c-Met signaling in the development of tumorigenesis and chemoresistance: Potential applications in pancreatic cancer

Table 1 Cancer stem cell markers are listed with previously described functions

CSC marker	Proposed function
CD44	ECM binding, organization of actin cytoskeleton, modulation of mitogenic signaling[112]
CD24	P-Selectin binding, cell migration[113]
ESA	Mediation of epithelial intercellular adhesion[114]
CD133	Activation of Wnt signaling and angiogenesis[115,116]
CXCR4	Receptor of SDF-1, hematopoietic stem cell homing, invasion[117]
MET	Receptor of HGF, promotes cell growth, proliferation, migration[11]
u-PA	ECM degradation, cell migration[118]

Note the pattern of migratory functions associated with cancer stem cell (CSC) markers. ECM: Extracellular matrix; ESA: Epithelial specific antigen; CXCR4: Chemokine receptor type 4; SDF-1: Stromal cell-derived factor 1; MET: Mesenchymal-epithelial transition factor; HGF: Hepatocyte growth factor; u-PA: Urokinase-type plasminogen activator.

Table 2 Mechanisms of hepatocyte growth factor-mesenchymal-epithelial transition factor induced chemoresistance in different cancer types

Cancer type	Chemotherapy	Mechanism of HGF-MET signaling in chemoresistance
Multiple myeloma	Bortezomib	MET overexpression: Apoptotic resistance via PI3K-Akt activation[92]
Glioblastoma	Radiation, cisplatin, camptothecin, adriamycin, and taxol groups	Addition of HGF: Anti-apoptotic effects via PI3K-Akt dependent pathways[91]
Rhabdomyosarcoma	Vincristine/etoposide, radiation	Addition of HGF: Enhanced migration, MMP secretion, PI3K-Akt activation[119]
Non-small cell lung carcinoma	Cisplatin	Addition of HGF: Downregulation of apoptosis-inducing factor (AIF)[87]
Non-small cell lung carcinoma	Erlotinib	c-met amplification: Activation of EGFR, preservation of PI3K-Akt activation[88]
Gastric adenocarcinoma	Adriamycin	Addition of HGF: Anti-apoptotic effects via PI3K-Akt upregulation[93]
Pancreatic adenocarcinoma	Gemcitabine	MET overexpression: Anti-apoptotic effects via PI3K-Akt activation, induction of EMT-like changes[94,95]
Ovarian adenocarcinoma	Carboplatin/paclitaxel	MET overexpression: Apoptotic resistance via PI3K-Akt activation[89,90]

MET: Mesenchymal-epithelial transition factor; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; HGF: Hepatocyte growth factor; MMP: Matrix metalloproteinase; EGFR: Epidermal growth factor receptor; EMT: Epithelial-mesenchymal transition.

Table 3 Mesenchymal-epithelial transition factor inhibitors are shown with specific targets and evidence of anti-tumor effect

Drug	Target(s)	Impact
Cabozantinib	MET	Induced apoptosis in gemcitabine-resistant pancreatic cancer cell lines, currently in phase I clinical trials[101]
Crizotinib	ALK, MET	Inhibited growth of gemcitabine resistant pancreatic cancer cell lines[95], FDA approved for ALK-expressing NSCLC and myofibroblastic sarcomas
Foretinib	MET, VEGFR	Inhibited tumor growth in lung metastasis animal model but failed to show benefit in multiple phase II clinical trials[110,120,121]
Tivantinib	MET	Inhibited growth in multiple cancer cell lines via MET targeting as well as inhibition of microtubule formation[122]
E7050	MET, VEGFR	Inhibited growth in xenograft models of lung, gastric and pancreatic cancer[123]
PF-04217903	MET	Inhibited growth and metastasis of pancreatic neuroendocrine tumors[124]
SU11274	MET	Inhibited growth and proliferation in colon cancer cell lines[125]
T-1840383	MET, VEGFR	Inhibited tumor growth in a variety of murine xenograft models[126]

MET: Mesenchymal-epithelial transition factor; ALK: Anaplastic lymphoma kinase; NSCLC: Non-small cell lung carcinoma; VEGFR: Vascular endothelial growth factor receptor.