Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents

Stewart, Keri Schadler; Kleinerman, Eugenie S.

doi:10.1155/2011/165837

Cited by 23 publications

(19 citation statements)

References 37 publications

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“…The cure rates for Ewing’s sarcoma patients, especially those who present with metastasis, have remained unchanged for over 20 years, emphasizing the urgency for new therapies (30). We previously demonstrated that vasculogenesis is essential for the expansion of Ewing’s sarcoma tumor vasculature and that inhibiting this process, inhibits tumor growth (12, 13).…”

Section: Discussionmentioning

confidence: 99%

Blocking SDF-1α/CXCR4 Downregulates PDGF-B and Inhibits Bone Marrow–Derived Pericyte Differentiation and Tumor Vascular Expansion in Ewing Tumors

Hamdan

Zhou

Kleinerman

2014

Molecular Cancer Therapeutics

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Bone marrow cells (BMCs) are critical to the expansion of the tumor vessel network that supports Ewing’s 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 BM-derived pericyte differentiation in vitro. We investigated the role of SDF-1α/PDGF-B in the tumor microenvironment in vivo in promoting BM-derived pericyte differentiation in Ewing’s tumors. The CXCR4 antagonist, AMD 3100, was used to disrupt the SDF-1α/CXCR4 axis in vivo in two xenograft Ewing’s tumor models. BMCs from green fluorescent protein (GFP+) transgenic mice were transplanted into lethally irradiated nude mice in order 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-1α in the tumor microenvironment plays a critical role in promoting pericyte formation and Ewing’s sarcoma tumor neovascularization by regulating PDGF-B expression. Interfering with this pathway affects tumor vascular morphology and expansion.

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Section: Discussionmentioning

confidence: 99%

Blocking SDF-1α/CXCR4 Downregulates PDGF-B and Inhibits Bone Marrow–Derived Pericyte Differentiation and Tumor Vascular Expansion in Ewing Tumors

Hamdan

Zhou

Kleinerman

2014

Molecular Cancer Therapeutics

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“…EWS basically rely on a combination of angiogenesis and vasculogenesis [20]. Apart from what is known about the role of vasculogenesis in EWS vascular tumor blood supply [20], little is known about the regulation of angiogenesis sprouting. As shown previously, CAV1 silencing in EWS cells impairs tumor growth in nude mice [2].…”

Section: Discussionmentioning

confidence: 99%

“…EWS cells express a variety of pro-angiogenic factors [14], [20], [26]. Analysis of the levels of a group of pro-angiogenic factors released by tumor cells showed that only the expression of the bFGF gene was reduced by CAV1 silencing.…”

Section: Discussionmentioning

confidence: 99%

EphA2-Induced Angiogenesis in Ewing Sarcoma Cells Works through bFGF Production and Is Dependent on Caveolin-1

et al. 2013

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Angiogenesis is the result of the combined activity of the tumor microenvironment and signaling molecules. The angiogenic switch is represented as an imbalance between pro- and anti-angiogenic factors and is a rate-limiting step in the development of tumors. Eph receptor tyrosine kinases and their membrane-anchored ligands, known as ephrins, constitute the largest receptor tyrosine kinase (RTK) subfamily and are considered a major family of pro-angiogenic RTKs. Ewing sarcoma (EWS) is a highly aggressive bone and soft tissue tumor affecting children and young adults. As other solid tumors, EWS are reliant on a functional vascular network for the delivery of nutrients and oxygen and for the removal of waste. Based on the biological roles of EphA2 in promoting angiogenesis, we explored the functional role of this receptor and its relationship with caveolin-1 (CAV1) in EWS angiogenesis. We demonstrated that lack of CAV1 results in a significant reduction in micro vascular density (MVD) on 3 different in vivo models. In vitro, this phenomenon correlated with inactivation of EphA2 receptor, lack of AKT response and downregulation of bFGF. We also demonstrated that secreted bFGF from EWS cells acted as chemoattractant for endothelial cells. Furthermore, interaction between EphA2 and CAV1 was necessary for the right localization and signaling of the receptor to produce bFGF through AKT and promote migration of endothelial cells. Finally, introduction of a dominant-negative form of EphA2 into EWS cells mostly reproduced the effects occurred by CAV1 silencing, strongly suggesting that the axis EphA2-CAV1 participates in the promotion of endothelial cell migration toward the tumors favoring EWS angiogenesis.

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“…One new treatment option focuses on anti-angiogenic therapy, based on the observation that EWS-ETS fusion proteins upregulate the transcription of vascular endothelial growth factor (VEGF), which is overexpressed in Ewing tumors and whose inhibition can suppress growth of Ewing tumor cells in vitro [86–88]. Respective clinical trials are still ongoing and their outcomes are eagerly awaited [89]. …”

Section: Chromosomal Translocations In Ewing Tumorsmentioning

confidence: 99%

ETV1, 4 and 5: An oncogenic subfamily of ETS transcription factors

Shin

Janknecht

2012

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

190

242

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The homologous ETV1, ETV4 and ETV5 proteins form the PEA3 subfamily of ETS transcription factors. In Ewing tumors, chromosomal translocations affecting ETV1 or ETV4 are an underlying cause of carcinogenesis. Likewise, chromosomal rearrangements of the ETV1, ETV4 or ETV5 gene occur in prostate tumors and are thought to be one of the major driving forces in the genesis of prostate cancer. In addition, these three ETS proteins are implicated in melanomas, breast and other types of cancer. Complex posttranslational modifications govern the activity of PEA3 factors, which can promote cell proliferation, motility and invasion. Here, we review evidence for a role of ETV1, 4 and 5 as oncoproteins and describe modes of their action. Modulation of their activation or interaction with cofactors as well as inhibiting crucial target gene products may ultimately be exploited to treat various cancers that are dependent on the PEA3 group of ETS transcription factors.

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Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents

Cited by 23 publications

References 37 publications

Blocking SDF-1α/CXCR4 Downregulates PDGF-B and Inhibits Bone Marrow–Derived Pericyte Differentiation and Tumor Vascular Expansion in Ewing Tumors

Blocking SDF-1α/CXCR4 Downregulates PDGF-B and Inhibits Bone Marrow–Derived Pericyte Differentiation and Tumor Vascular Expansion in Ewing Tumors

EphA2-Induced Angiogenesis in Ewing Sarcoma Cells Works through bFGF Production and Is Dependent on Caveolin-1

ETV1, 4 and 5: An oncogenic subfamily of ETS transcription factors

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