Table 1.

The markers for characterization of OCSCs, their function, and clinical significance.

OCSC marker	Function	Clinical significance	Reference
CD44 CD44 spliced variant 6 (CD44v6)	Cell-surface glycoprotein, receptor for the hyaluronic acid receptor Activates EGFR/Ras/ERK and NANOG-dependent signaling pathways Resulting NANOG/STAT3 interaction upregulates multi-drug resistance CD44+ cells possess self-renewal, tumor-initiating and sphere-forming capability	High number of CD44+ cells in early stage HGSOC correlated with shorter PFS Expression correlated with advanced HGSOC, p53 positivity, tumor grade, and chemoresistance CD44+ cells are overrepresented in recurrent compared to primary HGSOC Increased CD44v6+ cell numbers in primary ovarian tumors correlated with shorter OS CD44v6+ cells are overrepresented in metastases Distant metastases-free survival is better in patients with CD44v6-low tumors Population of CD44+CD166+ cells is abundant in platinum-resistant ovarian cancer	(16–24)
CD117	Receptor tyrosine kinase coded by c-kit proto-oncogene Regulates cell proliferation, differentiation, apoptosis, and adhesion Binding CD117 to SCF is followed by activation of several pathways, including Ras/ERK, PI3K/AKT, and Src/JAK/STAT SCF produced by TAMs and CAFs is highly expressed in ascites of patients with HGSOC CD117+ cells are abundant in a sphere-forming non-adherent OCSCs and the “side population” OCSCs with increased capacity of self-renewal, tumorigenicity, and chemoresistance, as well as selective expression of ABC transporters	CD117+ cells correlate with chemoresistance shorter OS, and shorter DFI CD117+ expression present in HGSOC and correlated with chemoresistance CD44+/CD117+ cells are abundant in chemoresistant HGSOC and cell lines resistant to paclitaxel-induced apoptosis	(25–30)
CD133	Prominin-1 is a transmembrane glycoprotein Activates PI3K/AKT pathway Is responsible for tumorigenicity, vascularization and chemoresistance Cooperation between CD133 and ETRA augments sphere-forming capacity and homing to peritoneal surface NF-κB and p38/MAPK-dependent pathways enhance self-renewal of CD133+ cells	CD133+ cells are more abundant in recurrent chemoresistant tumors Expression of CD133+ correlated with the HGSOC type, stage, ascites, and chemoresistance CD133+ cells correlated with shorter PFS and OS CD133+/CXCR4+ cells are more platinum-resistant compared to CD133 negative cells	(31–37)
CD24	Heat-stable antigen CD24, a transmembrane adhesion molecule Activates JAK/STAT3 signaling pathways and NANOG and OCT4 expression Through stimulation of PI3K/AKT/MAPK pathway is able to stimulate EMT Stimulates stemness, tumor growth, and chemoresistance CD24+ cells form spheroid structures Exosomes present in ascites contain CD24 and EpCAM, which regulate signals between OCSCs and TME	CD24+ cells are abundant in peritoneal implants compared to primary tumor Inhibition of JAK/STAT3 pathway reduces OCSC stemness and improves patient’s survival CD24+ expression is a predictor of poor outcome in patients with ovarian cancer Expression of CD24+ correlates with cancer stage and presence of peritoneal implants and metastases	(29, 38–43)
EpCAM	Epithelial cell adhesion molecule is a type I transmembrane glycoprotein regulating intercellular adhesion EpCAM+ cells show greater tumor-initiating potential EpCAM/Bcl-2 pathway prevents platinum-dependent apoptosis of cancer cells EpCAM+CD45+ cells constitute the chemoresistant phenotype in the ascitic fluid of patients with ovarian cancer. These cells overexpress SIRT1, ABCA1, and BCL2 genes. EpCAM+CD45+ population is highly invasive with signature mesenchymal gene expression and also consists of CD133+ and CD117+CD44+ OCSCs	EpCAM expression is increased in chemoresistant tumors and correlated with poor outcome EpCAM+ cells are a source of relapse after the chemotherapy	(20, 44, 45)
MyD88	Myeloid differentiation primary response gene 88 is an adaptor protein for signals generated from TLR-4 receptor TLR-4/MyD88 pathway is responsible for chemoresistance and activates inflammatory pathways in carcinogenesis	Expression of MyD88 is an unfavorable prognostic factor in ovarian cancer CD44+/MyD88+ cells show increased tumorigenicity, sphere formation, and chemoresistance	(28, 46)
LGR5 and LGR6	Leucine-rich repeat containing G protein–coupled receptor-5 and receptor-6 are biomarkers of adult stem cells Expression of LGR5 promotes proliferation and metastasis, and EMT in ovarian cancer LGR5- and LGR6-mediated signaling is responsible for activation of Wnt/β-catenin pathway in OCSCs	LGR5 expression is correlated to ovarian tumor stage and histologic grade LGR6 expression and activation of Wnt/β-catenin pathway are observed in tubal fimbria of patients with HGSOC	(47, 48)
ALDH	Aldehyde dehydrogenases are aldehyde-converting enzymes ALDH1 subgroup of enzymes is engaged in protection of cancer cells against chemotherapy and radiation ALDH1A1 and ALDH1A2 are the most popular phenotypes found in OCSCs ALDH1 activates the Wnt/β-catenin pathway and transmembrane transporters	Ovarian cancer cells pre-treated with growing doses of platinum show increased number of ALDH1+ cells HGSOC cells showing ALDH1+/EGFR+ phenotype are correlated with the worse prognosis High expression of ALDH1+ cells correlates with chemoresistance CD44+/CD133+/ALDH1A1+ cells are increased in recurrent tumors Expression of CD133+/ALDH1+ correlates with shorter PFS and OS in HGSOC	(49–52)
NANOG	Homeobox protein NANOG transcription factor Regulates self-renewal and pluripotency of embryonic and CSCs cells, and EMT Through STAT3 signaling pathway upregulates chemoresistance	Expression of NANOG+ cells correlates with clinical stage, histologic grade, and chemoresistance	(17)
SOX2	Sex determining region Y-box 2 transcription factor Regulates self-renewal and pluripotency of embryonic and CSCs cells Overexpression of SOX2 enhances stemness by inhibition of PI3K/AKT signaling pathway	Highly SOX2+ cells are present in epithelium of tubal fimbriae in HGSOC and BRCA1/2+ patients	(53, 54)
OCT4	Octamer-binding transcription factor-4 is engaged in self-renewal of undifferentiated embryonic stem cells Stabilizes structure of chromatin in the NANOG locus Cytoplasmic expression of OCT4 regulates EMT Mechanosensory signals in the peritoneum stimulate EMT; enhance stemness by upregulation of OCT4, CD44, and CD117; and increase chemoresistance	Upregulation of OCT4 in ovarian cancer is correlated to chemoresistance Increased expression of OCT4 is observed in CD24+ OCSC cells	(40, 55–57)
FOXM1	Forkhead box protein M1 is a member of the FOX family of transcription factors Regulates cell cycle and controls genomic stability Upregulation of FOXM1 is followed by activation of Wnt/β-catenin signaling pathway and enhances chemoresistance	Overexpression of FOXM1 is observed in OCSCs exposed to LPA present in ascites FOXM1 deactivation results in restoration of chemosensitivity and loss of ability to spheroid creation in peritoneum	(58–60)
MSH-1/MSH-2	MSH proteins regulate stemness of OCSCs and are aberrantly expressed in tumors. MSH proteins activate the NOTCH signaling	High expression of MSH proteins is correlated to shorter OS and enhances paclitaxel chemoresistance	(61–64)

CD, cluster of differentiation; EGFR, epidermal growth factor receptor; Ras, Ras small GTPase protein; ERK, extracellular signal–regulated kinase; NANOG, homeobox protein NANOG transcription factor; STAT3, signal transducer and activator of transcription 3; PFS, progression-free survival; OS, overall survival; SCF, stem cell factor; PI3K, phosphoinositide-3-kinase; AKT, protein kinase B; Src, non-receptor tyrosine kinase Src; JAK, Janus kinase; TME, tumor microenvironment; TAMs, tumor-associated macrophages; CAFs, cancer-associated fibroblasts; ABC transporters, ATP-binding cassette drug membrane transporters; DFI, disease-free interval; ETRA, endothelia receptor A; NF-κB, nuclear factor-κ-light chain enhancer of activated B cells; p38/MAPK, p38 mitogen-activated protein kinase; CXCR4, C-X-C chemokine receptor type-4; OCT4, octamer-binding transcription factor-4; EMT, epithelial–mesenchymal transition; Bcl-2, B-cell lymphoma-2 molecule; TLR-4, Toll-like receptor type-4; LGR5, leucine-rich repeat containing G protein–coupled receptor-5; ALDH, aldehyde dehydrogenase; Wnt, wingless and Int-1; SOX2, sex determining region Y-box 2; FOXM1, forkhead box protein M1; LPA, lysophosphatidic acid; SIRT1, sirtuin-1; BCL2, B-cell lymphoma-2; MSH, Musashi protein; NOTCH, neurogenic locus notch homolog.