Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome.
OBJECTIVE
Over-expression of the c-Met receptor tyrosine kinase has been described in a variety of cancers and implicated in tumor progression. Unlike some solid tumors, current evidence indicates that c-Met activation in colon cancer is unrelated to gene mutation, is ligand dependent, and occurs via a paracrine fashion. We hypothesize that over-expression of the c-Met receptor and its ligand, hepatocyte growth factor (HGF) in the tumor microenvironment is associated with tumor progression and metastases.


METHODS
Primary tumor c-Met and HGF mRNA expression was analyzed in 60 colon adenocarcinomas. Receptor and ligand expression was analyzed for correlation and association with clinicopathologic features and outcome.


RESULTS
Compared to adjacent normal mucosa, 69% and 48% of tumors showed a greater than 2- and greater than 10-fold elevation in c-Met mRNA, respectively. Elevated HGF mRNA was noted in 47% of tumors with 19% having a greater than 10-fold increase. Tumor c-Met expression was correlated with HGF expression, and a cohort of 33 patients could be defined with both low c-Met and HGF expression. Compared with the 27 tumors with either high c-Met or HGF, the cohort with low c-Met and HGF expression had fewer nodal and distant metastases as well as improved overall survival (HR=2.3, p<0.05).


CONCLUSIONS
Evaluation of the c-Met receptor in context of ligand, HGF, allows identification of a metastatic phenotype that correlates with advanced stage and poor survival. c-Met and HGF co-expression in the tumor microenvironment could be useful in the molecular staging of colon cancer and viable therapeutic targets.
Kammula
Udai S
US
Surgery Branch, National Cancer Institute, Bethesda, MD, USA.
Kuntz
Eleanor J
EJ
Francone
Todd D
TD
Zeng
Zhaoshi
Z
Shia
Jinru
J
Landmann
Ron G
RG
Paty
Philip B
PB
Weiser
Martin R
MR
D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met