title: Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma.
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. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically dissimilar cancer cells could provide novel points of therapeutic intervention.
authors: University of California, San Diego, La Jolla, CA 92093, USA.
authors: Maria-del-Mar
authors: MM
authors: Inda
authors: Rudy
authors: R
authors: Bonavia
authors: Akitake
authors: A
authors: Mukasa
authors: Yoshitaka
authors: Y
authors: Narita
authors: Dinah W Y
authors: DW
authors: Sah
authors: Scott
authors: S
authors: Vandenberg
authors: Cameron
authors: C
authors: Brennan
authors: Terrance G
authors: TG
authors: Johns
authors: Robert
authors: R
authors: Bachoo
authors: Philipp
authors: P
authors: Hadwiger
authors: Pamela
authors: P
authors: Tan
authors: Ronald A
authors: RA
authors: Depinho
authors: Webster
authors: W
authors: Cavenee
authors: Frank
authors: F
authors: Furnari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000503:physiopathology*; D005910:Glioma / Q000503:physiopathology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; C494199:IL6ST protein, human; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008024:Ligands; D050822:Cytokine Receptor gp130; D066246:ErbB Receptors