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Blocking SDF-1?/CXCR4 downregulates PDGF-B and inhibits bone marrow-derived pericyte differentiation and tumor vascular expansion in Ewing tumors.

ABSTRACT: Bone marrow cells (BMC) are critical to the expansion of the tumor vessel network that supports Ewing sarcoma growth. BMCs migrate to the tumor and differentiate into endothelial cells and pericytes. We recently demonstrated that stromal-derived growth factor 1? (SDF-1?) regulates platelet-derived growth factor B (PDGF-B) and that this pathway plays a critical role in bone marrow-derived pericyte differentiation in vitro. We investigated the role of SDF-1?/PDGF-B in the tumor microenvironment in vivo in promoting bone marrow-derived pericyte differentiation in Ewing tumors. The CXCR4 antagonist AMD 3100 was used to disrupt the SDF-1?/CXCR4 axis in vivo in two xenograft Ewing tumor models. BMCs from GFP(+) transgenic mice were transplanted into lethally irradiated nude mice to track BMC migration to the tumor site. Following BMC engraftment, tumor-bearing mice received daily subcutaneous injections of either PBS or AMD 3100 for 3 weeks. Tumors were resected and tumor sections were analyzed by immunohistochemistry. AMD 3100 inhibited BMC differentiation into desmin(+) and NG2(+) pericytes, affected the morphology of the tumor vasculature, decreased perfusion, and increased tumor cell apoptosis. We observed smaller vessels with tiny lumens and a decrease in the microvessel density. AMD 3100 also inhibited PDGF-B protein expression in vitro and in vivo. SDF-1? in the tumor microenvironment plays a critical role in promoting pericyte formation and Ewing sarcoma tumor neovascularization by regulating PDGF-B expression. Interfering with this pathway affects tumor vascular morphology and expansion.

SUBMITTER: Hamdan R

PROVIDER: S-EPMC3926209 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Blocking SDF-1α/CXCR4 downregulates PDGF-B and inhibits bone marrow-derived pericyte differentiation and tumor vascular expansion in Ewing tumors.

Hamdan Randala R Zhou Zhichao Z Kleinerman Eugenie S ES

Molecular cancer therapeutics 20131126 2

Bone marrow cells (BMC) are critical to the expansion of the tumor vessel network that supports Ewing sarcoma growth. BMCs migrate to the tumor and differentiate into endothelial cells and pericytes. We recently demonstrated that stromal-derived growth factor 1α (SDF-1α) regulates platelet-derived growth factor B (PDGF-B) and that this pathway plays a critical role in bone marrow-derived pericyte differentiation in vitro. We investigated the role of SDF-1α/PDGF-B in the tumor microenvironment in ...[more]

PMID: 24282276

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Project description:BackgroundFibrotic scar formation and inflammation are characteristic pathologies of spinal cord injury (SCI) in the injured core, which has been widely regarded as the main barrier to axonal regeneration resulting in permanent functional recovery failure. Pericytes were shown to be the main source of fibroblasts that form fibrotic scar. However, the mechanism of pericyte-fibroblast transition after SCI remains elusive.MethodsFibrotic scarring and microvessels were assessed using immunofluorescence staining after establishing a crush SCI model. To study the process of pericyte-fibroblast transition, we analyzed pericyte marker and fibroblast marker expression using immunofluorescence. The distribution and cellular origin of platelet-derived growth factor (PDGF)-BB were examined with immunofluorescence. Pericyte-fibroblast transition was detected with immunohistochemistry and Western blot assays after PDGF-BB knockdown and blocking PDGF-BB/PDGFRβ signaling in vitro. Intrathecal injection of imatinib was used to selectively inhibit PDGF-BB/PDGFRβ signaling. The Basso mouse scale score and footprint analysis were performed to assess functional recovery. Subsequently, axonal regeneration, fibrotic scarring, fibroblast population, proliferation and apoptosis of PDGFRβ+ cells, microvessel leakage, and the inflammatory response were assessed with immunofluorescence.ResultsPDGFRβ+ pericytes detached from the blood vessel wall and transitioned into fibroblasts to form fibrotic scar after SCI. PDGF-BB was mainly distributed in the periphery of the injured core, and microvascular endothelial cells were one of the sources of PDGF-BB in the acute phase. Microvascular endothelial cells induced pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway in vitro. Pharmacologically blocking the PDGF-BB/PDGFRβ pathway promoted motor function recovery and axonal regeneration and inhibited fibrotic scar formation. After fibrotic scar formation, blocking the PDGFRβ receptor inhibited proliferation and promoted apoptosis of PDGFRβ+ cells. Imatinib did not alter pericyte coverage on microvessels, while microvessel leakage and inflammation were significantly decreased after imatinib treatment.ConclusionsWe reveal that the crosstalk between microvascular endothelial cells and pericytes promotes pericyte-fibroblast transition through the PDGF-BB/PDGFRβ signaling pathway. Our finding suggests that blocking the PDGF-BB/PDGFRβ signaling pathway with imatinib contributes to functional recovery, fibrotic scarring, and inflammatory attenuation after SCI and provides a potential target for the treatment of SCI.

Dataset Information

Blocking SDF-1?/CXCR4 downregulates PDGF-B and inhibits bone marrow-derived pericyte differentiation and tumor vascular expansion in Ewing tumors.

Publications

Blocking SDF-1α/CXCR4 downregulates PDGF-B and inhibits bone marrow-derived pericyte differentiation and tumor vascular expansion in Ewing tumors.

Similar Datasets

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