The role of insulin and incretin-based drugs in biliary tract cancer: epidemiological and experimental evidence

Abstract

Insulin and incretin-based drugs are important antidiabetic agents with complex effects on cell growth and metabolism. Emerging evidence shows that insulin and incretin-based drugs are associated with altered risk of biliary tract cancer (BTC). Observational study reveals that insulin is associated with an increased risk of extrahepatic cholangiocarcinoma (ECC), but not intrahepatic cholangiocarcinoma (ICC) or gallbladder cancer (GBC). This type-specific effect can be partly explained by the cell of origin and heterogeneous genome landscape of the three subtypes of BTC. Similar to insulin, incretin-based drugs also exhibit very interesting contradictions and inconsistencies in response to different cancer phenotypes, including BTC. Both epidemiological and experimental evidence suggests that incretin-based drugs can be a promoter of some cancers and an inhibitor of others. It is now more apparent that this type of drugs has a broader range of physiological effects on the body, including regulation of endoplasmic reticulum stress, autophagy, metabolic reprogramming, and gene expression. In particular, dipeptidyl peptidase-4 inhibitors (DPP-4i) have a more complex effect on cancer due to the multi-functional nature of DPP-4. DPP-4 exerts both catalytic and non-enzymatic functions to regulate metabolic homeostasis, immune reaction, cell migration, and proliferation. In this review, we collate the epidemiological and experimental evidence regarding the effect of these two classes of drugs on BTC to provide valuable information.

Keywords: Antidiabetic; Biliary tract cancer; Cholangiocarcinoma; Incretin; Insulin.

Fig. 1

Insulin signaling and crosstalk with the IGF-1 systems. Insulin regulates the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways to influence the development of BTC. In the condition of hyperinsulinemia, insulin can directly bind to IGF-1R and IR/IGF-1Rs or indirectly increase the biologically active free IGF-1 to augment its mitogenic and antiapoptotic effects. IGF-I insulin-like growth factor-1, MAPK mitogen-activated protein kinase, PI3K phosphatidylinositol-3-kinase, Akt protein kinase B, mTOR mammalian target of rapamycin, BTC biliary tract cancer, IGF-1R insulin-like growth factor-1 receptor, IR/IGF-1Rs hybrid receptors of insulin receptor and insulin-like growth factor-1 receptor, IRS insulin receptor substrates, IRs(A/B) insulin receptor A or B isoform, IGFBPs insulin-like growth factor-binding proteins, ULK Unc-51 like autophagy activating kinase, MEK mitogen-activated protein kinase kinase, ERK extracellular signal-regulated kinase

Fig. 2

Cell of origin and molecular alterations of three subtypes of BTC. The difference in the cell of origin and molecular alterations lays the foundation of the risk discrepancy between insulin and three subtypes of BTC. Compared to ICC and GBC, ECC originates mainly from cells residing in PBGs and has more frequent mutations in P53, KRAS, and SMAD4, resulting in greater sensitivity to insulin stimulation. BTC biliary tract cancer, ICC intrahepatic cholangiocarcinoma, ECC extrahepatic cholangiocarcinoma, GBC gallbladder cancer, PBGs peribiliary glands, FGFR 1–3 fibroblast growth factor receptor 1–3, IDH 1/2 isocitrate dehydrogenase, BAP1 BRCA1-associated-protein 1,ubiquitin carboxyl-terminal hydrolase, ARID1A AT-rich interactive domain-containing protein 1 A, EPHA2 ephrin type-A receptor 2, TP53 tumor protein P53, KRAS kirsten rat sarcoma viral oncogene homolog, SMAD4 mothers against decapentaplegic homolog 4, PRKACA protein kinase cyclic adenosine monophosphate (cAMP)-activated catalytic subunit alpha, PRKACB protein kinase cAMP-activated catalytic subunit beta, ELF3 E74 like ETS transcription factor 3, ARID1B/A AT-rich interactive domain-containing protein 1 B/A, GNAS guanine nucleotide-binding protein-alpha stimulating, BRCA1/2 breast cancer gene 1/2, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, EGFR epidermal growth factor receptor, ERBB3 erythroblastic leukemia viral oncogene homologue3, PTEN phosphatase and tensin homolog, ARID2 AT-rich interactive domain 2, MLL2/3 histone-lysine N-methyltransferase, TERT telomerase reverse transcriptase. (Fig. 2 is created with BioRender.com)

Fig. 3

Signaling pathways of GLP-1 and DPP-4. GLP-1 elicits its incretin effects via an acute elevation in cAMP levels and subsequent activation of PKA and EPAC when binding to GLP-1 receptors on beta-cells. GLP-1 slows the progressive loss of beta-cell function by the activation of pro-survival CREB signaling. This figure shows two of the common ways by which DPP-4 promotes cancer progression: truncating CCL11 to decrease the migration of eosinophils and CXCL10 to inhibit the migration of T and NK cells. GLP-1 glucagon-like peptide-1, DPP-4 dipeptidyl peptidase-4, cAMP cyclic adenosine monophosphate, PKA protein kinase A, PKC Protein kinase C, Akt/PKB Protein kinase B, EPAC exchange protein directly activated by cAMP, CREB cAMP-response element binding protein, NK natural killer cells, DPP-4i dipeptidyl peptidase-4 inhibitors, MAPK mitogen-activated protein kinase, PI3K phosphatidylinositol-3-kinase, mTOR mammalian target of rapamycin, JNK c-Jun N-terminal kinase, ERK1/2 extracellular signal-regulated kinase 1/2, ATP adenosine triphosphate, IRS insulin receptor substrates, PDX-1 pancreatic and duodenal homeobox 1, CCL C-C motif chemokine ligand, CXCL chemokine (C-X-C motif) ligand