Clinical significance of angiopoietin-2 expression at the deepest invasive tumor site of advanced colorectal carcinoma.
Angiopoietin (Ang)-2 and vascular endothelial growth factor (VEGF) are thought to be critical regulators in tumor angiogenesis. We investigated the clinical significance of Ang-2 expression at the deepest invasive tumor site under the influence of VEGF expression in relation to angiogenesis, invasive/metastatic potential, and prognosis of advanced colorectal carcinoma (CRC). One hundred and fifty-two patients who underwent surgical resection for advanced CRC were enrolled in this study. Ang-2 and VEGF expression were examined immunohistochemically. Tumor microvessel density (MVD) was examined by immunohistochemical staining against CD34. Ang-2 and VEGF were expressed at the deepest invasive tumor site in 90 (59.2%) and 64 (42.1%) of 152 lesions, respectively. Patients with Ang-2 expression at the deepest invasive tumor site showed significantly (p<0.01) more frequent poorly histologic grade (71.9%), lymphatic involvement (65.9%), venous involvement (69.1%), lymph node metastasis (75.0%), liver metastasis (80.0%) and advanced disease (Dukes' stage C, 70.2%; stage D, 80.0%) than patients without Ang-2 expression. MVD was not significantly up-regulated by Ang-2 expression alone at the deepest invasive tumor site but was significantly up-regulated by VEGF expression at the deepest invasive tumor site under the positive-Ang-2 condition. In patients treated by curative surgery, patients with tumors showing both positive-Ang-2 and positive-VEGF condition at the deepest invasive tumor site had significantly poorer prognoses than patients with tumors under other conditions. Multivariate analysis with logistic regression for 5-year survival in cases of curative surgery showed that lymph node metastasis, VEGF expression and Ang-2 expression were significant factors to predict poor prognosis. Our results suggest that Ang-2 expression in collaboration with VEGF expression at the deepest invasive tumor site may result in tumor angiogenesis and that these angiogenic factors at the deepest invasive tumor site may be correlated with invasive/malignant potential and prognosis of advanced CRC.
Ochiumi
Takehiko
T
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biochemical Research, Graduated School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Tanaka
Shinji
S
Oka
Shiro
S
Hiyama
Toru
T
Ito
Masanori
M
Kitadai
Yasuhiko
Y
Haruma
Ken
K
Chayama
Kazuaki
K
D000230:Adenocarcinoma / Q000378:metabolism; D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000096:biosynthesis*; D018952:Antigens, CD34 / Q000096:biosynthesis; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D011379:Prognosis; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism
D042702:Angiopoietin-2; D018952:Antigens, CD34; D042461:Vascular Endothelial Growth Factor A