Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species

Mizuno, Tomoko; Suzuki, Noriko; Makino, Hiroshi; Furui, Tatsuro; Morii, Eiichi; Aoki, Hitomi; Kunisada, Takahiro; Yano, Mitsutake; Kuji, Shiho; Hirashima, Yasuyuki; Arakawa, Atsushi; Nishio, Yukihiro; Ushijima, Kimio; Ito, Kimihiko; Itani, Yoshio; Morishige, Ken‐ichirou

doi:10.1016/j.ygyno.2014.12.005

Cited by 80 publications

(55 citation statements)

References 29 publications

(3 reference statements)

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“…Although some reports suggest that ovarian cancer may not follow a hierarchical model (9), numerous potential CSC populations, defined by various cell markers, have been reported (1,10). Aldehyde dehydrogenase enzymatic activity (ALDH) and the stem cell marker CD133, either alone or in combination, are perhaps the best supported ovarian CSC (OvCSC) markers (11)(12)(13)(14)(15)(16). We recently reported that ALDH and CD133 can be used to define distinct heterogeneous populations of ovarian cancer cells (17 …”

Section: Cd133mentioning

confidence: 99%

Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2

Choi

Ingram

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Whether human cancer follows a hierarchical or stochastic model of differentiation is controversial. Furthermore, the factors that regulate cancer stem-like cell (CSC) differentiation potential are largely unknown. We used a novel microfluidic single-cell culture method to directly observe the differentiation capacity of four heterogeneous ovarian cancer cell populations defined by the expression of the CSC markers aldehyde dehydrogenase (ALDH) and CD133. We evaluated 3,692 progeny from 2,833 cells. CD133+ cell expansion while suppressing the proliferation of ALDH − CD133 − cells. As such, BMP2 suppressed bulk cancer cell growth in vitro but increased tumor initiation rates, tumor growth, and chemotherapy resistance in vivo whereas BMP2 knockdown reduced CSC numbers, in vivo growth, and chemoresistance. These data suggest a hierarchical differentiation pattern in which BMP2 acts as a feedback mechanism promoting ovarian CSC expansion and suppressing progenitor proliferation. These results explain why BMP2 suppresses growth in vitro and promotes growth in vivo. Together, our results support BMP2 as a therapeutic target in ovarian cancer.ovarian cancer | cancer stem cells | BMP2 | differentiation capacity | hierarchical

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Section: Cd133mentioning

confidence: 99%

Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2

Choi

Ingram

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Although further studies are needed to better define this mechanism in our model, it has been shown that intracellular ROS concentration can affect CSC viability and self-renewal (33)(34)(35). CSC upregulate the key regulator of the antioxidant response nuclear factor erythroid 2-related factor 2 (36) and many antioxidant enzymes, such as superoxide dismutase 2, GSH peroxidases, and heme oxygenase 1, which attempt to maintain intracellular ROS at levels lower than those observed in differentiated cancer cells (37). In accordance with this, a basal increase in GSH and decrease in ROS levels were observed in tumorspheres as compared with TUBO cells, which can be explained by xCT upregulation in tumorspheres and proven by the fact that xCT downregulation reverts this phenotype.…”

Section: Discussionmentioning

confidence: 99%

Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer

Lanzardo

Conti

Rooke³

et al. 2016

Cancer Research

138

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Resistance to therapy and lack of curative treatments for metastatic breast cancer suggest that current therapies may be missing the subpopulation of chemoresistant and radioresistant cancer stem cells (CSC). The ultimate success of any treatment may well rest on CSC eradication, but specific anti-CSC therapies are still limited. A comparison of the transcriptional profiles of murine Her2 þ breast tumor TUBO cells and their derived CSC-enriched tumorspheres has identified xCT, the functional subunit of the cystine/glutamate antiporter system x c À , as a surface protein that is upregulated specifically in tumorspheres. We validated this finding by cytofluorimetric analysis and immunofluorescence in TUBO-derived tumorspheres and in a panel of mouse and human triple negative breast cancer cell-derived tumorspheres. We further show that downregulation of xCT impaired tumorsphere generation and altered CSC intracellular redox balance in vitro, suggesting that xCT plays a functional role in CSC biology. DNA vaccination based immunotargeting of xCT in mice challenged with syngeneic tumorsphere-derived cells delayed established subcutaneous tumor growth and strongly impaired pulmonary metastasis formation by generating anti-xCT antibodies able to alter CSC self-renewal and redox balance. Finally, anti-xCT vaccination increased CSC chemosensitivity to doxorubicin in vivo, indicating that xCT immunotargeting may be an effective adjuvant to chemotherapy. Cancer Res; 76(1); 62-72. Ó2015 AACR.

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“…The mutations are also commonly observed in CCC (33). PTEN is a synthetic lethality partner for PARP, ATM, or NLK, while ARID1A and ATR are synthetic lethal pairs (33,35,36). Applications of PARP inhibition are now being expanded to tumor suppressor genes ARID1A and PTEN.…”

Section: Discussionmentioning

confidence: 99%

“…PTEN loss associated with HR deficiency increased chemosensitivity and therapeutic ratio (34). siRNA screening strategies also identified a synthetic lethal genetic interaction between PTEN (35,36) and ATM as well as PTEN and nemo-like kinase (NLK) (33). Thus, PTEN may play a role in cisplatin and PARP inhibitor sensitivity in CCC.…”

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratio mentioning

confidence: 99%

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

et al. 2017

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Abstract. Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies. We conducted a literature review for putative PARP sensitivity genes that are associated with the CCC pathophysiology. Previous studies identified a variety of putative target genes from several pathways associated with DNA damage repair, chromatin remodeling complex, PI3K-AKT-mTOR signaling, Notch signaling, cell cycle checkpoint signaling, BRCA-associated complex and Fanconi's anemia susceptibility genes that could be used as biomarkers or therapeutic targets for PARP inhibition. BRCA1/2, ATM, ATR, BARD1, CCNE1, CHEK1, CKS1B, DNMT1, ERBB2, FGFR2, MRE11A, MYC, NOTCH1 and PTEN were considered as candidate genes for synthetic lethality gene partners for PARP interactions. When considering the biological background underlying PARP inhibition, we hypothesized that PARP inhibitors would be a novel synthetic lethal therapeutic approach for CCC tumors harboring homologous recombination deficiency and activating oncogene mutations. The results showed that the majority of CCC tumors appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of CCC.

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Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species

Cited by 80 publications

References 29 publications

Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2

Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2

Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

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