Table 2.

Summary of the tumorigenic roles played by c-Met.

Stemness pathways	c-Met is a direct transcriptional target of WNT/β-catenin. MET is co-expressed with CD133 and/or CD15. MET-overexpression correlates with higher clonogenic survival. c-Met expressing cells were preferentially localized in perivascular regions GSCs. Stimulation of c-Met signaling pathway increased expression of Oct4, Nanog, and Klf4. HGF induced c-Met activation was most pronounced in the SHH subgroup of medulloblastoma.
Epigenetic dysregulation	JARID1B activates c-Met in cancer stem cells. c-Met and its ligand HGF/SF are involved in epigenetic dysregulation. SPINT2/HAI-2, an inhibitor of HGF/c-Met signaling, was silenced by promoter methylation in medulloblastoma.
Aberrant signaling	VEGFR cross-talks with c-Met. c-MET cross-talks with IGF1R, TGF-β, and EGFR. c-Met activation is mediated via the PI3K-AKT and RAS-MAPK. c-Met activation induces CDC42. c-Met and TrkA-B pathways trans-activate each other. PDRX1 expression stabilizes c-Met. TGF-β inhibits stemness in GSCs partly through its antagonism of c-Met activity. TNF-α induces MET transcription to sustain MEK/ERK activation and promote invasive growth.
Therapeutic resistance	MET enhances GSC radio-resistance via AKT activity through activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair. Sole inhibition of CDK4/6 led to a NF-κB-mediated upregulation of hepatocyte growth factor, brain-derived neurotrophic factor, and nerve growth factor, which further activates both c-Met and TrkA-B pathways. Treatment with altiratinib (inhibitor of MET/TIE2/VEGFR2) in human glioma stem cells inhibited expression of mesenchymal markers, microvessel density, and TIE2-expressing monocyte infiltration. Foretinib overcomes entrectinib resistance associated with the NTRK1-G667C mutation in NTRK1 fusion-positive tumors.

Summary of the tumorigenic roles played by c-MET signaling on cancer stemness maintenance, epigenetic dysregulation, aberrant signaling, and therapeutic evasion. Abbreviations, c-MET, mesenchymal epithelial transition factor; WNT/β-catenin, wingless-related integration site/β-catenin pathway; CD 133, CD15, transmembrane phosphoglycoprotein protein 133 and 15; GSC, glioma stem cells; Oct 4, octamer-binding transcription factor 4; Nanog, transcription factor that is involved in the self-renewal of embryonic stem cells; Klf 4, Krüppel-like factor; JARID 1B, Jumonji C-domain-containing histone demethylase 1B; HGF/SF, hepatocyte growth factor/scatter factor; SPINT2/HAI-2, serine peptidase inhibitor, Kunitz type 2/hepatocyte growth factor activator inhibitor-2; VEGFR, vascular endothelial growth factor receptor; IGF 1R, insulin-like growth factor 1 receptor; TGF-β, transforming growth factor β; EGFR, epidermal growth factor receptor; PI3K-AKT, phosphoinositide 3-kinase-AK strain transforming; RAS-MAPK, RAS-mitogen-activated protein kinase; CDC42, cell division control protein 42; TrKA-B, tropomyosin receptor kinase A-B; PDRX1, peroxiredoxin 1; TNF-α, tumor necrosis factor α; MEK/ERK, MAPK/ERK kinase/extracellular receptor kinase; ATM kinase, ataxia-telangiectasia-mutated (ATM) protein kinase; CDK 4/6, cyclin-dependent kinase 4/6; NF-κB, nuclear factor κB; TIE 2, receptor tyrosine kinase 2; NTRK-1, neurotrophic tyrosine receptor kinase 1.