Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance.
A major burden in the treatment of ovarian cancer is the high percentage of recurrence and chemoresistance. Cancer stem cells (CSCs) provide a reservoir of cells that can self-renew, can maintain the tumor by generating differentiated cells [non-stem cells (non-CSCs)] which make up the bulk of the tumor and may be the primary source of recurrence. We describe the characterization of human ovarian cancer stem cells (OCSCs). These cells have a distinctive genetic profile that confers them with the capacity to recapitulate the original tumor, proliferate with chemotherapy, and promote recurrence. CSC identified in EOC cells isolated form ascites and solid tumors are characterized by: CD44+, MyD88+, constitutive NFkappaB activity and cytokine and chemokine production, high capacity for repair, chemoresistance to conventional chemotherapies, resistance to TNFalpha-mediated apoptosis, capacity to form spheroids in suspension, and the ability to recapitulate in vivo the original tumor. Chemotherapy eliminates the bulk of the tumor but it leaves a core of cancer cells with high capacity for repair and renewal. The molecular properties identified in these cells may explain some of the unique characteristics of CSCs that control self-renewal and drive metastasis. The identification and cloning of human OCSCs can aid in the development of better therapeutic approaches for ovarian cancer patients.
Alvero
Ayesha B
AB
Department of Obstetrics and Gynecology , Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Chen
Rui
R
Fu
Han-Hsuan
HH
Montagna
Michele
M
Schwartz
Peter E
PE
Rutherford
Thomas
T
Silasi
Dan-Arin
DA
Steffensen
Karina D
KD
Waldstrom
Marianne
M
Visintin
Irene
I
Mor
Gil
G
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D010641:Phenotype; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016207:Cytokines; D018960:Hyaluronan Receptors; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051197:Toll-Like Receptor 4