1 immunostaining as well as the CGH results might complement the PASS score in predicting a metastasized course of PCC. Regardless of tumor weight, tumors with a ‘malignant histology’ are highly prone to metastasize when more than 5% of MIB1-positive nuclei are present or CD44-S immunostaining is negative, or both. PCC with 10 or more copy number changes on CGH must be referred to as malignant tumors.

View all citing articles on Scopus

¹: To whom correspondence should be addressed at Hacettepe Üniversitesi Tip Fakültesi, Kadin Hastaliklan ve Doğum ABD, 06100, Sihhiye, Ankara, Turkey. Fax: +90 312 311 63 72/+90 312 447 39 99. E-mail: [email protected].

View full text

Regular ArticleOverexpression of CD44 Variant 6 in Human Endometrial Cancer and Its Prognostic Significance

Abstract

Gynecol Oncol

Am J Obstet Gynecol

Am J Obstet Gynecol

Gynecol Oncol

Gynecol Oncol

Cancer Lett

Gynecol Oncol

Hum Pathol

Cancer statistics, 1996

CA Cancer J Clin

Regular Article
Overexpression of CD44 Variant 6 in Human Endometrial Cancer and Its Prognostic Significance