2. Academic Validation
  3. Autocrine BMP4 Signaling Enhances Tumor Aggressiveness via Promoting Wnt/β-Catenin Signaling in IDH1-mutant Gliomas

Autocrine BMP4 Signaling Enhances Tumor Aggressiveness via Promoting Wnt/β-Catenin Signaling in IDH1-mutant Gliomas

  • Transl Oncol. 2020 Feb;13(2):125-134. doi: 10.1016/j.tranon.2019.10.019.
Yiqiang Zhou 1,  Yang Liu 1,  Junwen Zhang 2,  Di Yu 1,  Aiguo Li 1,  Hua Song 1,  Wei Zhang 1,  Dionne Davis 1,  Mark R Gilbert 1,  Fusheng Liu 3,  Chunzhang Yang 4
Affiliations

Affiliations

  • 1 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 Brain Tumor Research Center, Beijing Neurosurgical Institute, Department of Neurosurgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing Laboratory of Biomedical Materials, Beijing 100050, China.
  • 3 Brain Tumor Research Center, Beijing Neurosurgical Institute, Department of Neurosurgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing Laboratory of Biomedical Materials, Beijing 100050, China. Electronic address: liufushengs@hotmail.com.
  • 4 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: yangc2@mail.nih.gov.
PMID: 31865175 DOI: 10.1016/j.tranon.2019.10.019
Abstract

The isocitrate dehydrogenase (IDH1/2) mutations are frequent genetic abnormalities in the majority of WHO grade II/III glioma and secondary GBM. IDH1-mutated (IDH1Mut) glioma exhibits distinctive patterns in Cancer biology and metabolism. In the present study, we showed that bone morphogenetic proteins (BMP4) are significantly upregulated in IDH1Mut glioma. Further, we demonstrated that cancer-associated BMP4 is secreted to tumor microenvironment, which enhances the tumor migration and invasion through an autocrine manner. Mechanistically, BMP4 activates its receptor and concomitant SMAD1/5/8 signaling, which potentiates Wnt/β-catenin signaling by enhancing Frizzled receptor expression. LDN-193189, a selective BMP Receptor inhibitor, prolonged the overall survival of mice bearing IDH1-mutated intracranial xenografts by limiting BMP/catenin signaling. These findings demonstrate the pivotal role of BMP4 on tumor aggressiveness in IDH1Mut gliomas, suggesting a possible therapeutic strategy for this type of malignancy.

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