title: Expression of VEGF-C and VEGF-D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma.
abstract: Vascular endothelial growth factor (VEGF)-C and VEGF-D are potent lymphangiogenic factors produced by tumor and stromal cells. The purpose of this study was to determine whether expression of VEGF-C and/or VEGF-D correlates with clinicopathological features of human colorectal carcinoma. Expression of mRNAs for VEGF-C, VEGF-D, and their receptor VEGFR-3 was examined by reverse transcription-polymerase chain reaction (RT-PCR) in six colon carcinoma cell lines and in fresh endoscopic biopsy specimens from 20 patients with colorectal carcinoma. Expression of VEGF-C and VEGF-D protein was also examined immunohistochemically in 139 archival surgical specimens of human colorectal carcinoma. Of the six cell lines, one (Colo320D) constitutively expressed VEGF-C and four (Colo320D, DLD-1, km12sm, km12c) constitutively expressed VEGF-D mRNA. Expression of VEGF-D mRNA was increased under low oxygen conditions, and all six cell lines constitutively expressed VEGF-D mRNA under hypoxic conditions. Of the 139 specimens of human colorectal carcinoma, 65 (46.8%) showed intense VEGF-C immunoreactivity and 41 (29.5%) showed intense VEGF-D immunoreactivity. In 49 (75.3%) of the 65 and 20 (48.8%) of the 41 cases, heterogeneous intratumoral staining was observed for VEGF-C and VEGF-D, respectively, with the highest levels of expression at the invasive edges. VEGF-C expression correlated with the depth of tumor invasion, lymphatic involvement, venous involvement, lymph node metastasis, and liver metastasis, and VEGF-D expression correlated with the depth of tumor invasion, lymph node metastasis, and liver metastasis. No correlation was observed between VEGF-C and VEGF-D expression in tumors. The survival time of patients with VEGF-C-positive tumors was significantly shorter than that of patients with VEGF-C-negative tumors, and the survival time of patients with VEGF-D-positive tumors was significantly shorter than that of patients with VEGF-D-negative tumors. The survival time of patients with both VEGF-C- and VEGF-D-positive tumors was significantly shorter than that of patients with both VEGF-C- and VEGF-D-negative tumors. These results suggest that VEGF-C and VEGF-D may be independent and important prognostic factors in patients with human colorectal carcinoma.
authors.affiliation: Department of Medicine, Hiroshima University Graduate School of Biomedical Science, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Onogawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kitadai
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Toshio
authors.initials: T
authors.lastname: Kuwai
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kimura
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000230:Adenocarcinoma / Q000556:secondary*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis / Q000473:pathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis
chemical_list: D012333:RNA, Messenger; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3