Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma

Maria-del-Mar Inda, Rudy Bonavia, Akitake Mukasa, Yoshitaka Narita, Dinah W Y Sah, Scott Vandenberg, Cameron Brennan, Terrance Grant Johns, Robert Bachoo, Philipp Hadwiger, Pamela Tan, Ronald A DePinho, Webster K Cavenee, Frank B Furnari

Research output: Contribution to journalArticleResearchpeer-review

374 Citations (Scopus)

Abstract

Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/DeltaEGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the DeltaEGFR lesion. We hypothesized that the minor DeltaEGFR-expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by DeltaEGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf(-/-) astrocytes that express DeltaEGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines.
Original languageEnglish
Pages (from-to)1731 - 1745
Number of pages15
JournalGenes & Development
Volume24
Issue number16
DOIs
Publication statusPublished - 2010

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