Abstract
Members of the vascular endothelial growth factor (VEGF) family are critical players in angiogenesis and lymphangiogenesis. Although VEGF-A has been shown to exert fundamental functions in physiologic and pathologic angiogenesis, the exact role of the VEGF family member placental growth factor (PlGF) in tumor angiogenesis has remained controversial. To gain insight into PlGF function during tumor angiogenesis, we have generated transgenic mouse lines expressing human PlGF-1 in the beta cells of the pancreatic islets of Langerhans (Rip1PlGF-1). In single-transgenic Rip1PlGF-1 mice, intra-insular blood vessels are found highly dilated, whereas islet physiology is unaffected. Upon crossing of these mice with the Rip1Tag2 transgenic mouse model of pancreatic beta cell carcinogenesis, tumors of double-transgenic Rip1Tag2;Rip1PlGF-1 mice display reduced growth due to attenuated tumor angiogenesis. The coexpression of transgenic PlGF-1 and endogenous VEGF-A in the beta tumor cells of double-transgenic animals causes the formation of low-angiogenic hPlGF-1/mVEGF-A heterodimers at the expense of highly angiogenic mVEGF-A homodimers resulting in diminished tumor angiogenesis and reduced tumor infiltration by neutrophils, known to contribute to the angiogenic switch in Rip1Tag2 mice. The results indicate that the ratio between the expression levels of two members of the VEGF family of angiogenic factors, PlGF-1 and VEGF-A, determines the overall angiogenic activity and, thus, the extent of tumor angiogenesis and tumor growth.
Highlights
Tumor-induced neoangiogenesis is an essential step during tumor progression
In double-transgenic Rip1Tag2;Rip1PlGF-1 mice, tumor growth is attenuated due to a significant reduction in tumor angiogenesis caused by the formation of low-angiogenic hPlGF-1/mVEGF-A heterodimers
Expression analysis by reverse transcription-PCR (RT-PCR) and immunohistochemical analyses revealed that one founder line exhibited specific expression of hPlGF-1 in the islets of Langerhans at levels lower than the expression of hPlGF in human placenta (Fig. 1A; data not shown)
Summary
Tumor-induced neoangiogenesis is an essential step during tumor progression. Newly formed intratumoral vessels are required for the delivery of nutrients and for sufficient oxygenation of growing tumors. In double-transgenic Rip1Tag2;Rip1PlGF-1 mice, tumor growth is attenuated due to a significant reduction in tumor angiogenesis caused by the formation of low-angiogenic hPlGF-1/mVEGF-A heterodimers. To investigate the biological function of PlGF-1 during tumor progression, we crossed Rip1PlGF-1 mice with Rip1Tag2 transgenic mice and analyzed the effects of hPlGF-1 www.aacrjournals.org expression on h cell tumorigenesis in double-transgenic mice.
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