The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma
Open accessAbstract
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/ΔEGFR) 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 ΔEGFR lesion. We hypothesized that the minor ΔEGFR-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 ΔEGFR 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 ΔEGFR 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.
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Citations
Cites
Comprehensive genomic characterization defines human glioblastoma genes and core pathways
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Principles of interleukin (IL)-6-type cytokine signalling and its regulation
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“IL-6-type cytokines are well known potent activators of the JAK/STAT3 pathway (Schaefer et al. 2000; Heinrich et al. 2003), the inhibition of which has been shown to promote apoptosis in GBM cells (Rahaman et al. 2002).”
BackgroundMalignant astrocytic glioma: genetics, biology, and paths to treatment
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Self-citationMolecular characterization of the tumor microenvironment in breast cancer
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Self-citationA mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity.
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Self-citationPrognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme.
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Self-citation
Cited by
The Somatic Genomic Landscape of Glioblastoma
Brennan, C. W., Verhaak, R. G. W., McKenna, A., Campos, B., Noushmehr, H., Salama, S. R., Zheng, S., Chakravarty, D., Sanborn, J. Z., Berman, S. H., et al. (2013) · Cell · doi:10.1016/j.cell.2013.09.034 · Cited by 5,016
Self-citationClonal heterogeneity and tumor evolution: past, present, and the future
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The causes and consequences of genetic heterogeneity in cancer evolution
Burrell, R. A., McGranahan, N., Bartek, J., & Swanton, C. (2013) · Nature · doi:10.1038/nature12625 · Cited by 2,262
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Biological and therapeutic impact of intratumor heterogeneity in cancer evolution
McGranahan, N., & Swanton, C. (2015) · Cancer Cell · doi:10.1016/j.ccell.2014.12.001 · Cited by 1,077
Metadata
- Authors
- Inda, M.-D.-M., Bonavia, R., Mukasa, A., Narita, Y., Sah, D. W. Y., Vandenberg, S., Brennan, C., Johns, T. G., Bachoo, R., Hadwiger, P., Tan, P., DePinho, R. A., Cavenee, W., & Furnari, F.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-08-15
- Volume
- 24
- Issue
- 16
- Pages
- 1731-1745
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2102626211
- Cited by
- 543
- References
- 57
- Type
- posted content
- Language
- en
- Open access
- diamond
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- Inda, M.-D.-M., Bonavia, R., Mukasa, A., Narita, Y., Sah, D. W. Y., Vandenberg, S., Brennan, C., Johns, T. G., Bachoo, R., Hadwiger, P., Tan, P., DePinho, R. A., Cavenee, W., & Furnari, F. (2010). Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes & Development. https://doi.org/10.1101/gad.1890510
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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