Targeting Farnesoid X Receptor in Tumor and the Tumor Microenvironment: Implication for Therapy

Abstract

The farnesoid-X receptor (FXR), a member of the nuclear hormone receptor superfamily, can be activated by bile acids (BAs). BAs binding to FXR activates BA signaling which is important for maintaining BA homeostasis. FXR is differentially expressed in human organs and exists in immune cells. The dysregulation of FXR is associated with a wide range of diseases including metabolic disorders, inflammatory diseases, immune disorders, and malignant neoplasm. Recent studies have demonstrated that FXR influences tumor cell progression and development through regulating oncogenic and tumor-suppressive pathways, and, moreover, it affects the tumor microenvironment (TME) by modulating TME components. These characteristics provide a new perspective on the FXR-targeted therapeutic strategy in cancer. In this review, we have summarized the recent research data on the functions of FXR in solid tumors and its influence on the TME, and discussed the mechanisms underlying the distinct function of FXR in various types of tumors. Additionally, the impacts on the TME by other BA receptors such as takeda G protein-coupled receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic receptors (CHRM2 and CHRM3), have been depicted. Finally, the effects of FXR agonists/antagonists in a combination therapy with PD1/PD-L1 immune checkpoint inhibitors and other anti-cancer drugs have been addressed.

Keywords: FXR; TME; combination therapy; immunotherapy; tumor.

Figure 3

The effects of the FXR natural agonist CDCA on progression of different types of cancer including breast cancer [125,126,128], biliary tract carcinoma [196], colorectal carcinoma [199], hepatocellular carcinoma [86,201], prostate cancer [142], ovarian cancer [202], endometrial cancer [203], and esophageal adenocarcinoma [204].   represents activation, while   represents inhibition.

Figure 4

The effects of the FXR synthetic agonist GW4064 on progression of different types of cancer including breast cancer [128], biliary tract carcinoma [92], colorectal carcinoma [205], hepatocellular carcinoma [86,197], pancreatic cancer [122], prostate cancer [141], esophageal squamous cell carcinoma [110], and osteosarcoma [144].   represents activation, while represents inhibition.

Figure 1

Synthesis of bile acids via the classic (neutral) and alternative (acidic) pathways. The classic pathway takes place in the liver and is initiated by cholesterol conversion to 7α hydroxycholesterol mediated by cholesterol 7α hydroxylase (CYP7A1) [21,25]. The alternative pathway occurs in both the liver and extrahepatic tissues including the brain, adrenal glands, macrophages, and ovarian follicles [21,29]. The alternative pathway is initiated by the conversion of cholesterol to 25(R)-26-hydroxy cholesterol (27-hydroxycholesterol) metabolized by sterol 27-hydroxylase (CYP27A1), 25-hydroxy cholesterol produced by sterol 25-hydroxylase (CH25H), and 24-hydroxycholesterol catalyzed by sterol 24-hydroxylase (CYP46A1) in the brain [30]. Secondary bile acids such as DCA, LCA, and UDCA are formed from intestinal bacterial deconjugation/dehydroxylation/7β epimerization [31]. The secondary bile acids are absorbed and returned to the liver through enterohepatic circulation. Detailed information on BA biosynthesis can be found in the text. The figure was generated using Mind the Graph. CYP7A1: cholesterol 7α hydroxylase, HSD3B7: hydroxysteroid dehydrogenase 3B7, C4: 7α-hydroxy-4-cholesten-3-one, CYP8B1: Sterol 12α-hydroxylase, CYP27A1: sterol 27-hydroxylase, BACS: bile acid-CoA synthetase, BAAT: bile acid-CoA amino acid N-acyltransferase, CDCA: chenodeoxycholic acid, CA: cholic acid, CH25H: 25-hydroxylase, CYP7B1: 25-hydroxycholesterol 7-alpha-hydroxylase, DCA: deoxycholic acid, LCA: lithocholic acid, UDCA: ursodeoxycholic acid; BSEP: bile salt export pump, NTCP: sodium taurocholate co-transporting polypeptide, ASBT: apical sodium-dependent bile acid transporter, OSTα/β: organic solute transporter alpha/beta, IBABP: ileal bile-acid-binding protein.

Figure 2

Effects of FXR on macrophages. FXR is highly expressed in innate immune cells including monocytes, macrophages, dendritic cells, NK cells, and NKT cells [14]. FXR activation induces itssumoylation in macrophages resulting in the inhibition of pro-inflammatory cytokine secretion by affecting SHP (co-repressor for several cytokines such as IL1β and TNFα), stabilizing NCoR1, and preventing NF-KB binding [61,73,74]. Additionally, FXR activation by GW4064 induces a switch in macrophage polarization towards the M2-anti-inflamatory type [75]. The figure was generated using Mind the Graph. CDCA: chenodeoxycholic acid, NCoR1: nuclear receptor co-repressor 1, SHP: small heterodimer partner, SUMO: Sumoylation.