Co-overexpression of Met and hepatocyte growth factor promotes systemic metastasis in NCI-H460 non-small cell lung carcinoma cells.
Complete resection of early-stage non-small cell lung cancer (NSCLC) is potentially curative, yet approximately 50% of patients are at risk for developing metastatic recurrence. Met, the receptor for hepatocyte growth factor (HGF) is a receptor tyrosine kinase with demonstrated roles in regulating cellular proliferation, motility, morphogenesis, and apoptosis. Met receptor and its ligand, HGF, are commonly overexpressed in NSCLC, and their overexpression has been associated with poor prognosis, which could potentially involve a paracrine and/or autocrine activation loop. However, there is as yet no direct evidence that HGF-Met signaling directly promotes metastasis in NSCLC cells. Using retroviral transduction, we overexpressed the human c-met and hgf complementary DNA, alone or in combination in the NCI-H460 human large cell carcinoma cell line. The HGF/Met co-overexpressing (H460-HGF/Met) cells demonstrated enhanced tumorigenicity in xenograft SCID mice. When these cells are implanted orthotopically into the lungs of nude rats, only the H460-HGF/Met cells showed higher spontaneous metastases to distant organs including bone, brain, and kidney. These results provide evidence that autocrine overactivation of the Met- HGF loop enhances systemic metastases in NSCLC. Targeted interference of this loop may potentially be an effective adjuvant therapy to improve survival of early-stage NSCLC patients.
Navab
Roya
R
Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Ontario, Canada.
Liu
Jiang
J
Seiden-Long
Isolde
I
Shih
Warren
W
Li
Ming
M
Bandarchi
Bizhan
B
Chen
Yan
Y
Lau
Davina
D
Zu
Yen-Fen
YF
Cescon
Dave
D
Zhu
Chang Qi
CQ
Organ
Shawna
S
Ibrahimov
Emin
E
Ohanessian
Dina
D
Tsao
Ming-Sound
MS
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011923:Rats, Nude; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014183:Transplantation, Heterologous
C066855:HGF protein, human; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met