The Angiogenic and Lymphangiogenic Factor Vascular Endothelial Growth Factor-D Exhibits a Paracrine Mode of Action in Cancer

Abstract

Vascular endothelial growth factor-D (VEGF-D) promotes angiogenesis, lymphangiogenesis and metastatic spread via the lymphatics, however, the mode of VEGF-D action (e.g. paracrine vs. autocrine) was unknown. We analyzed VEGF-D action in human tumors and a mouse model of metastasis. VEGF-D was localized in tumor cells and endothelium in human non-small cell lung carcinoma and breast ductal carcinoma in situ. Tumor vessels positive for VEGF-D were also positive for its receptors, VEGF receptor-2 (VEGFR-2) and/or VEGFR-3 but negative for VEGF-D mRNA, indicating that VEGF-D is secreted by tumor cells and subsequently associates with endothelium via receptor-mediated uptake. The mature form of VEGF-D was detected in tumors demonstrating that VEGF-D is proteolytically processed and bioactive. In a mouse model of metastasis, VEGF-D synthesized in tumor cells became localized on the endothelium and thereby promoted metastatic spread. These data indicate that VEGF-D promotes tumor angiogenesis, lymphangiogenesis and metastatic spread by a paracrine mechanism.

Vascular endothelial growth factor and its receptors in multiple myeloma

“…23 VEGF-C and VEGF-D are both angiogenic via VEGFR-2 and VEGFR-3 and lymphangiogenic (primarily VEGF-D) via VEGFR-3. 24,25 VEGFR have seven immunoglobulin-like loops in their extracellular domain and display tyrosine kinase activity in their intracellular domains. 26 VEGFR-1 and VEGFR-2 are expressed on the surface of endothelial cells as well as trophoblast and placenta cells, 27 monocytes, 28,29 mesangial cells 30 (VEGFR-1), hematopoietic stem cells 31,32 and retinal progenitor cells 33 (VEGFR-2), while VEGFR-3 is expressed on the surface of lymphatic endothelial cells.…”

Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway

“…Other members of the VEGF family include VEGF-B, VEGF-C, VEGF-D, VEGF-E (orf virus VEGF) and placental growth factor (P1GF) (Chilov et al, 1997;Enholm et al, 1997;Achen et al, 1998Achen et al, , 2002Olofsson et al, 1999;Dvorak, 2000;Carmeliet et al, 2001). All of these ligands mainly bind to and activate three receptor tyrosine kinases (TRK) to initiate their downstream signaling.…”

Elucidation of the Molecular Mechanisms Underlying Lymph Node Metastasis in Prostate Cancer

“…Other members of the VEGF family include VEGF-B, VEGF-C, VEGF-D, VEGF-E (orf virus VEGF) and placental growth factor (P1GF) (Chilov et al, 1997;Enholm et al, 1997;Achen et al, 1998Achen et al, , 2002Olofsson et al, 1999;Dvorak, 2000;Carmeliet et al, 2001). All of these ligands mainly bind to and activate three receptor tyrosine kinases (TRK) to initiate their downstream signaling.…”