A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma

Yujie Huang; Prajwal Rajappa; Wenhuo Hu; Caitlin Hoffman; Babacar Cisse; Joon Hyung Kim; Emilie Gorge; Rachel Yanowitch; William Cope; Emma Vartanian; Raymond Xu; Tuo Zhang; David Pisapia; Jenny Xiang; Jason Huse; Irina Matei; Hector Peinado; Jacqueline Bromberg; Eric Holland; Bi Sen Ding; Shahin Rafii; David Lyden; Jeffrey Greenfield

doi:10.1172/JCI86443

A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma

Yujie Huang, Prajwal Rajappa, Wenhuo Hu, Caitlin Hoffman, Babacar Cisse, Joon Hyung Kim, Emilie Gorge, Rachel Yanowitch, William Cope, Emma Vartanian, Raymond Xu, Tuo Zhang, David Pisapia, Jenny Xiang, Jason Huse, Irina Matei, Hector Peinado, Jacqueline Bromberg, Eric Holland, Bi Sen DingShahin Rafii, David Lyden, Jeffrey Greenfield

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.

Original language	English
Pages (from-to)	1826-1838
Number of pages	13
Journal	Journal of Clinical Investigation
Volume	127
Issue number	5
DOIs	https://doi.org/10.1172/JCI86443
State	Published - 1 May 2017
Externally published	Yes

Access to Document

10.1172/JCI86443

Cite this

Huang, Y., Rajappa, P., Hu, W., Hoffman, C., Cisse, B., Kim, J. H., Gorge, E., Yanowitch, R., Cope, W., Vartanian, E., Xu, R., Zhang, T., Pisapia, D., Xiang, J., Huse, J., Matei, I., Peinado, H., Bromberg, J., Holland, E., ... Greenfield, J. (2017). A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma. Journal of Clinical Investigation, 127(5), 1826-1838. https://doi.org/10.1172/JCI86443

@article{a362821dd142472ea50634969815c173,

title = "A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma",

abstract = "Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.",

author = "Yujie Huang and Prajwal Rajappa and Wenhuo Hu and Caitlin Hoffman and Babacar Cisse and Kim, {Joon Hyung} and Emilie Gorge and Rachel Yanowitch and William Cope and Emma Vartanian and Raymond Xu and Tuo Zhang and David Pisapia and Jenny Xiang and Jason Huse and Irina Matei and Hector Peinado and Jacqueline Bromberg and Eric Holland and Ding, {Bi Sen} and Shahin Rafii and David Lyden and Jeffrey Greenfield",

year = "2017",

month = may,

day = "1",

doi = "10.1172/JCI86443",

language = "English",

volume = "127",

pages = "1826--1838",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "5",

}

Huang, Y, Rajappa, P, Hu, W, Hoffman, C, Cisse, B, Kim, JH, Gorge, E, Yanowitch, R, Cope, W, Vartanian, E, Xu, R, Zhang, T, Pisapia, D, Xiang, J, Huse, J, Matei, I, Peinado, H, Bromberg, J, Holland, E, Ding, BS, Rafii, S, Lyden, D & Greenfield, J 2017, 'A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma', Journal of Clinical Investigation, vol. 127, no. 5, pp. 1826-1838. https://doi.org/10.1172/JCI86443

TY - JOUR

T1 - A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma

AU - Huang, Yujie

AU - Rajappa, Prajwal

AU - Hu, Wenhuo

AU - Hoffman, Caitlin

AU - Cisse, Babacar

AU - Kim, Joon Hyung

AU - Gorge, Emilie

AU - Yanowitch, Rachel

AU - Cope, William

AU - Vartanian, Emma

AU - Xu, Raymond

AU - Zhang, Tuo

AU - Pisapia, David

AU - Xiang, Jenny

AU - Huse, Jason

AU - Matei, Irina

AU - Peinado, Hector

AU - Bromberg, Jacqueline

AU - Holland, Eric

AU - Ding, Bi Sen

AU - Rafii, Shahin

AU - Lyden, David

AU - Greenfield, Jeffrey

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.

AB - Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.

UR - http://www.scopus.com/inward/record.url?scp=85018942941&partnerID=8YFLogxK

U2 - 10.1172/JCI86443

DO - 10.1172/JCI86443

M3 - Article

C2 - 28394259

AN - SCOPUS:85018942941

SN - 0021-9738

VL - 127

SP - 1826

EP - 1838

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 5

ER -

A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma

Abstract

Access to Document

Fingerprint

Cite this