VEGF exerts an angiogenesis-independent function in cancer cells to promote their malignant progression.
VEGF/vascular permeability factor (VEGF/VPF or VEGF-A) is a pivotal driver of cancer angiogenesis that is a central therapeutic target in the treatment of malignancy. However, little work has been devoted to investigating functions of VEGF that are independent of its proangiogenic activity. Here, we report that VEGF produced by tumor cells acts in an autocrine manner to promote cell growth through interaction with the VEGF receptor neuropilin-1 (NRP-1). Reducing VEGF expression by tumor cells induced a differentiated phenotype in vitro and inhibited tumor forming capacity in vivo, independent of effects on angiogenesis. Autocrine activation of tumor cell growth was dependent on signaling through NRP-1, and Ras was determined to be a critical effector signaling molecule downstream of NRP-1. Our findings define a novel function for VEGF in dedifferentiation of tumor cells expanding its role in cancer beyond its known proangiogenic function.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Ying
Y
Cao
Guangqi
G
E
Enfeng
E
Wang
Krishnendu
K
Pal
Shamit K
SK
Dutta
Dafna
D
Bar-Sagi
Debabrata
D
Mukhopadhyay
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D054337:Cell Dedifferentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1