title: Clinical significance of thrombospondin-1 expression in relation to vascular endothelial growth factor and interleukin-10 expression at the deepest invasive tumor site of advanced colorectal carcinoma.
abstract: Various angiogenic and angiostatic factors regulate angiogenesis. Tumor angiogenesis is a complicated process for which the detailed mechanisms remain unclear. The aim of this study was to elucidate the clinical significance of TSP-1 expression in relation to expression of VEGF and IL-10 and angiogenesis at the deepest invasive tumor site as a predictor of invasive/metastatic potential and prognosis of advanced colorectal carcinoma (CRC). Patients (n=152) who had undergone surgical resection for advanced CRC were entered in this study. Expression of TSP-1, VEGF, and IL-10 was examined immunohistochemically with specific antibodies. Tumor microvessel density (MVD) was also determined immunohistochemically with anti-CD34 antibody (NU-4A1). Expression of TSP-1, VEGF, and IL-10 at the deepest invasive tumor site was detected in 46 (30.3%), 62 (40.8%), and 39 (25.7%) of 152 lesions, respectively. TSP-1, VEGF, and IL-10 expression at the superficial part was detected in 60 (39.5%), 35 (23.0%), and 46 (30.3%) of 152 lesions, respectively. Although there was no significant difference between the incidence of TSP-1 and IL-10 expression at the deepest invasive site or at the superficial part, there was a significant difference between the incidence of VEGF expression at the deepest invasive site and that at the superficial part. Expression of TSP-1 and IL-10 at the deepest invasive tumor site was inversely correlated with metastatic potential and prognosis in relation to MVD. Furthermore, lesions that were TSP-1-negative and VEGF-positive at the deepest invasive tumor site showed the strongest association with MVD. The 5-year survival rate for patients with TSP-1-negative or IL-10 negative lesions at the deepest invasive tumor site was significantly poorer than that for patients with TSP-1-positive or IL-10-positive lesions, respectively. The 5-year survival rate for patients with VEGF expression at the deepest invasive tumor site was significantly poorer than that for patients without VEGF expression. The 5-year survival rate for patients with TSP-1-negative, VEGF-positive lesions at the deepest invasive site were significantly poorer than that for patients with lesions without these characteristics. Multivariate analysis with logistic regression for 5-year survival in patients with curative surgery showed that lymph node metastasis and VEGF expression were significant prognostic factors. Although lack of TSP-1 or IL-10 expression was associated significantly with poorer prognosis, this may be less important in poorer prognosis than the presence of VEGF expression.
authors.affiliation: Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biochemical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Eijiro
authors.initials: E
authors.lastname: Kaio
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Shiro
authors.initials: S
authors.lastname: Oka
authors.forename: Toru
authors.initials: T
authors.lastname: Hiyama
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kitadai
authors.forename: Ken
authors.initials: K
authors.lastname: Haruma
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000368:Aged; D018952:Antigens, CD34 / Q000096:biosynthesis; D002277:Carcinoma / Q000175:diagnosis / Q000201:enzymology*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000201:enzymology*; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D011379:Prognosis; D019700:Thrombospondin 1 / Q000096:biosynthesis*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10