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Table 1 Summary of existing research studies that exploited NRs in different tumor stromal cells and investigated the impacts on carcinogenesis and tumor microenvironment

From: Exploiting vulnerabilities of cancer by targeting nuclear receptors of stromal cells in tumor microenvironment

Stromal cell types Cancer types Models Target NR(s) Agonists/antagonists Key findings References
CAF Cutaneous squamous cell carcinoma (SCC) Cell culture; Mice with SCC + CAF xenograft 48 known NRs in cell-based studies; AR and RARβ in mice models Transfection of siRNA/expression vectors of targeted NRs into CAFs; PPARβ/δ agonist – GW0742; VDR agonist – EB1089; GR agonist – Fluticasone propionate; RARβ antagonist – LE135; AR antagonist – Bicalutamide • PPARβ/δ, VDR, GR, RARβ and AR in CAFs are important modifiers of tumorigenic activities. • Concurrent therapy of cisplatin, LE135 and bicalutamide attenuated chemoresistance in mice tumor xenografts. [15]
CAF Prostate cancer Cell culture; Mice with prostate cancer (PC3) + CAF xenograft AR Transfection of AR-expressing vectors into CAFs AR-expressing stromal cells suppressed prostate cancer growth and invasiveness in vitro and in vivo. [20]
CAF Prostate cancer Cell culture; Mice with prostate cancer (PC3) + CAF xenograft AR Transfection of AR-expressing vectors into CAFs • Low stromal AR expression decreased castration-induced apoptosis. • Loss of AR signaling in CAFs disrupted extracellular matrix integrity, promoting cancer cells invasion. [22]
CAF Prostate cancer Cell culture AR Transfection of siRNA into CAFs • Knockdown of AR in CAFs downregulated the expression of various growth factors and impaired the growth of tumor cells. [28]
CAF Prostate cancer Cell culture AR Agonist – R1881; Antagonist – RD162 • Migration of prostate cancer cells was inhibited by conditioned medium of CAFs treated with R1881, but was reversed by RD162. [29]
CAF Prostate cancer Cell culture AR Knockdown with AR antisense oligonucleotides • Suppression of AR expression in CAFs inhibited cancer cell growth, but promoted stem cell phenotypes. [30]
CAF Breast cancer Cell culture AR Agonist – Mibolerone • Exposure of conditioned medium from Mibolerone-treated CAFs reduced breast cancer cell motility. [31]
CAF Prostate cancer Cell culture; Mice with prostate cancer (22RV1) + CAF xenograft ERα Transfection of ERα-expressing vectors into CAFs • Conditioned medium from ERα-expressing CAFs stimulated proliferation of various prostate cancer cell lines. • Co-implantation of ERα-expressing CAFs and prostate cancer cells increased tumor size in mice. [36]
CAF Prostate cancer Cell culture; Mice with prostate cancer (22RV1) + CAF xenograft ERα Transfection of ERα-expressing vectors into CAFs • Stromal ERα reduced cancer cell invasion. • Mice co-injected with ERα-expressing CAFs and prostate cancer cells had less tumor foci, less metastases and reduced angiogenesis. [37]
CAF Prostate cancer Cell culture; Mice with prostate cancer (22RV1) + CAF xenograft ERα Transfection of ERα-expressing vectors into CAFs ERα-expressing CAFs suppressed cancer invasiveness via reduced macrophage infiltration. [38]
CAF Breast cancer Cell culture ERα, PR Using CAFs isolated from ERα+/PR+ or ERα/PR breast tumors • Cancer cells co-cultured with ERα+/PR+ tumor-derived CAFs had higher tamoxifen sensitivity. [39]
CAF Cervical cancer Cell culture ERα Agonist – Estradiol; Antagonist – ICI 182780, methyl piperidino pyrazole • ERα antagonists downregulated genes associated with cell cycle, metabolism and angiogenic processes. [40]
CAF Prostate cancer Cell culture PR Transfection of PRα- and PRβ-expressing vectors into CAFs • Conditioned medium from PR-expressing CAFs inhibited cancer cell migration and invasiveness, but not cell proliferation. [51]
CAF Prostate cancer Cell culture PR Transfection of PRα- and PRβ-expressing vectors into CAFs • PR regulated prostate stromal cell differentiation. [52]
CAF Colorectal cancer Cell culture GR Agonist – Dexamethasone • Dexamethasone induced GR translocation into CAF nucleus, negatively regulating the expression of pro-inflammatory genes and paracrine factors that promote cancer invasiveness. [56]
CAF Colorectal cancer Cell culture GR Agonist – Dexamethasone • Conditioned medium from dexamethasone-treated CAFs decreased cancer cell proliferation and invasiveness. [57]
CAF Colorectal cancer Cell culture GR Agonist – Dexamethasone • Conditioned medium from dexamethasone-treated CAFs impaired endothelial cell migration by altering CAF secretome. [58]
CAF Pancreatic cancer Cell culture; Mice with pancreatic ductal adenocarcinoma (PDA) xenograft VDR Agonist – Calcipotriol • Calcipotriol maintained the quiescent state of pancreatic stellate cells. • Co-administration of calcipotriol and gemcitabine decreased tumor volume, enhanced intratumoral gemcitabine and increased survival rates of mice with tumor xenograft. [62]
CAF Liver cancer Cell culture; p62KO mice VDR Agonist – Calcipotriol • p62 is a mediator of calcipotriol-induced VDR activation which prevented hepatic stellate cell activation. [64]
CAF Pancreatic cancer Cell culture VDR Agonist – Calcitriol • Calcitriol modified miRNA composition in CAF exosomes. [65]
CAF Breast cancer Cell culture PPARγ, RXR PPARγ agonist – Pioglitazone; RXR agonist – 6-OH-11-O-hydrophenanthrene • PPARγ/RXR agonists inhibited NF-κB and metalloproteinase activities in CAFs. [70]
CAF Melanoma Cell culture PPARγ PPARγ agonist – Ciglitazone, troglitazone, WY14643, 15d-PGJ2 • 15d-PGJ2 inhibited the growth of CAFs and tube formation of endothelial cells. [71]
CAF Colorectal cancer Cell culture; Fibroblast-specific PPARβ/δ knockout mice PPARβ/δ PPARβ/δ gene knockout • Fibroblast-specific PPARβ/δ knockout mice had prolonged survival and fewer intestinal polyps. • CAFs with PPARβ/δ deletion reduced oxidative stress in cancer epithelium. [72]
CAF Breast cancer Cell culture; Mice with breast cancer (MCF-7) + CAF xenograft FXR Agonist – GW4064 • Conditioned medium from GW4064-treated CAFs inhibited leptin signaling, growth, motility and invasiveness of cancer cells. • GW4064-treated tumors had smaller sizes in in vivo xenograft studies. [77]
CAF Breast cancer Cell culture FXR Agonist – GW4064 • GW4064 reduced migration and contractility of CAFs besides inhibiting growth and motility of cancer cells. [78]
CAF Breast cancer RARβ knockout mice RARβ RARβ gene knockout RARβ knockout mice had reduced angiogenesis, inflammatory cell infiltration and myofibroblast count. [79]
TAM Cell culture GR Agonist – Dexamethasone • Dexamethasone-dependent GR activation promoted alternative differentiation of monocytes to macrophages with a M2 phenotype. [83]
TAM Breast cancer Mice with breast cancer (TS/A) + TAM xenograft GR Agonist – Glucocorticoid • TAMs exposed to a mixture containing conditioned medium from MS4A8A-expressing tumors, interleukin-4 and glucocorticoids enhanced tumor growth in mice with tumor xenograft. [84]
TAM Inflammatory cell-specific ERα and ERβ knockout mice ERα, ERβ ERα and ERβ gene knockout; ER agonist – 17β-estradiol • ERα signaling promoted alternative activation of macrophages. [90]
TAM Breast cancer Cell culture; Female MMTV-PyMT mice PPARγ • Cleavage of PPARγ by caspase-1 promoted TAM differentiation. • Inhibition of caspase-1 attenuated caspase-1/PPARγ interaction and suppressed tumor growth. [98]
TAM Ovarian cancer Cell culture PPARβ/δ Agonist – L165041; Inverse agonist – ST247, PT-S264 • Activation of PPARβ/δ upregulated immunity- and tumorigenesis-related genes in TAMs. • Inverse agonists of PPARβ/δ reversed the abnormal gene expression. [99]
TAM Cell culture PPARγ Agonist – Rosiglitazone, 15d-PGJ2 • PPARγ agonists reversed the suppressive effect of TAMs on antitumor cytotoxic T-cells. [100]
TAM Breast cancer Cell culture; Macrophage PPARγ knockout mice PPARγ Agonist – Rosiglitazone • Macrophage PPARγ ablation promoted breast tumor growth and nullified anti-tumor effects of rosiglitazone. [101]
TAM & MDSC Mice with fibrosarcoma (MN/MCA1) xenograft; MMTV-PyMT mice RORγ RORC1 gene knockout • RORγ protected MDSCs from apoptosis, promoted TAM differentiation and prevented neutrophil infiltration into tumor, thus leading to tumor growth and metastasis. [107]
Endothelial cell Cell culture; Tie2CrePPARγflox/flox mice PPARγ PPARγ gene knockout • Deletion of PPARγ impaired angiogenesis and cellular migration in vitro and in vivo. [114]
Endothelial cell Melanoma, lung cancer, glioblastoma, fibrosarcoma Cell culture; Mice with melanoma (B16-F10), Lewis lung carcinoma, glioblastoma (U87) or fibrosarcoma (HT1080) xenograft PPARα PPARα gene knockout; Agonist – Fenofibrate, gemfibrozil, bezafibrate, WY14643 and 5, 8, 11, 14-eicosatetraynoic acid • Fenofibrate strongly suppressed endothelial cell proliferation, angiogenesis and primary tumor growth in mice. • Anti-angiogenic effect of fenofibrate was reversed by PPARα knockout. [115]
Endothelial cell Cell culture; C57BL6 mice PPARβ/δ Agonist – GW501516 • GW501516 induced endothelial cell proliferation and angiogenesis in vitro and in vivo. [116]
Endothelial cell Lung cancer PPARβ/δ knockout mice PPARβ/δ PPARβ/δ gene knockout PPARβ/δ knockout impaired endothelial cell maturation, causing diminished blood flow to the tumors and abnormal microvascular structures. [117]
Endothelial cell Squamous cell carcinoma Cell culture VDR Agonist – Calcitriol • Tumor-derived endothelial cells were sensitive to the anti-proliferative effects of calcitriol. [119]
Endothelial cell Squamous cell carcinoma Cell culture VDR Agonist – Calcitriol • Calcitriol induced cell cycle arrest and apoptosis in tumor-derived endothelial cells, which were attributable to CYP24 inhibition. [121]
Endothelial cell Squamous cell carcinoma Cell culture VDR Agonist – Calcitriol • Methylation silencing of CYP24 promoter led to differential sensitivity to calcitriol-dependent growth inhibition in endothelial cells. [123]
Endothelial cell Cell culture GR Agonist – Dexamethasone, cortisol; Antagonist – RU38486 • GR agonists blocked microvessel tubule formation, but did not affect viability. The anti-angiogenic effects were reversed by RU38486. [128]
Endothelial cell Melanoma Cell culture; Mice with melanoma (B16.F10) xenograft GR Agonist – Prednisolone, dexamethasome, budesonide, methylprednisolone • All GR agonists inhibited tumor size and growth of endothelial cells. [129]
Extra-hematopoietic Tie2-positive cells Melanoma, lung cancer, breast cancer Ovariectomized mice with melanoma (B16K1), Lewis lung carcinoma (LL2) or breast cancer (4 T1) xenograft ERα Agonist – Estradiol • Extra-hematopoietic Tie2-expressing cells were responsible for increased tumor growth and intratumoral vessel density induced by estradiol treatment. [130]
Adipocyte Prostate cancer Cell culture; Mice with prostate cancer (22RV1) xenograft AR • Recruitment of adipocytes to prostate cancer cells enhanced cancer invasiveness via suppression of AR activity and induction of TGF-β1/Smad/MMP9 signals. [135]
Adipocyte Breast cancer Cell culture ERα • Adipocytes exposed to hypoxic condition triggered ERα suppression and promoted endothelial-to-mesenchymal transition of breast cancer cells. [136]