Characterization of aldehyde dehydrogenase 1 high ovarian cancer cells: Towards targeted stem cell therapy

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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Characterization of a Stem-like Subpopulation in Basal-like Ductal Carcinoma in Situ (DCIS) Lesions

Journal of Biological Chemistry ◽

10.1074/jbc.m113.502278 ◽

2013 ◽

Vol 289 (3) ◽

pp. 1303-1312 ◽

Cited By ~ 53

Author(s):

Qinglin Li ◽

Gabriel Eades ◽

Yuan Yao ◽

Yongshu Zhang ◽

Qun Zhou

Keyword(s):

Cancer Cells ◽

Aldehyde Dehydrogenase ◽

Breast Cancer Cells ◽

Ductal Carcinoma ◽

Chemopreventive Agent ◽

Aldehyde Dehydrogenase 1 ◽

Aldh1 Expression ◽

Migration Potential

Previously, we found that basal-like ductal carcinoma in situ (DCIS) contains cancer stem-like cells. Here, we characterize stem-like subpopulations in a model of basal-like DCIS and identify subpopulations of CD49f+/CD24− stem-like cells that possess aldehyde dehydrogenase 1 activity. We found that these cells show enhanced migration potential compared with non-stem DCIS cells. We also found that the chemopreventive agent sulforaphane can target these DCIS stem-like cells, reduce aldehyde dehydrogenase 1 (ALDH1) expression, and decrease mammosphere and progenitor colony formation. Furthermore, we characterized exosomal trafficking of microRNAs in DCIS and found that several microRNAs (miRs) including miR-140, miR-29a, and miR-21 are differentially expressed in exosomes from DCIS stem-like cells. We found that SFN treatment could reprogram DCIS stem-like cells as evidenced by significant changes in exosomal secretion more closely resembling that of non-stem cancer cells. Finally, we demonstrated that exosomal secretion of miR-140 might impact signaling in nearby breast cancer cells.

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Autophagy Is Indispensable for the Self-Renewal and Quiescence of Ovarian Cancer Spheroid Cells with Stem Cell-Like Properties

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/7010472 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15 ◽

Cited By ~ 12

Author(s):

Qian Wang ◽

Shixia Bu ◽

Dedong Xin ◽

Boning Li ◽

Lan Wang ◽

...

Keyword(s):

Ovarian Cancer ◽

Stem Cell ◽

Cancer Cells ◽

Feedback Regulation ◽

Soft Agar ◽

The Self ◽

Ovarian Cancer Cells ◽

Quiescent State ◽

Bafilomycin A1 ◽

Self Renewal

Epithelial ovarian cancer has the highest mortality rate of all gynecologic cancers. Cancer stem cells are considered to be the initiating cells of tumors. It is known that spheroid culture promotes ovarian cancer cells to acquire stem cell characteristics and to become stem cell-like. But the mechanisms remain largely unclear. Our data show that autophagy is sustainably activated in ovarian cancer spheroid cells. Inhibition of autophagy by knockdown of ATG5 abolishes the self-renewal ability of ovarian cancer spheroid cells. Knockdown of ATG5 prevents ovarian cancer spheroid cells to enter quiescent state. Autophagy is critical for quiescent ovarian cancer spheroid cells to reenter the cell cycle because rapamycin can promote quiescent ovarian cancer spheroid cells to form colonies on soft agar and knockdown of ATG5 can arrest ovarian cancer cells in G0/G1. Autophagy and NRF2 form a positive feedback regulation loop to regulate reactive oxygen species (ROS) levels in ovarian cancer spheroid cells. The optimal ROS level, neither too high nor too low, facilitates the self-renewal marker, NOTCH1, to reach to the highest level. Bafilomycin A1 can impair the self-renewal of ovarian cancer spheroid cells by disturbing ROS levels.

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