Significance of lymphatic invasion and cancer invasion-related proteins on lymph node metastasis in gastric cancer.
OBJECTIVE
Cancer invasion and metastasis are critical events for patient prognosis; however, the most important step in the whole process of lymph node (LN) metastasis in gastric cancer remains obscure. In this study, the significance of cancer cell behaviors, such as cell detachment, stromal invasion and lymphatic invasion on regional LN metastasis in gastric cancer was investigated by comprehensive immunohistochemistry.


METHODS
A total of 210 cases with gastric cancer were selected. These consisted of 105 cases with regional LN metastasis (LN[+] group) and 105 cases without LN metastasis (LN[-] group). Both groups exhibited the same depth of invasion. Cancer tissues were subjected to immunohistochemistry with antibodies against claudin-3, claudin-4, beta-catenin, matrix metalloproteinase (MMP)-1, and MMP-2, as well as endothelial markers of lymphatic vessel endothelial hyaluronan receptor-1 and von Willebrand factor for the objective discrimination between lymphatics and blood vessels. The expression of each protein as well as the histopathological parameters were compared between LN(+) and LN(-) groups.


RESULTS
Along with lymphatic invasion by cancer cells and gross tumor size, MMP-1 expression in cancer cells at the invasive front of the primary tumor was a significant, independent predictor of LN metastasis. The expression of claudins and beta-catenin was associated with the histopathological type of cancer, but not with LN status.


CONCLUSIONS
Among the cancer invasion-related proteins examined, MMP-1 plays a vital role in LN metastasis of gastric cancer. Tumor size, lymphatic invasion and MMP-1 expression level at the invasive front were the predictive factors of LN metastasis of gastric cancer.
Kamata
Itaru
I
Department of Pathology, Toho University School of Medicine, Tokyo, Japan.
Ishikawa
Yukio
Y
Akishima-Fukasawa
Yuri
Y
Ito
Kinji
K
Akasaka
Yoshikiyo
Y
Uzuki
Miwa
M
Fujimoto
Ai
A
Morita
Hiroshi
H
Tamai
Seiichi
S
Maehara
Tadaaki
T
Ogata
Kentaro
K
Shimokawa
Reiko
R
Igarashi
Yoshinori
Y
Miki
Kazumasa
K
Ishii
Toshiharu
T
D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D016022:Case-Control Studies; D062465:Claudin-3; D062506:Claudin-4; D005260:Female; D005743:Gastrectomy; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000737:chemistry / Q000473:pathology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000032:analysis*; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D013274:Stomach Neoplasms / Q000737:chemistry / Q000556:secondary* / Q000601:surgery*; D016896:Treatment Outcome; D033921:Vesicular Transport Proteins / Q000032:analysis; D051176:beta Catenin / Q000032:analysis; D014841:von Willebrand Factor / Q000032:analysis
D014408:Biomarkers, Tumor; C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; C495270:CTNNB1 protein, human; D062465:Claudin-3; D062506:Claudin-4; C119248:LYVE1 protein, human; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; D051176:beta Catenin; D014841:von Willebrand Factor; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1