Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression

Franco, Marcela; Roswall, Pernilla; Cortez, Eliane; Hanahan, Douglas; Pietras, Kristian

doi:10.1182/blood-2011-01-331694

Cited by 264 publications

(203 citation statements)

References 45 publications

(61 reference statements)

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“…As previously reported for PDGF-BB (33,34), the other known ligand for PDGFRβ, ECs in tumors from RIP1-TAg2 mice appear to be the major source for PDGF-DD. The effect of EC-secreted factors on the regulation of tissue and tumor growth has recently been highlighted (35)(36)(37), emphasizing the potential benefit of targeting the cross talk between ECs and tumor cells to supplement conventional antiangiogenic therapies.…”

Section: Discussionsupporting

confidence: 78%

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Cortez

Gladh

Braun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, plateletderived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development.However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.tumor heterogeneity | platelet-derived growth factor-DD | neuroendocrine tumor

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Section: Discussionsupporting

confidence: 78%

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Cortez

Gladh

Braun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Endothelial cell survival correlates with the extent of pericyte coverage in tumor vessels (30). As Olfml3 was coexpressed in tumor endothelial cells and pericytes (Fig.…”

Section: Impaired Pericyte Coverage Of Tumor Vessels After Anti-olfmlmentioning

confidence: 91%

Targeting Olfactomedin-like 3 Inhibits Tumor Growth by Impairing Angiogenesis and Pericyte Coverage

Miljkovic‐Licina

Hammel

Garrido‐Urbani

et al. 2012

Molecular Cancer Therapeutics

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Antiangiogenic drugs have been used as anticancer agents to target tumor endothelial cells or pericytes. Because of limited efficacy of the current monotherapies, there is a strong demand for the dual targeting of endothelial cells and pericytes. Here, we identify Olfactomedin-like 3 (Olfml3) as a novel proangiogenic cue within the tumor microenvironment. Tumor-derived Olfml3 is produced by both tumor endothelial cells and accompanying pericytes and deposited in the perivascular compartment. Blockade of Olfml3 by anti-Olfml3 antibodies is highly effective in reducing tumor vascularization, pericyte coverage, and tumor growth. In vitro, Olfml3 targeting is sufficient to inhibit endothelioma cell migration and sprouting. Olfml3 alone or through binding to BMP4 enhances the canonical SMAD1/5/8 signaling pathway required for BMP4-induced angiogenesis. Therefore, Olfml3 blockade provides a novel strategy to control tumor growth by targeting two distinct cell types within the tumor microenvironment using a single molecule.

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“…Moreover, recent research efforts revealed that pericytes, in addition to producing VEGF-A that acts in a paracrine fashion (Figure 3), can stimulate the autocrine expression of VEGF-A by tumor ECs, both of which could lead to a general suppression of EC apoptosis [49]. Interestingly, HemSCs and Hem-pericytes also secrete high levels of the angiogenic VEGF-A [21,42].…”

Section: Upregulated Autocrine Vegf-a/vegfr-2 Loop In Hemecmentioning

confidence: 99%

Wnt3a Expression is Associated with MMP-9 Expression in Primary Tumor and Metastatic Site in Recurrent or Stage IV Colorectal Cancer

2014

Cancer Cell Signaling

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Infantile hemangioma (IH), which is the most common tumor in infants, is a benign vascular neoplasm resulting from the abnormal proliferation of endothelial cells and pericytes. For nearly a century, researchers have noted that IH exhibits diverse and often dramatic clinical behaviors. On the one hand, most lesions pose no threat or potential for complication and resolve spontaneously without concern in most children with IH. On the other hand, approximately 10% of IHs are destructive, disfiguring and even vision-or life-threatening. Recent studies have provided some insight into the pathogenesis of these vascular tumors, leading to a better understanding of the biological features of IH and, in particular, indicating that during hemangioma neovascularization, two main pathogenic mechanisms prevail, angiogenesis and vasculogenesis. Both mechanisms have been linked to alterations in several important cellular signaling pathways. These pathways are of interest from a therapeutic perspective because targeting them may help to reverse, delay or prevent hemangioma neovascularization. In this review, we explore some of the major pathways implicated in IH, including the VEGF/VEGFR, Notch, β-adrenergic, Tie2/angiopoietins, PI3K/AKT/mTOR, HIF-α-mediated and PDGF/PDGF-R-β pathways. We focus on the role of these pathways in the pathogenesis of IH, how they are altered and the consequences of these abnormalities. In addition, we review the latest preclinical and clinical data on the rationally designed targeted agents that are now being directed against some of these pathways.

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Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression

Cited by 264 publications

References 45 publications

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Targeting Olfactomedin-like 3 Inhibits Tumor Growth by Impairing Angiogenesis and Pericyte Coverage

Wnt3a Expression is Associated with MMP-9 Expression in Primary Tumor and Metastatic Site in Recurrent or Stage IV Colorectal Cancer

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