Lymphovascular invasion is associated with poor survival in gastric cancer: an application of gene-expression and tissue array techniques.
OBJECTIVE
To examine a population-based cohort for the association between clinicopathologic predictors of survival and immunohistochemical markers (IHC), and to assess changes in gene expression that are associated with lymphovascular invasion (LVI).


BACKGROUND
LVI has been associated with poor survival and aggressive tumor behavior. The molecular changes responsible for the behavior of gastric cancer have yet to be determined. Characterization of IHC markers and gene expression profiles may identify molecular alterations governing tumor behavior.


METHODS
: Clinicopathologic and survival data of 114 patients were reviewed. Archival specimens were used to construct a multitumor tissue array that was subjected to IHC of selected protein targets. Correlation of IHC with tumor thickness (T status), LVI and prognosis was studied. Microarray analysis of fresh gastric cancer tissue was conducted to examine the gene expression profile with respect to LVI.


RESULTS
In a multivariate analysis, nodal status (N), metastasis (M), and LVI were independent predictors of survival. LVI was associated with a 5-year survival of 13.9% versus 55.9% in patients in whom it was absent. LVI correlated with advancing T status (P = 0.001) and N status (P < 0.001). IHC staining of cyclooxygenase-2 (COX-2) correlated with T status, tumor grade, lymph node positivity, and IHC staining of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Microarray analyses suggested differential expression of oligophrenin-1 (OPHN1) and ribophorin-II (RPNII) with respect to LVI.


CONCLUSIONS
LVI was an independent predictor of survival in gastric cancer. Expression of COX-2 may facilitate tumor invasion through MMP-2 and MMP-9 activation. OPHN1 and RPN II appeared to be differentially expressed in gastric cancers exhibiting LVI. The reported function of OPHN1 and RPN II makes these gene products promising candidates for future studies involving LVI in gastric cancer.
Dicken
Bryan J
BJ
Department of Surgery, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
Graham
Kathryn
K
Hamilton
Stewart M
SM
Andrews
Sam
S
Lai
Raymond
R
Listgarten
Jennifer
J
Jhangri
Gian S
GS
Saunders
L Duncan
LD
Damaraju
Sambasivarao
S
Cass
Carol
C
D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D016019:Survival Analysis
D011451:Prostaglandin-Endoperoxide Synthases; D020782:Matrix Metalloproteinases