The Side Population of Ovarian Cancer Cells Is a Primary Target of IFN-α Antitumor Effects

Moserle, Lidia; Indraccolo, Stefano; Ghisi, Margherita; Frasson, Chiara; Fortunato, Elena; Canevari, Silvana; Miotti, Silvia; Tosello, Valeria; Zamarchi, Rita; Corradin, Alberto; Minuzzo, Sonia; Rossi, Elisabetta; Basso, Giuseppe; Amadori, Alberto

doi:10.1158/0008-5472.can-07-6341

Cited by 114 publications

(119 citation statements)

References 48 publications

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“…In a separate study, the SP fraction of a primary human EOC xenograft line, PDOVCA#1, was found to be more tumourigenic than the non-SP fraction (Moserle et al 2008). Interestingly, unsorted cells appeared more tumourigenic than either fraction alone.…”

Section: Sp Analysismentioning

confidence: 89%

Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm

Garson¹,

Vanderhyden²

2015

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The lack of significant progress in the treatment of epithelial ovarian cancer (EOC) underscores the need to gain a better understanding of the processes that lead to chemoresistance and recurrence. The cancer stem cell (CSC) hypothesis offers an attractive explanation of how a subpopulation of cells within a patient's tumour might remain refractory to treatment and subsequently form the basis of recurrent chemoresistant disease. This review examines the literature defining somatic stem cells of the ovary and fallopian tube, two tissues that give rise to EOC. In addition, considerable research has been reviewed, that has identified subpopulations of EOC cells, based on marker expression (CD133, CD44, CD117, CD24, epithelial cell adhesion molecule, LY6A, ALDH1 and side population (SP)), which are enriched for tumour initiating cells (TICs). While many studies identified either CD133 or CD44 as markers useful for enriching for TICs, there is little consensus. This suggests that EOC cells may have a phenotypic plasticity that may preclude the identification of universal markers defining a CSC. The assay that forms the basis of quantifying TICs is the xenograft assay. Considerable controversy surrounds the xenograft assay and it is essential that some of the potential limitations be examined in this review. Highlighting such limitations or weaknesses is required to properly evaluate data and broaden our interpretation of potential mechanisms that might be contributing to the pathogenesis of ovarian cancer.

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Section: Sp Analysismentioning

confidence: 89%

Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm

Garson¹,

Vanderhyden²

2015

Reproduction

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“…Compared with other ovarian cancer cells, ovarian CSCs have relatively high aldehyde dehydrogenase (ALDH1) enzymatic activity (9)(10)(11), which may serve to detoxify intracellular aldehydes or various cytotoxic drugs (12,13). Ovarian CSCs also can extrude small molecules, such as various chemotherapeutic drugs or fluorescent dyes, allowing for their identification as a less fluorescent "side population" in flowcytometric analysis of tumor cells stained with the DNA-binding dye Hoechst 33342 (14)(15)(16). Furthermore, ovarian CSCs may express various surface antigens, such as CD44, CD117, or CD133 (7,8,(17)(18)(19).…”

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.

161

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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“…We know that the expression of Oct-4 is restricted to the blastocyst stem cell population (inner cell mass, ICM). Following implantation, Oct-4 expression is limited to the epiblast compartment until gastrulation begins, as it is downregulated progressively using an anterior to posterior manner (86,87). Oct-4 expression is necessary in the maintenance of totipotency and synchronous division.…”

Section: Regulatory Mechanisms For Tumor Stem Cellsmentioning

confidence: 99%

Tumor stem cells: A new approach for tumor therapy (Review)

et al. 2012

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Abstract. Recent studies have demonstrated the existence of a minority of tumor cells possessing the stem cell properties of self-renewal and differentiation in leukemia and several solid tumors. However, these cells do not possess the normal regulatory mechanisms of stem cells. Following transplantation, they are capable of initiating tumorigenesis and are therefore known as 'tumor stem cells'. Cellular origin analysis of tumor stem cells has resulted in three hypotheses: Embryonal rest hypothesis, anaplasia and maturation arrest. Several signaling pathways which are involved in carcinogenesis, including Wnt/β-catenin, Notch and Oct-4 signaling pathways are crucial in normal stem cell self-renewal decisions, suggesting that breakdown in the regulation of self-renewal may be a key event in the development of tumors. Thus, tumors can be regarded as an abnormal organ in which stem cells have escaped from the normal constraints on self-renewal, thus, leading to abnormally differentiated tumor cells that lose the ability to form tumors. This new model for maligancies has significance for clinical research and treatment.

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The Side Population of Ovarian Cancer Cells Is a Primary Target of IFN-α Antitumor Effects

Cited by 114 publications

References 48 publications

Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm

Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm

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

Tumor stem cells: A new approach for tumor therapy (Review)

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