Gene Pair Acts in Tandem to Drive Aggressive Brain Cancer Growth

A pair of genes has been identified that work in tandem to drive the growth and development of the glioblastoma multiforme (GBM) type of aggressive brain tumor.

This form of brain cancer is the most common primary tumor of the central nervous system and is almost always fatal. The aggressive invasion of GBM cells into the surrounding normal brain makes complete surgical removal impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to eight months for patients with recurrent GBM.

Investigators at McGill University (Montreal, Canada), the Harvard University Medical School (Boston, MA, USA) and the Washington University School of Medicine (St. Louis, MO, USA) were searching for genes that would complement the activity of EGFR (epidermal growth factor receptor)vIII, which was known to produce an important tumor-forming protein in glioblastoma. However, disabling EGFRvIII had not been found to be effective in blocking growth of GBM.

The investigators reported in the April 25, 2016, online edition of the journal Nature Neuroscience that they had identified the cytokine receptor OSMR (oncostatin M receptor) as a direct target gene of the transcription factor STAT3 in mouse astrocytes and human brain tumor stem cells, and that OSMR functioned as an essential co-receptor for EGFRvIII.

The cellular transcription factor STAT3 (signal transducer and activator of transcription 3) is a member of the STAT protein family, which regulates many aspects of cell growth, survival, and differentiation. Malfunction of this signaling pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced tumor survival.

The investigators found that OSMR formed a physical complex with EGFRvIII and that depletion of OSMR impaired EGFRvIII-STAT3 signaling. Conversely, drugs that inhibited EGFRvIII phosphorylation also inhibited the EGFRvIII-OSMR interaction and activation of STAT3. EGFRvIII-OSMR signaling in tumors operated constitutively, whereas EGFR-OSMR signaling in normal cells was synergistically activated by the ligands EGF and OSM.

Genetic knockdown of OSMR strongly suppressed mouse glioblastoma cell proliferation and tumor growth as well as growth of human brain tumor stem cell xenografts in mice, and prolonged the lifespan of these animals.

“The discovery has important clinical implications,” said senior author Dr. Azad Bonni, professor of neurobiology at the Washington University School of Medicine. “It provides a new therapeutic avenue for treating this devastating disease, though developing any effective therapy targeting human patients could be years of work.”

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McGill University
Harvard University Medical School
Washington University School of Medicine