Clinical relevance of CD44 surface expression in advanced stage serous epithelial ovarian cancer: a prospective study

Elzarkaa, Alaa A; Sabaa, Bassma El; Abdelkhalik, Doaa; Mansour, Hassan; Melis, Mahmoud; Shaalan, Waleed; Farouk, Mohamed; Malik, Eduard; Soliman, Amr A.

doi:10.1007/s00432-016-2116-5

Cited by 19 publications

(15 citation statements)

References 25 publications

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“…We found five and seven ovarian cancer cell lines to be CD24- and CD44-positive, respectively ( Table I ). In some studies, CD44 expression has been associated with epithelial to mesenchymal transition and shorter disease-free and overall survival in patients with ovarian cancer ( 67 , 68 ). In this study, we found that treatment of SKOV3 cells with both afatinib and erlotinib was accompanied by the downregulation of CD44 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of small molecule tyrosine kinase inhibitors and cytotoxic drugs

Puvanenthiran

Essapen

Seddon

et al. 2016

International Journal of Oncology

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Increased expression and activation of human epidermal growth factor receptor (EGFR) and HER-2 have been reported in numerous cancers. The aim of this study was to determine the sensitivity of a large panel of human ovarian cancer cell lines (OCCLs) to treatment with various forms of small molecule tyrosine kinase inhibitors (TKIs) and cytotoxic drugs. The aim was to see if there was any association between the protein expression of various biomarkers including three putative ovarian cancer stem cell (CSC) markers (CD24, CD44, CD117/c-Kit), P-glycoprotein (P-gp), and HER family members and response to treatment with these agents. The sensitivity of 10 ovarian tumour cell lines to the treatment with various forms of HER TKIs (gefitinib, erlotinib, lapatinib, sapitinib, afatinib, canertinib, neratinib), as well as other TKIs (dasatinib, imatinib, NVP-AEW541, crizotinib) and cytotoxic agents (paclitaxel, cisplatin and doxorubicin), as single agents or in combination, was determined by SRB assay. The effect on these agents on the cell cycle distribution, and downstream signaling molecules and tumour migration were determined using flow cytometry, western blotting, and the IncuCyte Clear View cell migration assay respectively. Of the HER inhibitors, the irreversible pan-TKIs (canertinib, neratinib and afatinib) were the most effective TKIs for inhibiting the growth of all ovarian cancer cells, and for blocking the phosphorylation of EGFR, HER-2, AKT and MAPK in SKOV3 cells. Interestingly, while the majority of cancer cells were highly sensitive to treatment with dasatinib, they were relatively resistant to treatment with imatinib (i.e., IC50 >10 μM). Of the cytotoxic agents, paclitaxel was the most effective for inhibiting the growth of OCCLs, and of various combinations of these drugs, only treatment with a combination of NVP-AEW541 and paclitaxel produced a synergistic or additive anti-proliferative effect in all three cell lines examined (i.e., SKOV3, Caov3, ES2). Finally, of the TKIs, only treatment with afatinib, neratinib and dasatinib were able to reduce the migration of HER-2 overexpressing SKOV3 cells. We did not find any significant association between the expression of putative ovarian CSC marker, HER family members, c-MET, ALK, and IGF-IR and the response to the irreversible HER TKIs. Our results support the need for further investigations of the therapeutic potential of these irreversible HER family blockers in ovarian cancer, and the therapeutic potential of dasatinib when used in combination with the inhibitors of the HER family members in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of small molecule tyrosine kinase inhibitors and cytotoxic drugs

Puvanenthiran

Essapen

Seddon

et al. 2016

International Journal of Oncology

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“…CD44 is the hyaluronate receptor and is important in adhesion. In ovarian cancer CD44 correlates with chemoresistance and tumor progression [74][75][76] . One function of CD44 is to activate Stat3 77 .…”

Section: Cell Surface Markersmentioning

confidence: 99%

Can Stemness and Chemoresistance be Therapeutically Targeted via Signaling Pathways in Ovarian Cancer?

Roy

Dahl²

2018

Preprint

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Ovarian cancer is the most lethal gynecological malignancy. Poor overall survival, particularly for patients with high grade serous (HGS) ovarian cancer, are often attributed to late stage at diagnosis and relapse following chemotherapy. HGS ovarian cancer is a heterogenous disease in that few genes are consistently mutated between patients. Additionally, HGS ovarian cancer is characterized by high genomic instability. For these reasons personalized approaches may be necessary for effective treatment and cure. Understanding the molecular mechanisms that contribute to tumor metastasis and chemoresistance are essential to improve survival rates. One favored model for tumor metastasis and chemoresistance is the cancer stem cell (CSC) model. CSCs are cells with enhanced self-renewal properties that are enriched following chemotherapy. Elimination of this cell population is thought to be a mechanism to increase therapeutic response. Therefore, accurate identification of stem cell populations that are most clinically relevant is necessary. While many CSC identifiers (ALDH, OCT4, CD133, and side population) have been established, it is still not clear which population(s) will be most beneficial to targeted in patients. Therefore, there is a critical need to characterize CSCs with reliable markers and find their weaknesses that will make the CSCs amenable to therapy. Many signaling pathways are implicated for their roles in CSC initiation and maintenance. Therapeutically targeting pathways needed for CSC initiation or maintenance may be an effective way of treating HGS ovarian cancer patients. In conclusion, the prognosis for HGS ovarian cancer may be improved by combining CSC phenotyping with targeted therapies for pathways involved in CSC maintenance.

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“…Positive CD44 expression was demonstrated to be a prognostic indicator of shorter survival time in patients with ovarian cancer (4-7). CD44 expression was also reported to contribute to the development of carboplatin resistance in advanced serous epithelial ovarian cancer, and contribute to a worse prognosis for these patients (7). In addition, epithelial cadherin (E-cadherin) is a calcium-dependent cell-cell adhesion glycoprotein.…”

Section: Introductionmentioning

confidence: 99%

Effects of CD44 and E‑cadherin overexpression on the proliferation, adhesion and invasion of ovarian cancer cells

et al. 2017

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Abstract. CD44 is a prognostic indicator of shorter survival time in ovarian cancer. E-cadherin fragmentation promotes the progression of ovarian cancer. However, the effects of CD44 and E-cadherin overexpression on ovarian cancer cells have remained elusive. The present study aimed to investigate the effects of overexpression of CD44 and E-cadherin on cell proliferation, adhesion and invasion of SKOV-3 and OVCAR-3 ovarian cancer cells. Overexpression of CD44 and E-cadherin was achieved by transfecting SKOV-3 and OVCAR-3 cells with viruses carrying the CD44 or E-cadherin gene, respectively. Expression of CD44 and E-cadherin was detected by western blot analysis. The proliferation of SKOV-3 and OVCAR-3 cells was measured by a Cell Counting Kit-8 at 0, 24 and 48 h after viral transfection. The adhesion ability of SKOV-3 and OVCAR-3 cells to the endothelial layer was detected. A Transwell invasion assay was utilized to assess the invasion ability of the cells. Overexpression of CD44 and E-cadherin in SKOV-3 and OVCAR-3 cells was confirmed by western blot. Compared with the blank or negative control groups, the CD44 overexpression groups of SKOV-3 and OVCAR-3 cells exhibited an increased cell proliferation rate at 24 and 48 h, whereas overexpression of E-cadherin did not alter the proliferation of these cells. Furthermore, compared with the blank and negative control groups, the cell adhesion and invasion ability in the CD44 overexpression groups of SKOV-3 and OVCAR-3 cells was markedly higher. There were no significant differences in adhesion ability between the E-cadherin overexpression group and the blank/negative control group. Of note, overexpression of E-cadherin decreased the invasive ability of SKOV-3 and OVCAR-3 cells. In conclusion, Overexpression of CD44 increased the proliferation, adhesion and invasion of ovarian cancer cells, while overexpression of E-cadherin decreased the invasion of ovarian cancer cells. IntroductionOvarian cancer is a common malignant tumor type of the female reproductive system with a high mortality rate. The 5-year survival rate of patients with ovarian cancer is 25-30% (1). Although progress has been made in the treatment of ovarian cancer, the mortality rate remains high. The majority of ovarian cancer patients have tumor metastasis at the time-point of diagnosis, and tumor invasion and metastasis are important causes of treatment failure (2). Therefore, investigation of the molecular mechanisms involved in tumor proliferation, adhesion and invasion is of great importance for improving the therapeutic effectiveness of ovarian cancer treatments.CD44 is a transmembrane protein that mediates cell-cell interactions as well as cell adhesion and migration. It is widely expressed on the cell surface (3). CD44 participates in numerous biological processes such as tumor metastasis, hematopoiesis, lymphocyte activation, recirculation and homing. CD44 is a receptor for hyaluronic acid and interacts with other ligands, such as matrix metalloproteinases, collagens and osteopontin (3). Posit...

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Clinical relevance of CD44 surface expression in advanced stage serous epithelial ovarian cancer: a prospective study

Abstract: CD44 expression contributes to the development of carboplatin resistance in advanced serous EOC, and it may contribute to worse prognoses for patients, but it is neither an independent predictor of survival nor of recurrence.

Cited by 19 publications

References 25 publications

Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of small molecule tyrosine kinase inhibitors and cytotoxic drugs

Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of small molecule tyrosine kinase inhibitors and cytotoxic drugs

Can Stemness and Chemoresistance be Therapeutically Targeted via Signaling Pathways in Ovarian Cancer?

Effects of CD44 and E‑cadherin overexpression on the proliferation, adhesion and invasion of ovarian cancer cells

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