Endothelial VEGFR-3 expression in colorectal carcinomas is associated with hematogenous metastasis.
Vascular endothelial growth factor receptor 3 (VEGFR-3) is a major inducer of lymphangiogenic signalling and seems to be involved also in angiogenesis. Since both processes are closely linked with tumor metastasis this study investigated the expression of VEGFR-3 in tumor-associated vessels in colorectal carcinomas and evaluated its relevance for lymphogenous and hematogenous metastasis. In a comparative study between microvascular endothelial cells isolated from the tumor (HCTEC) and the corresponding non-neoplastic tissue (HCMEC) from five patients with colorectal cancer VEGFR-3 expression was measured using a specific ELISA. The expression pattern was individually different, with cases showing reduced, elevated and unchanged protein levels. Under hypoxic culture conditions (3% O2 for 24 h), which are more realistic for the tumor situation, the levels remained unchanged. In contrast, hypoxia exposure of macrovascular human umbilical vein endothelial cells (HUVEC) led to a consistent downregulation of VEGFR-3 protein. These data indicate a 'hypoxia-resistant' behaviour of VEGFR-3 in colonic microvasculature. Using immunohistochemistry the endothelial expression pattern of VEGFR-3 in 74 non-metastatic, lymphogenously-metastatic and hematogenously-metastatic colorectal carcinoma specimens was assessed. Positive VEGFR-3 expression was highly significantly associated with those cases showing distant metastasis (p=0.0003). In contrast, significant differences in the expression of VEGFR-3 between non-metastatic tumors and carcinomas with lymph node metastasis were not found. The majority of the detectable intratumoral VEGFR-3-positive vessels were of blood vascular origin (CD31 positive, D2-40 negative). Whereas intratumoral lymphatic vessels were collapsed, VEGFR-3 positive peritumoral lymphatic vessels had mostly open lumina. These morphological observations provide evidence for a predominant significance of VEGFR-3-positive, possibly angiogenesis-mediated, tumor-associated blood vessels in hematogenous metastasis of colorectal cancer. In addition, due to their patency VEGFR-3-positive peritumoral, but not intratumoral lymphatics could be the vascular substrate functionally mediating lymphogenous metastasis.
Institute of Pathology, Johannes Gutenberg University, 55101 Mainz, Germany. c.jayasinghe@gmx.de
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Jayasinghe
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Simiantonaki
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Michel-Schmidt
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Kirkpatrick
D015687:Cell Hypoxia; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000473:pathology; D004729:Endothelium, Lymphatic / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011379:Prognosis; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
D040321:Vascular Endothelial Growth Factor Receptor-3