Targeting the Cytosolic Innate Immune Receptors RIG-I and MDA5 Effectively Counteracts Cancer Cell Heterogeneity in Glioblastoma§

Authors


  • Author contributions: M.G.: conception and design, financial support, provision of study material, collection/assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; C.C. and D.T.: conception and design, collection/assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; J.D.: conception and design, data analysis and interpretation, and final approval of manuscript; M.S. and H.N.: provision of study material, data analysis and interpretation, and final approval of manuscript; P.K., M.L., and A.P.: conception and design, provision of study material, data analysis and interpretation, and final approval of manuscript; J.M. and T.Q.: conception and design, provision of study material, data analysis and interpretation, manuscript writing, and final approval of manuscript; R.G. and A.W.: data analysis and interpretation and final approval of manuscript; R.R., R.F. and U.H.: data analysis and interpretation, manuscript writing, and final approval of manuscript; K.R.: provision of study material, data analysis and interpretation, manuscript writing, and final approval of manuscript; M.S. and R.B.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript; O.B.: administrative support, data analysis and interpretation, manuscript writing, and final approval of manuscript; G.H.: conception and design, financial support and final approval of manuscript; B.S.: conception and design, financial support, administrative support, provision of study material, collection/assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. M.G., C.C., and D.T. contributed equally to this article. J.D. and M.S. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    first published online in STEM CELLS EXPRESS February 8, 2013.

Abstract

Cellular heterogeneity, for example, the intratumoral coexistence of cancer cells with and without stem cell characteristics, represents a potential root of therapeutic resistance and a significant challenge for modern drug development in glioblastoma (GBM). We propose here that activation of the innate immune system by stimulation of innate immune receptors involved in antiviral and antitumor responses can similarly target different malignant populations of glioma cells. We used short-term expanded patient-specific primary human GBM cells to study the stimulation of the cytosolic nucleic acid receptors melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). Specifically, we analyzed cells from the tumor core versus “residual GBM cells” derived from the tumor resection margin as well as stem cell-enriched primary cultures versus specimens without stem cell properties. A portfolio of human, nontumor neural cells was used as a control for these studies. The expression of RIG-I and MDA5 could be induced in all of these cells. Receptor stimulation with their respective ligands, p(I:C) and 3pRNA, led to in vitro evidence for an effective activation of the innate immune system. Most intriguingly, all investigated cancer cell populations additionally responded with a pronounced induction of apoptotic signaling cascades revealing a second, direct mechanism of antitumor activity. By contrast, p(I:C) and 3pRNA induced only little toxicity in human nonmalignant neural cells. Granted that the challenge of effective central nervous system (CNS) delivery can be overcome, targeting of RIG-I and MDA5 could thus become a quintessential strategy to encounter heterogeneous cancers in the sophisticated environments of the brain. STEM Cells 2013;31:1064–1074

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