Expression of vascular endothelial growth factor and receptor flk-1 in colon cancer liver metastases.
OBJECTIVE
This study investigated vascular endothelial growth factor (VEGF) and flk-1 expression in hepatic metastases from colon carcinoma, and their associations with tumor angiogenesis, proliferation, and apoptosis.


METHODS
Immunohistochemical studies were performed for VEGF/flk-1, Ki-67, p53, and bcl-2 expression, and microvessel density (MVD) in surgical specimens from 35 patients who underwent hepatectomy for colon cancer liver metastases between 1986 and 2001.


RESULTS
VEGF and flk-1 were expressed mainly in the cytoplasm of tumor cells. High VEGF expression was associated with high flk-1 expression (P = 0.043). MVDs of less than 15 and 15 or more were found in 5 (14.3%) and 30 (85.7%) of 35 hepatic metastases, respectively. A Ki-67 index (KI) of 50% or more was detected in 33/35 (94.3%) of tumors, and 23 of these (65.7%) showed a KI of 85% or more. A KI of less than 50% was present in 2/35 (5.7%) of tumors. The expression of VEGF/flk-1 was related to elevated MVD (P < or = 0.026). VEGF was also associated with an increased KI (P = 0.025). Mutant p53 and bcl-2 expressions were detected in 26/35 (74.3%) and 17/35 (48.6%) of liver metastases, respectively. Mutant p53 was not related to VEGF/flk-1 expression, but bcl-2 was highly associated with flk-1 (P = 0.007). The incidences of high flk-1 expression and a KI of 85% or more were significantly higher in tumors which were both p53- and bcl-2-positive (93.3% and 73.3%) than in tumors which were negative for both (42.9% and 14.3%; P < or = 0.021).


CONCLUSIONS
The VEGF-flk-1 system takes part in tumor angiogenesis, proliferation, and apoptosis in colon liver metastases. The bcl-2 pathway may upregulate VEGF activity via the flk-1 receptor. These findings are preliminary, requiring a larger sampling in order to elucidate the role of VEGF/flk-1 in metastatic colon cancer.
Cheng
Jun
J
General Surgery, TC-2926D, University of Michigan Health System, 1500 E. Medical Center Dr., 48109, Ann Arbor, MI, USA.
Slavin
Richard E
RE
Gallagher
Jennifer A
JA
Zhu
Guojing
G
Biehl
Thomas R
TR
Swanstrom
Lee L
LL
Hansen
Paul D
PD
D000328:Adult; D000368:Aged; D003110:Colonic Neoplasms / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D019254:Genes, bcl-2 / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2