Characteristics of CD133-Sustained Chemoresistant Cancer Stem-Like Cells in Human Ovarian Carcinoma

Abstract

Cancer stem cells (CSCs) are considered to be the origin of ovarian cancer (OC) development, recurrence, and chemoresistance. We investigated changes in expression levels of the CSC biomarker, cluster of differentiation 133 (CD133), from primary OC cell lines to induction of CSC-spheres in an attempt to explore the mechanisms related to modulation of stemness, drug resistance, and tumorigenesis in CSCs, thus facilitating the search for new therapeutics for OC. The effect of CD133 overexpression on the induction of CSC properties was evaluated by sphere-forming assays, RT-qPCR, flow cytometry, cell viability assays, and in vivo xenograft experiments. Moreover, the potential signaling molecules that participate in CD133 maintenance of stemness were screened by RNA-sequencing. CD133 expression was upregulated during OCSC induction and chemotherapeutic drug treatment over time, which increased the expressions of stemness-related markers (SOX2, OCT4, and Nanog). CD133 overexpression also promoted tumorigenesis in NOD/SCID mice. Several signalings were controlled by CD133 spheres, including extracellular matrix receptor interactions, chemokine signaling, and Wnt signaling, all of which promote cell survival and cell cycle progression. Our findings suggest that CD133 possesses the ability to maintain functional stemness and tumorigenesis of OCSCs by promoting cell survival signaling and may serve as a potential target for stem cell-targeted therapy of OC.

LncRNA MALAT1 Facilitates Ovarian Cancer Progression through Promoting Chemoresistance and Invasiveness in the Tumor Microenvironment

“…Moreover, stimulation of the EMT is often associated with inhibition of E-cadherin expression and/or with regulation of the PI3K/AKT pathway [ 16 ]. Consistent with most previous reports, lncRNA MALAT1-knockdown or -knockout was shown to inactivate the complexes of PI3K/Akt/mammalian targets of rapamycin (mTOR), MAPK/extracellular signal-regulated kinase (ERK), and Wnt/β-catenin signaling pathways [ 17 , 44 ], which significantly suppressed tumorigenicity and induced apoptosis in SKOV3 cells [ 45 ] and in other types of cancer cells, emphasizing the specific role of MALAT1 as an oncogenic lncRNA. However, one previous report showed opposite results, and claimed that the MALAT1 lncRNA suppresses metastasis in breast cancer [ 31 ], suggesting that further convincing evidence is required to clarify this discrepancy.…”

Changes in Stem Cell Regulation and Epithelial Organisation during Carcinogenesis and Disease Progression in Gynaecological Malignancies

“…A side population of cells expressing NANOG, OCT4 and ABCG2/BCRP1 was isolated from ovarian cancer cell lines and ascites of ovarian cancer patients, and was found to have increased tumourgenicity and chemoresistance [47]. Similar findings of increased tumourigenicity were associated with CD133, ALDH1, EpCAM, and CK7 expression in primary ovarian tumour and ascites samples [48,49] and ovarian cancer cell lines [50]. Knockdown of LGR6 in ovarian cancer cell lines showed improved sensitivity to cisplatin or paclitaxel, reduced spheroid formation, and reduced expression of CSC markers (CD133, SOX2, ALDH1, OCT4, NANOG) [51], thus suggesting a potential target for treatment, as loss of LGR6 led to reduced stemness and reversal of chemoresistance.…”

In Ovarian Cancer Multicellular Spheroids, Platelet Releasate Promotes Growth, Expansion of ALDH+ and CD133+ Cancer Stem Cells, and Protection against the Cytotoxic Effects of Cisplatin, Carboplatin and Paclitaxel

“…In OvCa, chemotherapy resistance is often associated with high ALDH enzymatic activity [ 33 ], a functional regulator [ 38 ] and a marker of stemness in many cancer models [ 39 ]. ALDH, in combination with CD133, represents a robust marker for OvCa-CSCs [ 40 , 41 , 42 ]. OvCa-CSCs are thought to contribute to disease recurrence and chemo-resistance; thus, it is challenging to clarify the mechanism leading to their expansion and survival during chemotherapy.…”