Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden

Abubaker, Khalid; Latifi, Ardian; Luwor, Rodney B; Nazaretian, Simon; Zhu, Hong; Quinn, Michael; Thompson, Erik W.; Findlay, Jock K.; Ahmed, Nuzhat

doi:10.1186/1476-4598-12-24

Cited by 186 publications

(214 citation statements)

References 52 publications

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“…In particular, it has been suggested that a small subpopulation of cells within tumors, called cancer stem cells (CSCs), by virtue of their relative resistance to chemotherapy may contribute to tumor recurrence (5,6). Consistent with these reports, several groups reported enrichment for CSCs when solid cancers were subjected to classical anticancer treatment (7)(8)(9)(10)(11). In accumulation, these studies suggest that significant improvement in patient outcome will require drugs that selectively target CSCs in combination with conventional chemotherapeutic regimens that target rapidly proliferating cells.…”

Section: Introductionsupporting

confidence: 59%

“…An explanation for this observation is partly provided by existing reports that NACT leads to enrichment of CSCs (7)(8)(9)(10)(11)39). However, this explanation alone is not enough to reason the recurrence of tumors as the CSC subpopulation, being a part of the primary tumor itself, must get removed during surgical resection of the tumor mass.…”

Section: Discussionmentioning

confidence: 99%

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Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB–IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells

et al. 2016

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Acquired chemoresistance has curtailed cancer survival since the dawn of chemotherapy. Accumulating evidence suggests a major role for cancer stem cells (CSC) in chemoresistance, although their involvement in acquired resistance is still unknown. The use of aspirin has been associated with reduced cancer risk and recurrence, suggesting that the anti-inflammatory drug may exert effects on CSCs. In this study, we investigated the contribution of CSCs to acquired chemoresistance of breast cancer and the avenues for reversing such effects with aspirin. We observed that the residual risk of recurrence was higher in breast cancer patients who had acquired chemoresistance. Treatment of preexisting CSCs with a genotoxic drug combination (5-fluorouracil, doxorubicin, and cyclophosphamide) generated an NFkB-IL6-dependent inflammatory environment that imparted stemness to nonstem cancer cells, induced multidrug resistance, and enhanced the migration potential of CSCs. Treatment with aspirin prior to chemotherapy suppressed the acquisition of chemoresistance by perturbing the nuclear translocation of NFkB in preexisting CSCs. Therefore, disruptions to the NFkB-IL6 feedback loop prevented CSC induction and sensitized preexisting CSCs to chemotherapy. Collectively, our findings suggest that combining aspirin and conventional chemotherapy may offer a new treatment strategy to improve recurrence-free survival of breast cancer patients.

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Section: Introductionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB–IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells

et al. 2016

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“…12 Using an animal model, Abubaker et al demonstrated that short-term application of chemotherapy (cisplatin and paclitaxel) enriched the cell population with high expression of Oct-4 and CD117. 13 Similar experiments were performed by Zhou et al 14 Following the administration of cisplatin, the dormant cells of human ovarian cancer manifested an augmented expression of cells with Oct-4, nestin, CD-117, and CD44 markers, proving the resistance of this stem cell fraction to cisplatin.…”

supporting

confidence: 53%

“…7,8,13 According to Massard et al, there are 2 options for eradicating CSCs: one involves the induction of their differentiation, upon which they lose their capacity of selfreplacement (retinoic acid demonstrated such an ability); the other one involves the elimination of CSCs by targeted inhibitors of signaling pathways.…”

mentioning

confidence: 99%

Ovarian cancer stem cells: A target for oncological therapy

Markowska¹,

Sajdak²,

Huczyński³

et al. 2018

Adv Clin Exp Med

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According to numerous studies, failures in treatment of ovarian cancer, i.e., a relapse and metastases, result from a small population of cancer stem cells (CSCs). They may also be responsible for tumor initiation. Cancer stem cells are resistant to chemo-and radiotherapy. Eradication of CSCs may involve the application of salinomycin, metformin and Clostridium perfringens; the effect of anti-angiogenic factors remains controversial. Salinomycin is an antibiotic isolated from Streptomyces albus bacteria. Its CSC-eradicating effect has been demonstrated both in ovarian cancer cell lines and in women with breast cancer. Clostridium perfringens enterotoxin (CPE) has been demonstrated to destroy CSCs in ovarian cancer both in vivo and in vitro. Metformin, apart from its hypoglycemic effect, reduces the CSC population and inhibits the proliferation of neoplastic cells and angiogenesis. Cancer stem cells with expression of VEGFR1+ have been described as affecting circulating cancer cells and influencing the formation of metastases. Both positive and negative effects of anti-angiogenic therapy on the CSC population have been documented.

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“…Furthermore, ovarian CSCs may express various surface antigens, such as CD44, CD117, or CD133 (7,8,(17)(18)(19). Functionally, human ovarian CSCs apparently can form nonadherent cellular spheres, called "spheroids," which in turn are enriched for ovarian cancer cells that have high ALDH1 activity, are relatively resistant to chemotherapeutic drugs, and have enhanced potential for seeding metastatic sites or engrafting immune-deficient mice (5,17,18,(20)(21)(22).…”

mentioning

confidence: 99%

Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy

Zhang

Cui

Lai

et al. 2014

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

166

156

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Although initially responsive to chemotherapy, many patients with ovarian cancer subsequently develop relapsed and potentially fatal metastatic disease, which is thought to develop from cancer stem cells (CSCs) that are relatively resistant to conventional therapy. Here, we show that CSCs express a type I receptor tyrosine kinase-like orphan receptor (ROR1), which is expressed during embryogenesis and by many different cancers, but not normal postpartum tissues. Ovarian cancers with high levels of ROR1 had stem cell-like gene-expression signatures. Furthermore, patients with ovarian cancers with high levels of ROR1 had higher rates of relapse and a shorter median survival than patients with ovarian cancers that expressed low-to-negligible amounts of ROR1. We found that ROR1-positive (ROR1 + ) cells isolated from primary tumor-derived xenografts (PDXs) also expressed aldehyde dehydrogenase 1 (ALDH1) and had a greater capacity to form spheroids and to engraft immune-deficient mice than did ROR1-negative (ROR1 Neg ) ovarian cancer cells isolated from the same tumor population. Treatment with UC-961, an anti-ROR1 mAb, or shRNA silencing of ROR1 inhibited expression of the polycomb ring-finger oncogene, Bmi-1, and other genes associated with the epithelial-mesenchymal transition. Moreover, shRNA silencing of ROR1, depletion of ROR1 + cells, or treatment with UC-961 impaired the capacity of ovarian cancer cells to form spheroids or tumor xenografts. More importantly, treatment with anti-ROR1 affected the capacity of the xenograft to reseed a virgin mouse, indicating that targeting ROR1 may affect CSC self-renewal. Collectively, these studies indicate that ovarian CSCs express ROR1, which contributes to their capacity to form tumors, making ROR1 a potential target for the therapy of patients with ovarian cancer.ROR1 | ovarian cancer stem cell | monoclonal antibody | PDX mice model

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Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden

Cited by 186 publications

References 52 publications

Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB–IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells

Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB–IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells

Ovarian cancer stem cells: A target for oncological therapy

Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy

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