Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer

Table 1 Studies published between 2018 and 2022 on receptor for advanced glycation products-ligands, related activated pathways, and cancer hallmarks in the most frequent neoplasms found in diabetic patients

Neoplasia	Ligands and signaling pathway	Molecule expressed	Cancer hallmarks	TS/AM/CL	Ref.
Breast cancer	AGE/RAGE, ERK1/2; Akt, c-fos	IL-8/CXCR1/2	Migration and invasion	CL; CAFs, TNBC (MDA-MB-231 cells)	Santolla et al[137]
	HMGA1		Cell proliferation, metastasis, and EMT	CL; TNBC (MDA-MB-231 and Hs578)	Shah et al[138]
	HMGB1/RAGE		Motility, migration, invasion, and dysregulation of metabolism	TS; human breast cancer, AM; NOD/SCID mice, CL; human breast cancer cells (MCF-7, T-470, BT474, MDA-MB-231, ZR-75-30, BT549) and human fibroblast cells HFL1	Chen et al[139]
	HMGB1/PI3K/Akt	PD-L1	Cell proliferation, migration, invasion, and T-cell apoptosis	CL; human breast cancer cells (MDA-MB-231 P, MDA-MB-231 BM)	Amornsupak et al[140]
	HMGB1, PI3K/Akt, mTOR	HIF-1α, VEGF	Migration and angiogenesis	TS; human breast cancer CL; human breast cancer cells MCF-7	He et al[141]
	HMGB1/RAGE	Downregulation of miR-205	Cell growth, invasion, and EMT	TS; human breast cancer CL; TNBC (MDA-MB-231, MDA-MB-453, MDA-MB-468) and NTNBC (MCF-7, MCF-10F)	Wang et al[142]
	HMGB1/RAGE, ERK 1/2, CREB		Bone metastasis and neurite outgrowth of nervous system cells	AM; 4T1 mice CL; mouse breast cancer 4T1, primary rat nervous system cells DRG, rat DRG/mouse neuroblastoma hybrid cells F11, immortalized rat DRG neuronal cells 50B11	Okui et al[143]
	S100A14/RAGE, NF-kB	CCL2/CXCL5	Migration, invasion, and lung metastasis	TS; human breast cancer and paired adjacent breast normal, metastatic lymph node, and non-metastatic lymph node AM; BALB/c, BALB/c, SCID beige, C57BL/6J, CMV-CreC57BL/6J, S200-/- and S100A14-/- PyMT mice CL; human breast cancer cells MCF7, MCF10A, T47D, SKBR3, BT549, MDA-MB-231, MCF10AT, MCFCA1h, MCFCA1α and mouse breast cancer cells 4T1	Li et al[144]
	S100A7/RAGE, PI3K/Akt, ERK1/2, STAT3	IGF-1	Angiogenesis	CL; human breast cancer cells MCF-7, T47D, and HUVECs cells	Muoio et al[145]
	S100A7/RAGE, cPLA	PGE2, CD163+	Immunosuppression, M2-macrophages, CD4+, CD8+, and T cells	AM; NOD SCID gamma mice CL; human breast cancer cells MDA-MB-231, MDA-MB-468 and mouse mammary cancer cells MVT-1	Mishra et al[146]
	S100A8/A9-RAGE, FAK, Akt, Hippo-YAK	FLNA, CTGF, Cyr61	Cell proliferation and migration	CL; HEK293T and TNBC (MDA-MB-23 and BT-549)	Rigiracciolo et al[147]
	LPS/S100A7/TLR4/RAGE		Migration and invasion	AM; orthotopic breast cancer C57BL/6 mice model CL; murine mammary cancer cells EO771, MTV-1, murine metastatic mammary cells EO.2, human breast carcinoma cells SUM 159, MDA-MB-231 and MDA-MB-468	Wilkie et al[148]
	acHMGB1/RAGE, S100A4/RAGE, Gas6/AXL	CXCR4, CXCL12, CCL2, CD151 and α3β1-integrin	Cell proliferation, invasion, intravasation, and EMT	AM; murine orthotopic mammary cancer CL; human MSCs, geminin overexpressing breast tumors Gem197, Gem240, Gem256, Gem257 and Gem270 cells, CAFs, and M0- TAMs and M2-TAMs	Ryan et al[149]
Colorectal cancer	S100A16		Cancer prognostic marker	TS; human colorectal cancer	Sun et al[150]
	HMGB1/RAGE	PD-1	Cancer prognostic marker	TS; human colorectal cancer CL; human colorectal cancer cells SW480, and SW620	Huang et al[151]
	S100B/RAGE, NF-kB	VEGF-A	Proliferation, migration, and angiogenesis	CL; human colon cancer cells HCT116	Zheng et al[152]
	IGF1R-Ras/RAGE-HMGB1,		Oncogenesis	TS; Human colorectal from diabetic patients	Niu et al[153]
	AGEs/RAGE, KLF5	MDM upregulation and RB and p53 downregulation	Cancer initiation and development	AM; diabetic mouse model and CL; human colon cancer cells HCT116	Wang et al[154]
	TCTP, HMGB1/RAGE, NF-kB		Invasion and metastasis	TS; human colorectal AM; tumor xenografts BALB/c nude mice CL; human colon adenocarcinoma cells LoVo	Huang et al[155]
	S100A9/RAGE/TLR4	Arg-1, iNOS, IL-10 and ROS	Immune suppression and MDSC chemotaxis	TS; human colorectal cancer and normal colon CL; Human colorectal cells LoVo, and MDSCs	Huang et al[156]
	HMGB1/RAGE, Kras/Yap1		Cell proliferation	CL; human colorectal cancer cells HCT116 and SW480	Qian et al[157]
	S100B/RAGE, p38/pAkt/mTOR	VEGF-R2, iNOS, VEGF	Cell proliferation, migration, invasion, and angiogenesis	CL; human colon adenocarcinoma cells CaCo	Seguella et al[158]
	HMGB1/RAGE, pERK1/2, pDRP1		Cell viability, autophagy, and chemoresistance	TS; human colorectal AM; athymic nude BALBC/c mice CL; human colorectal cells SW480, SW620, and LoVo	Huang et al[159]
Hepatocellular carcinoma	S100A9-TLR4/RAGE-ROS,	NET	Cell proliferation, invasion, and metastasis	TS; HBV+ and HBV-hepatocellular carcinoma AM; BALB/c mice and C57BL/6 mice CL; human liver cells QSG-7701, human hepatocellular carcinoma cells HepG2.2.15, mouse hepatocellular carcinoma cells H22 and HUVEC cells	Zhan et al[160]
	HMGB1/RAGE		Cell proliferation and tumor differentiation	TS; primary hepatocellular carcinoma	Ando et al[161]
	HMGB1/RAGE, ATG7		Cell proliferation, fibrosis, and autophagy	TS; mouse hepatocellular carcinoma AM; Atg7, RAGE, HMGB1 transgenic C57BL/6Jmouse	Khambu et al[128]
	HMGB1/RAGE, JNK, OCT4/TGFb1	miR-21, CD44	Migration and invasion	TS; human hepatocellular carcinoma AM; BALB/c nu/nu mice CL; human hepatocellular carcinoma cells HepG2, HCCLM3, Huh7, SMMC7721 and MHCC97H	Li et al[162]
	S100A4/RAGE, b-catenin	OCT4, SOX2, CD44 and Nanog (stem cell-associated genes)	Fibrosis and carcinogenesis	TS; human hepatocellular carcinoma AM; S100a4-EGFP, S100A4+/+GFP, S100A4-/- transgenic mice. CL; human hepatocellular carcinoma cells Huh7 and murine liver cancer cells Hep1-6	Li et al[163]
	HMGB1/RAGE, ERK1/2	CXCL2, IL-8, TNF, IL-6, IL-10, IL-23-p19	Macrophage activation and inflammation	AM; primary murine hepatocytes from male C57BI/6J mice, and primary murine splenocytes from male C57BI/CJ CC; murine hepatoma cells Hepa1-6 and Hep-56.1D, human hepatoma cells HepG2, RAW 264.7 macrophages and monocytic cells THP1	Bachmann et al[164]
	HMGB1/RAGE, NF-kB	circRNA 101368, miR-200a	Cell migration	TS; human hepatocellular carcinoma CL; human hepatocellular carcinoma cells HCCLM3, MHCC97L, SMMC7721, Hep3B, HepG2 cells, and normal hepatocyte cells THLE-3	Li et al[165]
Pancreatic cancer	RAGE	NET	Neutrophil autophagy	TS; human pancreatic carcinoma AM; Wild type C57BL6 mice and RAGE-/- C57BL6 mice, orthotopic pancreatic cancer model, CL; murine pancreatic cancer cells Panc02, MDSCs cells	Boone et al[166]
	RAGE, PI3K/AKT/mTOR		Cell viability	CL; human pancreatic cancer cells MIA Paca-2, BxPC-3, AsPC-1, HPAC, PANC-1, MIA PacaGEMR	Lan et al[167]
	RAGE, ERK1/2/Akt	Alpha 2 and alpha 1 integrin downregulation	Cell proliferation, invasion, and migration	CL; human pancreatic cancer cells Panc-1	Swami et al[129]
	AGE/RAGE, TGFb1	a-SMA, collagen 1, IL-6	Fibrosis and EMT	TS; human pancreatic ductal adenocarcinoma AM; WT-C57BL/6 and RG-C57BL/6 mice CL; primary PSC, human pancreatic ductal adenocarcinoma cells BxPC-3 and AsPC-1	Uchida et al[168]
	HMGB1/RAGE, PI3K/Akt	Atg5, Beclin-1, LC3-II	Autophagia and apoptosis inhibition	CL; human pancreatic cancer cells MIA Paca-2 and MIA PacaGEMR	Chen et al[169]

AGE: Advanced glycation end products; Akt: Protein kinase B; AM: Animal model; Arg-1: Arginase-1; ATG7: Autophagy related 7; CAFs: Cancer-associated fibroblasts; CCL2: CC-chemokine ligand 2; circRNA: Circular RNA; CL: Cell line; cPLA: Cytosolic phospholipase A2; CREB: cAMP response element-binding protein; CTGF: Connective tissue growth factor; CXCL: CXC motif chemokine ligand; CXCR: C-X-C Chemokine receptor; Cyr61: Cysteine-rich angiogenic 61; DRG: Dorsal rat ganglion; pDRP1: Phosphorylated dynamin-related protein 1; EMT: Epithelial-mesenchymal transition; ERK 1/2: Extracellular signal regulated kinase 1/2; FAK: Focal adhesion kinase; FLNA: Filamin A alpha; HIF-1α: Hypoxia-inducible factor-1 alpha; HBV: Hepatitis B virus; Gas6: Growth arrest-specific gene 6; HMG: High mobility group; acHMGB1: Acetylated high mobility group B1; HUVECs: Human umbilical vein endothelial cells; IGF-1: Insulin-like growth factor-1; JNK: Jun N-terminal kinase; KLF5: Kruppel-like factor 5; LPS: Lipopolysaccharide; MDA-MB-231 P: MDA-MB-231 Parental cells; MDA-MB-231 BM: MDA-MB-231 bone marrow; MDM: Mouse double minute 2 homolog; MDSCs: Myeloid-derived suppressor cells; MIA Paca^GEMR: MIA Paca gemcitabine resistant; MSCs: Mesenchymal stem cells; mTOR: Mammalian target of rapamycin; NET: Neutrophil extracellular traps; NF-kB: Nuclear factor-kappa B; iNOS: Inducible nitric oxide synthase; NTNBC: Non-triple-negative breast cancer; OCT-4: Octamer-binding transcription factor 4; PI3K: Phosphoinositide 3-kinase; PD-L1: Programmed death ligand 1; PGE2: Prostaglandin E2; PSC: Pancreatic stellate cell; Ras: Rat sarcoma virus; RB: Retinoblastoma; RAGE: Receptor for advanced glycation end products; S100: Soluble 100% protein; a-SMA: Alpha-smooth muscle actin; SOX2: SRY (sex determining region Y)-box 2; STAT3: Signal transducer and activator of transcription 3; TAMs: Tumor-associated macrophages; TCTP: Translationally controlled tumor protein; TGFb1: Tumor growth factor beta 1; THP1: Human monocytic cell line derived from acute monocytic leukemia; TLR: Toll-like receptor; TNBC: Triple-negative breast cancer; TNF: Tumor necrosis factor; TS: Tissue sample; VEGF: Vascular endothelial growth factor; Yap1: Yes associated protein 1.