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

Cheng, Hong Sheng; Lee, Jeannie Xue Ting; Wahli, Walter; Tan, Nguan Soon

doi:10.1186/s12943-019-0971-9

Molecular Cancer

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; Tie2CrePPARγ^flox/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]

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