Table 2.

The functional and clinical characterization of ovarian cancer stem cell signaling pathways.

Pathway	Function	Clinical significance	Reference
Wnt/β-catenin signaling	Activation of ABC transmembrane transporter member-2 (ABCG2) Cooperation with LGR5 and LGR6 stemness markers for activation of the pathway in OCSCs Regulation of EMT through increase of the SNAIL/E-cadherin ratio and enhancement of OCSC motility and chemoresistance Promotion of pro-inflammatory and tumor-supporting phenotype of CAFs	Knock-down of β-catenin restores chemosensitivity in ovarian cancer cells Restoration of SFRP5 function inhibits Wnt/β-catenin signaling, EMT and re-establishes chemosensitivity Chemoresistant HGSOC tumors show the upregulation of Wnt/β-catenin-dependent target genes and OCSC markers	(48, 59, 65–67)
Hedgehog signaling	Activation of this pathway in OCSCs stimulates chemoresistance and spheroid formation Proteins GLI1 and SMO are the downward effectors of Hedgehog signaling GLI1 upregulates function of ABCB1 and ABCG2 transporters, thus supporting chemoresistance Hedgehog signaling is important for the interaction between OCSCs and CAFs	Malignant and chemoresistant ovarian tumors show increased expression of GLI1 and SMO compared to benign and chemosensitive tumors	(68–70)
Hippo/YAP signaling	Pathway is activated by stiffness of ECM and shear stress in OCSC environment (mechanosensory signals) Hippo/YAP pathway stimulates proliferation, metastasis, and chemoresistance in ovarian cancer Overexpression of YAP promotes EMT and cancer cell migration while inhibiting cells’ anoikis Increase in the OCSC pool results from the activation of the Hippo pathway target genes upon MYPT1 downregulation	YAP expression is an indicator of poor prognosis in ovarian cancer Expression of the key genes related to Hippo/YAP signaling is correlated with PFS	(71–74)
NOTCH signaling	The NOTCH receptors are a membrane receptor proteins responsible for proliferation of cells and angiogenesis of the tumor NOTCH overexpression is observed in ovarian cancer, together with the downstream components of this pathway, like VEGF, VEGFR1, DLL4, and JAG1 Tumor hypoxia enhances NOTCH signaling, stemness, and migration of OCSCs NOTCH pathway upregulates NANOG, OCT4, and ABCB1 transporter, thus increasing chemoresistance	High activity of NOTCH pathway is found in paclitaxel-resistant ALDH1+ OCSCs High expression of NOTCH is correlated with poor OS and DFS, and advanced or recurrent cancer Inhibition of NOTCH signaling restores chemosensitivity	(75–77)
NF-κB signaling	NF-κB is a protein complex functioning as a transcription factor responsible for cellular response towards stress, cytokines, reactive oxygen species, antigens, and inflammation Inhibition of NF-κB signaling induces apoptosis, restores chemosensitivity, and decreases the CD44+ OCSC population Cooperation between CAFs and OCSCs results in the upregulation of NF-κB signaling in OCSCs Inflammatory signals from the tumor environment enhance NF-κB pathway and stemness of cancer cells NF-κB over-activity characterizes CD44+MyD88+ OCSCs A matrix protein periostin expressed in highly aggressive ovarian cancer is involved in NF-κB–mediated over-activity of M2 macrophages and CAFs that promote tumor growth The TLR4/NF-κB/HIF-1α signaling loop promotes progression of ovarian cancer	Overexpression of NF-κB is correlated with chemoresistance and poor prognosis in HGSOC Expression of NF-κB is correlated to high stage and grade of ovarian cancer NF-κB mediates the BRCA1-induced chemoresistance Signal transduction pathway activity analysis of HGSOC revealed that the low activity of PI3K together with the high activity of NF-κB pathway has favorable prognosis and indicates more active immune response, whereas the high PI3K and the low NF-κB pathway activity has poor prognosis and indicates high cell proliferation	(78–86)
HIF-1α signaling	Hypoxic environment is followed by increased expression of transcription factor HIF-1α HIF-1α signaling activates EMT and stemness-regulating pathways, like Wnt/β-catenin, Hedgehog, and NOTCH while downregulating NF-κB pathway HIF-1α signaling upregulates OCSC markers CD133, NANOG, and SOX2 SIRT1 is a downstream target gene for the HIF-1α pathway, involved in promotion of OCSCs by hypoxia, and NF-κB signaling cooperates with HIF-1α in SIRT1 upregulation	Patients with higher expression of HIF-1α have shorter OS Patients with III stage of platinum-resistant HGSOC has overrepresentation of HIF-1α signaling pathway	(87–90)
PI3K/AKT signaling	CAFs stimulate ovarian cancer invasiveness and chemoresistance through the activation of HGFR/PI3K/AKT signaling Interaction with MSCs leads to activation of PI3K/AKT pathway and MDR proteins in OCSCs Defective function of CTNNB1, PTC, SMO, NOTCH, k-Ras, and MEK genes disturbs between others the function of PI3K/AKT pathway in OCSCs Loss of BRCA expression is also followed by activation of PI3K/AKT pathway in OCSCs PI3K/AKT/mTOR pathway is activated by abundance of nutrients and growth factors in TME that inhibits autophagy in cancer cells Activation of PI3K/AKT/mTOR signaling results in upregulation of CD44v6, CD117, and ALDH1A1 OCSC markers as well as enhancement of EMT in chemo resistant ovarian cancer cell lines Shear stress exerted by ascites together with HGF stimulate stemness and chemoresistance by HGFR/PI3K/AKT-miR-199a-3p pathway Blocking CXCR4/PI3K/AKT/mTOR signaling results in reduction of OCSCs and inhibition of EMT Circular RNA circ_0000745 upregulated by IGF2BP2 stimulates stemness of ovarian cancer cells through a miR-3187-3p/ERBB4/PI3K/AKT pathway	High expression of PI3K or AKT is correlated to shorter OS in ovarian cancer UBE2S is a potential oncogene that, through stimulation of PI3K/AKT/mTOR pathway, enhances proliferation and migration of ovarian cancer. Its high expression is a poor prognostic factor Inhibition of PI3K in wild-type PI3KCA ovarian cancer induces BRCA downregulation and with PARP inhibitors shows synergistic effect against ovarian cancer	(91–103)
JAK/STAT signaling	Inhibition of JAK2/STAT3 signaling results in decrease of stemness and reduced tumor growth Inhibition of JAK/STAT pathway in HGSOC cells and CAFs has anti-tumor activity OCT4 accelerates tumor growth and enhances chemoresistance through activation of JAK/STAT pathway in OCSCs represented by “side population” LIF and IL-6 secreted by MSCs promote OCSC function by STAT3 signaling	Higher expression of STAT3 is correlated to poor prognosis in ovarian cancer	(38, 104–107)
TGF-β signaling	TGF-β is one of the pro inflammatory cytokines secreted by CAFs in the OCSC niche Spheroid cancer cells through secretion of TGF-β force mesothelial epithelium to home cancer implants TGF-β secreted by CAFs and TILs stimulates epigenetic changes that promote EMT Enrichment of OCSC population by MSCs is mediated by TGF-β Upregulation of TGF-β together with VEGF and HIF-1α enhances angiogenesis and stemness OCSCs convert the immature DCs into the TGF-β–secreting cells, which support the expansion of Treg lymphocytes defending the tumor TGF-β induces the population of pro-angiogenic N2-polarized TANs that support tumor growth and vascularization miR-33a-5p through the downregulation of CROT and activation of TGF-β signaling promotes tumor growth and paclitaxel resistance	miR-506 prevents TGF-β–induced EMT. Ovarian tumors showing increased miR-506 expression correlated with better prognosis for the patients STMN2 and RAD51AP1 genes overexpression are correlated with poor prognosis in HGSOC and associated with TGF-β signaling pathway TGF-β–induced stimulation of CAF-derived periostin secretion is correlated with reduced survival in HGSOC Seven unfavorable genotypes associated with regulation of TGF-β–mediated signaling are correlated to shorter OS and PFS in patients with ovarian cancer NR2F1 that reveals a high correlation with poor prognosis and tumor stage regulates EMT and immunosuppressive CAFs infiltration through TGF-β signaling	(84, 108–119)
Rho/ROCK signaling	ECM stiffness and tissue tension exerted by ascites activate Rho/ROCK pathway and regulate EMT Rho/ROCK signaling is an important mediator in tumor angiogenesis Rho/ROCK pathway is used by invading cell clusters and “leader cells”	Pharmacological inhibition of LPA-mediated stimulation of Rho/ROCK pathway decreases tumor aggressiveness Inhibition of Rho/ROCK pathway blocks HIF-1α signaling and restores platinum sensitivity of ovarian cancer cells	(120–124)

SNAIL, zinc-finger transcription factor SNAI1; SFRP5, secreted frizzled-related protein-5; CAFs, cancer-associated fibroblasts; GLI1, zinc-finger protein GLI1; SMO, smoothened class frizzled G protein–coupled receptor; YAP, yes-associated protein; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; MYPT1, myosin phosphatase targeting protein-1; PFS, progression-free survival; VEGF, vascular-endothelial growth factor; VEGFR1, VEGF receptor-1; DLL4, delta-like ligand-4; JAG1, protein Jagged 1; NANOG, homeobox protein NANOG transcription factor; OCT4, octamer-binding transcription factor-4; ABC transporter, ATP-binding cassette drug membrane transporter; OS, overall survival; DFS, disease-free survival; NF-κB, nuclear factor-κ-light chain enhancer of activated B cells; TLR-4, Toll-like receptor type-4; HIF-1α, hypoxia-induced factor-1α; BRCA1, breast cancer type-1 susceptibility protein; SIRT1, sirtuin type-1; HGFR, hepatocyte growth factor receptor; MSCs, mesenchymal stem cells; MDR, multi-drug resistance; CTNNB1, catenin beta-1; PTC, papillary thyroid cancer oncogene; SMO, smoothened protein-coding gene; NOTCH, NOTCH receptor-coding gene; k-RAS, Kirsten rat sarcoma virus gene; MEK, mitogen-activated protein kinase kinase-1 coding gene; TME, tumor microenvironment; HGF, hepatocyte growth factor; mTOR, mammalian target of rapamycin kinase; CXCR4, C-X-C chemokine receptor type-4; UBE2S, ubiquitin-conjugating enzyme E2S; PI3KCA, phosphatidylinositol-3-kinase oncogene; PARP, poly-ADP ribose polymerase; TGF, transforming growth factor; TILs, tumor-infiltrating lymphocytes; DCs, dendritic cells; TANs, tumor-associated neutrophils; STMN2, stathmin-2 gene; CROT, carnitine O-octanoyltransferase; RAD51AP1, RAD51-associated protein-1 gene; Rho/ROCK, Rho/Rho-associated protein kinase; LPA, lysophosphatidic acid.