E2F1 promotes angiogenesis through the VEGF-C/VEGFR-3 axis in a feedback loop for cooperative induction of PDGF-B

Abstract

Angiogenesis is essential for primary tumor growth and metastatic dissemination. E2F1, frequently upregulated in advanced cancers, was recently shown to drive malignant progression. In an attempt to decipher the molecular events underlying this behavior, we demonstrate that the tumor cell-associated vascular endothelial growth factor-C/receptor-3 (VEGF-C/VEGFR-3) axis is controlled by E2F1. Activation or forced expression of E2F1 in cancer cells leads to the upregulation of VEGFR-3 and its ligand VEGF-C, whereas E2F1 depletion prevents their expression. E2F1-dependent receptor induction is crucial for tumor cells to enhance formation of capillary tubes and neovascularization in mice. We further provide evidence for a positive feedback loop between E2F1 and VEGFR-3 signaling to stimulate pro-angiogenic platelet-derived growth factor B (PDGF-B). E2F1 or VEGFR-3 knockdown results in reduced PDGF-B levels, while the coexpression synergistically upregulates promoter activity and endogenous protein expression of PDGF-B. Our findings delineate an as yet unrecognized function of E2F1 as enhancer of angiogenesis via regulation of VEGF-C/VEGFR-3 signaling in tumors to cooperatively activate PDGF-B expression. Targeting this pathway might be reasonable to complement standard anti-angiogenic treatment of cancers with deregulated E2F1.

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

“…E2F1 upregulation in mammary cell lines causes carcinogenesis and aggressive distant metastasis in multiple cancers (34)(35)(36). E2F1 may enhance metastatic behavior in melanomas by directly binding with VEGFC and the corresponding receptor VEGFR-3 for transactivation (37). The oncogenic properties of E2F1 have been associated with high EMT transition (38).…”

E2F1 promotes tumor cell invasion and migration through regulating CD147 in prostate cancer

“…The transcription factor E2F1 expression has been detected in several human cancers, and oncogenic and tumor-suppressive roles have been proposed for E2F1 depending on the cancer type and, in some cases, the subtype. For example, Li et al (24) demonstrated the increased expression of E2F1 in small cell lung cancer (SCLC), and confirmed that E2F1 could directly enhance matrix metalloproteinase (MMP) transcription by binding to the E2F1 binding sequences in the promoter, or indirectly activate MMPs through enhanced Sp1 and NF-κB as a consequence of E2F1 activation in SCLC; Ma et al (25) indicated that the overexpression of E2F1 might promote tumor malignancy and correlates with TNM stages in clear cell renal cell carcinoma; Engelmann et al (26) also revealed that E2F1 might function as an enhancer of angiogenesis via regulation of VEGF-C/VEGFR-3 signaling in tumors to cooperatively activate PDGF-B expression, and targeting this pathway might be reasonable to complement standard anti-angiogenic treatment of cancers with deregulated E2F1; on the contrary, E2F1 has been revealed to be a mediator of apoptosis, and in clinical trials where its high expression leads to improved survival of patients with adjuvant chemoradiation therapy (27). These findings suggest that E2F1 exhibits dual properties, acting as a tumor suppressor and oncogene.…”

Realizing Cancer Precision Medicine by Integrating Systems Biology and Nanomaterial Engineering

“…Although the VEGFA/VEGFR2 pathway is important for angiogenesis, this process is regulated by multiple signaling pathways, all of which are complex and include various positive and negative feedbacks. [130][131][132] These complex circuits can generate complex network dynamics and drug resistance. In addition, crosstalks among the signaling pathways related to angiogenesis, such as pro-angiogenic signaling downstream of factors fibroblast growth factor 2 (FGF2) and phosphatidylinositol-glycan biosynthesis class F protein (PIGF), [133,134] can cause resistance to agents that stimulate vessel normalization.…”