Table 3.
The function and clinical significance of the main components of the tumor microenvironment inside the “metastatic niche”.
| TME component | Function | Clinical significance | Reference |
|---|---|---|---|
| CAFs | CAFs originate from peritoneal fibroblasts or MSCs activated by inflammatory signals, hypoxia, and exosomes produced by cancer cells Activated CAFs secrete TGF-β that stimulates EMT and metastases Increased expression of DKK3 protein enhances Hippo/YAP and Wnt/β-catenin signaling in CAFs thus supporting OCSCs CAFs enhance chemoresistance by activation of HGFR/PI3K/AKT pathway FGF secreted by CAFs stimulates VEGF secretion and OCSC stemness TME remodeling by secretion of ECM components and MMPs Suppression of cytotoxic TILs and enhancement of pro-inflammatory signals The existence of the functional loop between CAFs and ovarian cancer cells is reported, in which CAFs induce angiogenesis by secretion of IL-6, COX-2, and CXCL1, whereas cancer cells induce CAFs to secrete CXCL12, IL-6, and VEGF-A to further enhance angiogenesis |
Four genes—AXL, GPR176, ITGBL1, and TIMP3—identified as ovarian cancer CAF-specific genes allow to construct the prognostic CAF signature. High CAF signature correlates to chemoresistance and activation of signaling pathways regulating tumor progression Molecular CAF signature characterized by the expression of six CAF-related genes (COL16A1, COL5A2, GREM1, LUM, SRPX, and TIMP3) show that high-risk patients have worse prognosis, ineffective immune response, and low tumor mutational burden CAF-score based on molecular characteristics of CAF-related genes and signaling pathways allows classifying patients with ovarian cancer to high- or low-risk population. Higher CAF score is observed in advanced tumors and in patients with worse OS. Patients with low CAF score have better efficacy of immunotherapy CAFs mediate chemoresistance of ovarian cancer to anti-angiogenic therapy |
(91, 110, 146–157) |
| CAAs | Adipocytes are a source of lipids but also secrete adipokines, growth factors, immune mediators, and metabolic agents Omental implants are an example of OCSC niche supporting energetically and proliferatively stem cells Recruitment of OCSCs into the adipose tissue depends on IL-6, IL-8, MCP-1, and TIMP1 Interaction between IL-8 secreted by CAAs and CXCR1 on cancer cells activates metastases through p38MAPK/STAT3 pathway Lipid transfer from CAAs to cancer cells depends on FABP4, which is upregulated especially in metastatic tumors ALDH+CD133+ OCSCs show high levels of desaturation of lipids Survival of OCSCs in adipose tissue TME depends on the function of SCD1, and elimination of SCD1 is synonymous with OCSC depletion Fatty acids supply energy for EMT |
High levels of fatty acids desaturation and oxidation in FABP4-positive tumors correlate with poor prognosis FASN expression correlates with stage and grade of ovarian cancer, and patients showing high FASN expression have worse prognosis and chemoresistant tumors |
(158–164) |
| ADSCs | ADSCs promote generation of OCSCs with use of Hedgehog/BMP4 signaling. Through secretion of IL-6, IL-8, VEGF, and TNF-α, ADSCs enhance chemoresistance. They are capable to differentiate into CAFs and CAAs | (165–167) | |
| MSCs | MSCs are recruited from bone marrow, adipose tissue, and endometrium and are able to differentiate into CAFs MSCs stimulate proliferation, stemness, angiogenesis, and platinum resistance IL-6 and LIF secreted by MSCs enhance OCSC function in the STAT-dependent way MSC-derived TGF-β and VEGF/HIF-1α signals contribute to OCSC support and angiogenesis Bone marrow MSCs enhance chemoresistance of ovarian cancer by releasing miR-1180 that activates Wnt/β-catenin signaling |
Interactions with MSCs activate PI3K/AKT pathway and MDR in OCSCs followed by paclitaxel and platinum resistance | (94, 106, 111, 147, 166, 168–171) |
| TAMs | Conversion of monocytes into TAMs is triggered by LIF and IL-6 present in ascites TAMs residing inside “metastatic niche” show immunosuppressive M2 phenotype and take part in immune escape of the tumor, regulation of angiogenesis, invasion, and stemness Hypoxia in ovarian cancer TME shifts polarization of TAMs into M2 phenotype through miR-222-3p and miR-940 released from cancer cells and activation of STAT pathway Another signal for M2 differentiation of TAMs are cytokines IL-4, IL-10, and IL-13 secreted from both cancer and MSC cells By secretion of pro-inflammatory IL-17, TAMs stimulate p38MAPK and NF-κB pathways that induce self-renewal of CD133+ OCSCs TAMs secrete VEGF and EGF that induce spheroid formation and peritoneal spread of cancer implants M2-type TAMs create and support tumor tolerance by inhibition of NK and cytotoxic T-cell activity and by stimulation of Tregs |
Patients with higher M1/M2 TAMs ratio have better OS and PFS M2 TAM infiltration is correlated to worse OS |
(32, 172–182) |
| UBR5-mediated immunosuppressive TAM infiltration augments tumor growth and metastases and, through activation of p53/β-catenin/CCL2 pathway, stimulates spheroid formation CAPG gene expression is correlated with infiltration of tumors by Tregs, M2 TAMs, and exhausted T cells contributing to immunosuppression in HGSOC TAMs exert pro-tumor and immunosuppressive effects through secretion of IL10,TGFβ, VEGF, and expression of PD-1 and consumption of arginine to inhibit T-cell efficacy |
|||
| CD4+CD25+FoxP3+ Tregs | Expression of suppressive molecule IDO by cancer and dendritic cells contributes to recruitment of Tregs into the tumors Tregs from ovarian tumors show upregulation of TGF-β that inhibits secretion of IL-2, IFN-γ and TNF-α followed by impairment of T CD4+ and T CD8+ effector cells Ovarian OCSCs through CCL5–CCR5 interaction recruit Tregs, which, upon culture with CD133+ OCSCs, secrete high levels of IL-10 showing inhibitory immune function and MMP-9 that enables invasion of cancer cells Tregs infiltrating ovarian tumors show highly activated phenotype (PD-1, 4-1BB, and ICOS) responsible for immunosuppression |
High numbers of Tregs in tumor immune infiltrates are considered a sign of poor prognosis T CD8+/Tregs and CD4+/Tregs ratio are a good predictors of patient survival Abundance of Tregs and increased VEGF in ascites are observed in patients with poor prognosis However, the prognostic value of Tregs depends on the tumor type and stage, and, in HGSOC tumors, lower Th17/Tregs ratio was correlated with better survival |
(183–190) |
| mDCs and pDCs | Tumor and ascites DCs originate from peripheral blood mDCs express IDO and PD-1 and are associated with mmunosuppression of anti-cancer T CD4+ helper and T CD8+ cytotoxic effectors Tumor growth is accompanied by increasing numbers of mDCs, and tumor-derived PGE2 and TGF-β further promote the function of mDCs |
The correlation between higher concentration of tumor- associated pDCs and shorter PFS was found The presence of mature DCs correlates with improved prognosis in HGSOC |
(191–193) |
| Immature mDCs are capable to regulate angiogenesis in the tumor pDCs accumulate preferentially in ascites and their chemoattraction depends on expression of CXCL12 pDCs stimulate the generation of IL-10+ T CD8+ suppressor cells and promote angiogenesis through the secretion of IL-8 and TNF-α The population of tumor-associated pDCs differs functionally from ascitic pDCs and secretes lower levels of pro-inflammatory cytokines |
(187, 194–197) | ||
| MDSCs | MDSC cells possessing CD11b+/Gr-1+ phenotype are a cell population regulating both chronic inflammation and tumor progression MDSCs are able to suppress maturation of DCs and cytotoxic reactions against tumor mediated by T CD8+, NK, and NKT cells Recruitment and functional maturity of MDSCs in the ascites depend on CXCL12/CXCR4 interactions and PGE2 secretion IL-6 and IL10 in ascites increase the number of MDSCs and, through upregulation of STAT3 signaling, promote their suppressive activity by expression of ARG and iNOS Inhibition of mTOR activity decreases MDSC infiltration of ovarian tumors and slows progression PGE2 produced by MDSCs enhances expression of PD-L1 through mTOR pathway. PD-L1 expression is particularly high in OCSCs having ALDH1+ phenotype |
Blockade of a key cytokine for MDSCs function, IL10, restores immunosurveillance and improves survival Peripheral blood ARG/IDO/IL10+ MDSCs are especially abundant in patients with advanced ovarian cancer and their depletion is a good prognostic factor BRCA-mutated patients have less MDSCs and more T CD*+ effectors than patients with wild BRCA copy in early stage HGSOC, what could explain partly the survival benefit in this group of patients |
(198–205) |
| ECM | Mechanosensory signals produced by ascites and tumor expansion regulate EMT and interaction with EMC, as well as enhance angiogenesis, stemness, and chemoresistance Shear stress stimulates stemness by increase of CD44, CD117, and OCT4 activity ECM stiffness upregulates expression of stemness CD133 marker Compression changes activity of the Wnt/β-catenin pathway and regulates EMT Expression of PAX8 links migratory and adhesive properties of Fallopian tube epithelium, STIC, and HGSOC cells. Inhibition of PAX8 reduces ability of cancer cells to migrate and adhere to fibronectin and collagen |
Chondroitin sulfate is upregulated in the ECM of more than 90% of HGSOC and linked to poor prognosis Acquisition of mesothelial–mesenchymal phenotype by cancer cells, characterized by expression of CALB2 and PDPN, regulates adhesion to ECM and tumor progression and is correlated to poor outcome |
(55, 130, 206–212) |
| Exosomes | Exosomes loaded with miRNAs miR-409-3p and miR-339-5p are involved in Wnt/β-catenin signaling pathway and stimulation of metastases in HGSOC Ascites contain exosomes transferring cytokines, growth factors, miRNAs, lipids, and OCSC markers CD44 and EpCAM between tumor environment and OCSCs Exosomes from cancer cells transfer CD44 into mesothelial cells stimulating MMP-9, which supports adhesion and invasion of spheroid cells to the peritoneal surface Tumor cells stimulate conversion of omental fibroblasts into CAFs by production of exosomes containing deregulated miRNAs miR-31, miR-214, and miR-155 Hypoxic environment reprograms TAMs into M2 polarization through exosomes containing miR-222-3p and miR-940 Omental CAFs and CAAs upregulate cancer cells’ chemoresistance and activate anti-apoptotic pathways through miR-21–containing exosomes MSCs enhance tumor growth producing exosomes loaded with miR-21, miR-221, and miR-92a |
Exosomal miR-146a secreted from MSCs reduces cancer growth and chemoresistance to taxanes Abundance of CD117-containing small extracellular vesicles in ascites correlates with tumor grade, chemoresistance, and recurrence Higher concentration of exosomes containing miR-21, miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-205, and miR-214 is found in serum of patients with ovarian cancer compared to patients with benign ovarian tumors Expression of LBP, FGG, FGA, and GSN genes in exosomes isolated from plasma is involved in coagulation and apoptosis related pathways and can be a potential diagnostic and prognostic biomarker for OS and PFS CAV1 gene, which is the direct target of miR-1246, is involved in the process of exosomal transfer. Patients with high miR-1246 and low Cav1 expression have a significantly worse prognosis Serum exosomal level of lncRNA MALAT1 predicts advanced and metastatic ovarian cancer phenotype and correlates to OS |
(43, 172, 173, 213–226) |
| Exosomes containing miR-146b-5p produced by TAMs activate TRAF6/NF-κB/MMP2 pathway that deregulates endothelial cell migration inside tumor Adipose tissue MSC-derived exosomes secreted into ascites promote tumor growth and peritoneal implants by activation of FOXM1 signaling Small extracellular vesicles released from ascites OCSCs upon cisplatin treatment are capable to activate the pro-tumorigenic phenotype in MSCs Exosomes secreted by expanded tumor-derived NK cells containing cisplatin can reverse chemoresistance of cancer cells and augment NK cytotoxic activity CD163+ TAMs secrete exosomes containing miR-221-3p that downregulates ADAMTS6 and activate EMT, thus triggering the OCSC phenotype and chemoresistance FasL and TRAIL are components in exosomes secreted by cancer cells, responsible for apoptosis of immune cells of cancer infiltrate Ascite-derived exosomes transfer miR-6780b-5p to cancer cells promoting EMT and metastasizing CD47 is overexpressed in tumors and tumor-derived exosomes and facilitates tumor immune evasion. Inhibition of exosomal CD47 improves anti-cancer macrophage activity and suppresses peritoneal dissemination EXOSC4 is involved in RNA degradation. Knockdown of EXOSC4 inhibits the proliferation, migration, and invasion ability of ovarian cancer cells by suppressing the Wnt/β-catenin pathway |
Plasma exosomal miR-1260a, miR-7977, and miR-192-5p are significantly decreased in ovarian cancer compared with healthy controls Expression level of miR-205 in plasma exosomes of the ovarian cancer group is significantly higher compared to the benign and control groups and correlates with clinical stage and lymph node metastases |
(227–234) | |
| Hypoxia and acidosis | Hypoxia and HIF-1α activation are capable of sustaining the CD117 expression through Wnt/β-catenin signaling Hypoxia and HIF-1α enhance stemness and EMT via activation of Wnt/β-catenin, Hedgehog, and NOTCH pathways, as well as CD133, SOX2, and NANOG markers Hypoxia/NOTCH/SOX2 signaling is important for maintaining OCSCs, as it enhances spheroid formation, upregulation of ALDH and ABC proteins, and chemoresistance Hypoxia and HIF-1α promote MDSCs to secrete TGF-β, IL-6, and IL-8 that enhance immunosuppressive conditions Hypoxia activates MAPK pathway to induce autophagy in OCSC cells Hypoxia attracts TAMs that support immune tolerance against tumor cells and predisposes mature DC cells to apoptosis Acidosis increases the expression of stemness markers OCT4 and NANOG and secretion of VEGF and IL-8 in OCSC niche Increased aerobic glycolysis in cancer cells is a source of lactate that strongly inhibits T and NK effectors, shifts TAMs into M2 phenotype, and recruits Tregs |
The signature of genes associated with regulation of hypoxia and immune response allow to divide patients with ovarian cancer into high- or low-risk groups Higher ALOX5AP, ANXA1, PLK3, and SREBF1 mRNA levels are significantly associated with shorter OS, whereas LAG3 and IGFBP2 lower mRNA levels with better prognosis, respectively Expression of seven hypoxia-related genes—UQCRFS1, KRAS, KLF4, HOXA5, GMPR, ISG20, and SNRPD1—divides ovarian cancer into two populations with different prognosis Hypoxia-related miR-23a-3p is overexpressed in HGSOC showing chemoresistance and shorter PFS |
(96, 235–247) |
TME, tumor microenvironment; CAFs, cancer-associated fibroblasts; MSCs, mesenchymal stem cells; DKK3, dickopf-related protein-3; YAP, yes-associated protein; PI3K, phosphatidylinositol-3-kinase; AKT, protein kinase B; HGFR, hepatocyte growth factor receptor; FGF, fibroblast growth factor; VEGF, vascular endothelial growth factor; ECM, extracellular matrix; MMPs, metalloproteinases; TILs, tumor-infiltrating lymphocytes; AXL, tyrosine-protein kinase receptor UFO coding gene; GPR176, G protein–coupled receptor 176 coding gene; ITGBL1, integrin subunit beta–like 1 coding gene; TIMP3, TIMP metallopeptidase inhibitor-3 coding gene; COL16A1, alpha 1 chain type XVI collagen coding gene; COL5A2, alpha 2 chain type V collagen coding gene; GREM1, Gremlin-1 protein coding gene; LUM, lumina protein coding gene; SRPX, sushi repeat containing protein X-linked coding gene; OS, overall survival; IL-6, interleukin-6; COX-2, cyclooxygenase-2; CXCL1, C-X-C motif chemokine ligand 1; CXCL12, stromal cell-derived factor 1; CAAs, cancer-associated adipocytes; MCP-1, monocyte chemoattractant protein-1; TIMP1, tissue inhibitor of metalloproteinase-1; CXCR1, C-X-C chemokine receptor type-1; FABP4, fatty acid binding protein-4; SCD1, stearoyl-CoA desaturase-1; FASN, fatty acid synthase; ADSCs, adipose-derived stem cells; BMP4, bone morphogenetic protein-4; MSCs, mesenchymal stem cells; MDR, multi-drug resistance; LIF, leukemia inhibitory factor; HIF-1α, hypoxia-induced factor-1α; TAMs, tumor-associated macrophages; p38/MAPK, p38 mitogen-activated protein kinase; EGF, epithelial growth factor; NK, natural killer; Tregs, T regulatory lymphocytes; OS, overall survival; PFS, progression-free survival; UBR5, ubiquitin protein ligase E3 component n-recognin-5; CCL2, chemokine ligand-2; CAPG, capping actin protein gelsolin-like gene; PD-1, programmed death-1; IDO, indoleamine 2,3-dioxygenase; TGF-β, transforming growth factor-β; PGE2, prostaglandin E2; CCL5, C-C motif chemokine ligand-5; CCR5, CCL5 receptor; MMP-9, metalloproteinase-9; 4-1BB, CD137 or TNF factor receptor superfamily T-cell costimulatory receptor; ICOS, CD278 or inducible T-cell costimulator; mDCs, myeloid dendritic cells; pDCs, plasmacytoid dendritic cells; MDSCs, myeloid-derived suppressor cells; NKT, natural killer T cells; ARG, arginine; iNOS, inducible nitric oxide synthase; PAX8, paired box gene 8 protein; CALB, calretinin; PDPN, podoplanin; TRAF6, TNF receptor–associated factor protein-6; FOXM1, Forkhead box protein M1; ADAMTS6, ADAM metallopeptidase With thrombospondin type 1 motif 6; FasL, Fas ligand; TRAIL, TNF-related apoptosis-inducing ligand; LBP, lipopolysaccharide binding protein; FGG, fibrinogen gamma chain; FGA, fibrinogen alpha chain; GSN, gelsolin; CAF1, caveolin-1; lncRNA, long non-coding RNA; MALAT1, metastasis−associated lung adenocarcinoma transcript 1; EXOSC4, exosome component 4; ALOX5AP, arachidonate 5-lipoxygenase–activating protein; ANXA1, annexin-A1; PLK3, Polo-like kinase-3; SREBF1, sterol regulatory element–binding transcription factor 1; LAG3, lymphocyte activation gene-3; IGFBP2, insulin-like growth factor binding protein 2; UQCRFS1, ubiquinol-cytochrome C reductase, Rieske iron-sulfur polypeptide 1; KRAS, Kirsten rat sarcoma virus; KLF4, Kruppel-like factor 4; HOXA5, homeobox protein Hox-A5; GMPR, guanosine 5′-monophosphate oxidoreductase; ISG20, interferon-stimulated gene 20-kDa protein; SNRPD1, small nuclear ribonucleoprotein D1 polypeptide.