Overexpression of vascular endothelial growth factor C increases growth and alters the metastatic pattern of orthotopic PC-3 prostate tumors.

Abstract

BACKGROUND:

Prostate cancer metastasizes to regional lymph nodes and distant sites but the roles of lymphatic and hematogenous pathways in metastasis are not fully understood.

METHODS:

We studied the roles of VEGF-C and VEGFR3 in prostate cancer metastasis by blocking VEGFR3 using intravenous adenovirus-delivered VEGFR3-Ig fusion protein (VEGFR3-Ig) and by ectopic expression of VEGF-C in PC-3 prostate tumors in nude mice.

RESULTS:

VEGFR3-Ig decreased the density of lymphatic capillaries in orthotopic PC-3 tumors (p < 0.05) and inhibited metastasis to iliac and sacral lymph nodes. In addition, tumor volumes were smaller in the VEGFR3-Ig-treated group compared with the control group (p < 0.05). Transfection of PC-3 cells with the VEGF-C gene led to a high level of 29/31 kD VEGF-C expression in PC-3 cells. The size of orthotopic and subcutaneous PC-3/VEGF-C tumors was significantly greater than that of PC-3/mock tumors (both p < 0.001). Interestingly, while most orthotopic PC-3 and PC-3/mock tumors grown for 4 weeks metastasized to prostate-draining lymph nodes, orthotopic PC-3/VEGF-C tumors primarily metastasized to the lungs. PC-3/VEGF-C tumors showed highly angiogenic morphology with an increased density of blood capillaries compared with PC-3/mock tumors (p < 0.001).

CONCLUSION:

The data suggest that even though VEGF-C/VEGFR3 pathway is primarily required for lymphangiogenesis and lymphatic metastasis, an increased level of VEGF-C can also stimulate angiogenesis, which is associated with growth of orthotopic prostate tumors and a switch from a primary pattern of lymph node metastasis to an increased proportion of metastases at distant sites.

• Authors: Johanna Tuomela, Maija Valta, Jani Seppänen, Kati Tarkkonen, H Kalervo Väänänen, Pirkko Härkönen
• Journal: BMC cancer (BMC Cancer) Vol. 9 Pg. 362 (Oct 12 2009) ISSN: 1471-2407 [Electronic] England
• PMID: 19821979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Vascular Endothelial Growth Factor C

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Lymphangiogenesis
• Lymphatic Metastasis
• Male
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Prostatic Neoplasms (genetics, metabolism, pathology, physiopathology)
• Vascular Endothelial Growth Factor C (genetics, metabolism)