HER2 decreases drug sensitivity of ovarian cancer cells via inducing stem cell-like property in an NFκB-dependent way

Abstract Increasing evidence shows that cancer stem cells are responsible for drug resistance and relapse of tumors. In breast cancer, human epidermal growth factor receptor 2 (HER2) induces Herceptin resistance by inducing cancer stem cells. In the present study, we explored the effect of HER2 on cancer stem cells induction and drug sensitivity of ovarian cancer cell lines. First, we found that HER2 overexpression (HER2 OE) induced, while HER2 knockdown (HER2 KD) decreased CD44+/CD24− population. Consistently, HER2 expression was closely correlated with the sphere formation efficiency (SFE) of ovarian cancer cells. Second, we found that NFκB inhibition by specific inhibitor JSH23 or siRNA targetting subunit p65 dramatically impaired the induction of ovarian cancer stem cells by HER2, indicating that NFκB mediated HER2-induced ovarian cancer stem cells. Third, we found that HER2 KD significantly attenuated the tumorigenicity of ovarian cancer cells. Further, we found that HER2 inhibition increased drastically the sensitivity of ovarian cancer cells to doxorubicin (DOX) or paclitaxel (PTX). Finally, we examined the correlation between HER2 status and stem cell-related genes expression in human ovarian tumor tissues, and found that expressions of OCT4, COX2, and Nanog were higher in HER2 positive tumors than in HER2 negative tumors. Consistently, the 5-year tumor-free survival rate of HER2 positive patients was dramatically lower than HER2 negative patients. Taken together, our data indicate that HER2 decreases drug sensitivity of ovarian cancer cells via inducing stem cell-like property.

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Ovarian cancer stem cells (OCSCs): Therapy for advanced chemoresistant ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e16542 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e16542-e16542

Author(s):

Prattusha Sengupta ◽

Sudeshna Gangopadhyay ◽

Saubhik Sengupta ◽

Ujjal Kanti Ray ◽

Ashis Mukhopadhyay

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Cancer Patients ◽

Drug Sensitivity ◽

Ex Vivo ◽

Cancer Site ◽

Chemotherapeutic Drugs ◽

Ovarian Cancer Stem Cells

e16542 Background: Invasive and mesenchymal property of Ovarian Cancer Stem Cells (OCSCs)with CD44+/CD133+has made them promising target for targeted treatment. Chemotherapy treatment uses medicine to weaken and destroy cancer cells in body, including cells at original cancer site and any cancer cells that may have spread to another part of body. Chemotherapeutic drugs for advanced chemo-resistant ovarian cancer are yet to be well defined. Combination of drugs is also not fully known. Our objective is to define chemotherapeutic drugs and its action in OCSC which is the major reason for chemo resistance in case of advanced chemo-resistant ovarian cancer patients. Methods: A total of twenty biopsy proven advanced chemo-resistant ovarian cancer patients in the age group of 22-36 years were selected randomly and tested for CD44/CD133 via flow cytometry. Isolated OCSCs were cultured for ex vivo drug sensitivity towards platinum, anthracyclin, docetaxel, rapamycin, sunitinib, sorafenib and gefitinib. Correlation was drawn between cell differentiations, % of stem cells and drug response. Accordingly chemotherapy was designed for a particular patient. Results: We detected OCSCs in 90% of cases. Among positive samples ex vivo drug sensitivity was seen in 4(20%) to rapamycin, 1(5%) to sunitinib, 1(5%) to sorafenib, 1(5%) to gefitinib, 3(15%) to platinum, 1(5%) to anthracyclin, 1(5%) to docetaxel and rest showed no sensitivity to any drug. Conclusions: Thus primary aim to target OCSCs at onset of tumors in ovarian cancer patients to control metastasis and relapse of disease was somewhat obtained. Most interestingly, we found that the chemotherapeutic drugs which were less prescribed for ovarian cancer showed greater sensitivity in comparison to the widely used ones. We like to do animal model study followed by phase I, II and III human clinical trial to establish our hypothesis for better management of chemo-resistant ovarian cancer.

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Ovarian Cancer Stemness: Biological and Clinical Implications for Metastasis and Chemotherapy Resistance

Cancers ◽

10.3390/cancers11070907 ◽

2019 ◽

Vol 11 (7) ◽

pp. 907 ◽

Cited By ~ 9

Author(s):

Takeshi Motohara ◽

Hidetaka Katabuchi

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Cancer Cells ◽

Cancer Metastasis ◽

Chemotherapy Resistance ◽

Clinical Implications ◽

Ovarian Cancer Stem Cells

Epithelial ovarian cancer is a highly lethal gynecological malignancy that is characterized by the early development of disseminated metastasis. Though ovarian cancer has been generally considered to preferentially metastasize via direct transcoelomic dissemination instead of the hematogenous route, emerging evidence has indicated that the hematogenous spread of cancer cells plays a larger role in ovarian cancer metastasis than previously thought. Considering the distinctive biology of ovarian cancer, an in-depth understanding of the biological and molecular mechanisms that drive metastasis is critical for developing effective therapeutic strategies against this fatal disease. The recent “cancer stem cell theory” postulates that cancer stem cells are principally responsible for tumor initiation, metastasis, and chemotherapy resistance. Even though the hallmarks of ovarian cancer stem cells have not yet been completely elucidated, metastasized ovarian cancer cells, which have a high degree of chemoresistance, seem to manifest cancer stem cell properties and play a key role during relapse at metastatic sites. Herein, we review our current understanding of the cell-biological mechanisms that regulate ovarian cancer metastasis and chemotherapy resistance, with a pivotal focus on ovarian cancer stem cells, and discuss the potential clinical implications of evolving cancer stem cell research and resultant novel therapeutic approaches.

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