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
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
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Research Article Angiogenesis Oncology

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.

Authors

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

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Figure 3

KO of KDR in BMDCs suppresses spontaneous malignant transformation of RCAS/TVA gliomas.

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KO of KDR in BMDCs suppresses spontaneous malignant transformation of RC...
(A) Schematic diagram of experimental design. PDGF and Cre genes were transduced to P0–P2 mouse pups on an Ink4a/Arf+/– Ptenfl/fl background. Mice received a lethal dose of irradiation and received bone marrow transplant (BMT) at week 2. Tamoxifen was applied to mice at approximately week 5 to induce the ablation of the KDR gene in BMDCs. Tumors were monitored by MRI and histological analyses over the process. (B) Kaplan-Meier symptom-free survival curve for RCAS/TVA mice transplanted with Rosa26-CreERT2Kdrfl/fl and Rosa26-CreERT2Kdrfl/+ BM cells (BM-KDR KO and BM-KDR CTL, respectively) and RCAS/TVA mice without irradiation/transplantation (without BMT). ****P < 0.0001, log-rank test. (C) At weeks 6, 9, and 12, tumors in each group of mice were assessed and graded based on MRI and further confirmation with histology. n = 19–26 for each group. (D) Representative T2-MRI images of intracranial tumors in RCAS/TVA mice transplanted with Rosa26-CreERT2Kdrfl/fl and Rosa26-CreERT2Kdrfl/+ BM cells at indicated time points. n = 12. (E) Representative images of H&E and IHC (CD11b, CD31) staining of tumor tissue sections from BM-KDR KO and BM-KDR control groups, respectively, at week 9. n = 10. Scale bar: 50 μm.