Abstract
Glioblastoma (GBM), the most severe and common brain tumor in adults, is characterized by multiple somatic mutations and aberrant activation of inflammatory responses. Immune cell infiltration and subsequent inflammation cause tumor growth and resistance to therapy. Somatic loss-of-function mutations in the gene encoding tumor suppressor protein p53 (TP53) are frequently observed in various cancers. However, numerous studies suggest that TP53 regulates malignant phenotypes by gain-of-function (GOF) mutations. Here we demonstrate that a TP53 GOF mutation promotes inflammation in GBM. Ectopic expression of a TP53 GOF mutant induced transcriptomic changes, which resulted in enrichment of gene signatures related to inflammation and chemotaxis. Bioinformatics analyses revealed that a gene signature, upregulated by the TP53 GOF mutation, is associated with progression and shorter overall survival in GBM. We also observed significant correlations between the TP53 GOF mutation signature and inflammation in the clinical database of GBM and other cancers. The TP53 GOF mutant showed upregulated C–C motif chemokine ligand 2 (CCL2) and tumor necrosis factor alpha (TNFA) expression via nuclear factor kappa B (NFκB) signaling, consequently increasing microglia and monocyte-derived immune cell infiltration. Additionally, TP53 GOF mutation and CCL2 and TNFA expression correlated positively with tumor-associated immunity in patients with GBM. Taken together, our findings suggest that the TP53 GOF mutation plays a crucial role in inflammatory responses, thereby deteriorating prognostic outcomes in patients with GBM.
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References
Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. J Am Med Assoc. 2013;310:1842–50.
Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro Oncol. 2014;16:iv1–63.
Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77.
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709–22.
Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2:a001008.
Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014;14:359–70.
The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.
The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519–25.
The Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–90.
The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43–9.
Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25:304–17.
Alexandrova EM, Yallowitz AR, Li D, Xu S, Schulz R, Proia DA, et al. Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature. 2015;523:352–6.
Soragni A, Janzen DM, Johnson LM, Lindgren AG, Thai-Quynh Nguyen A, Tiourin E, et al. A designed inhibitor of p53 aggregation rescues p53 tumor suppression in ovarian carcinomas. Cancer Cell. 2016;29:90–103.
Shalapour S, Karin M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Invest. 2015;125:3347–55.
Terzic J, Grivennikov S, Karin E, Karin M. Inflammation and colon cancer. Gastroenterology. 2010;138:2101–14.
Oeckinghaus A, Ghosh S. The NF-κB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009;1:a000034.
Granata F, Frattini A, Loffredo S, Staiano RI, Petraroli A, Ribatti D, et al. Production of vascular endothelial growth factors from human lung macrophages induced by group IIA and group X secreted phospholipases A2. J Immunol. 2010;184:5232–41.
Tjiu JW, Chen JS, Shun CT, Lin SJ, Liao YH, Chu CY, et al. Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction. J Investig Dermatol. 2009;129:1016–25.
Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.
Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74:5057–69.
Whibley C, Pharoah PD, Hollstein M. p53 polymorphisms: cancer implications. Nat Rev Cancer. 2009;9:95–107.
Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A. PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex. Genes Dev. 2008;22:2496–506.
Bendjennat M, Boulaire J, Jascur T, Brickner H, Barbier V, Sarasin A, et al. UV irradiation triggers ubiquitin-dependent degradation ofp21(WAF1) to promote DNA repair. Cell. 2003;114:599–610.
Stuart SA, Wang JY. Ionizing radiation induces ATM-independent degradation of p21Cip1 in transformed cells. J Biol Chem. 2009;284:15061–70.
Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, et al. New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci USA. 2016;113:E1738–46.
Tarella C, Ferrero D, Gallo E, Pagliardi GL, Ruscetti FW. Induction of differentiation of HL-60 cells by dimethyl sulfoxide: evidence for a stochastic model not linked to the cell division cycle. Cancer Res. 1982;42:445–9.
Padilla PI, Wada A, Yahiro K, Kimura M, Niidome T, Aoyagi H, et al. Morphologic differentiation of HL-60 cells is associated with appearance of RPTPbeta and induction of Helicobacter pylori VacA sensitivity. J Biol Chem. 2000;275:15200–6.
Bossen C, Ingold K, Tardivel A, Bodmer JL, Gaide O, Hertig S, et al. Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human. J Biol Chem. 2006;281:13964–71.
Tang X, Asano M, O’Reilly A, Farquhar A, Yang Y, Amar S. p53 is an important regulator of CCL2 gene expression. Curr Mol Med. 2012;12:929–43.
Cooks T, Pateras IS, Tarcic O, Solomon H, Schetter AJ, Wilder S, et al. Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell. 2013;23:634–46.
Eruslanov EB, Bhojnagarwala PS, Quatromoni JG, Stephen TL, Ranganathan A, Deshpande C, et al. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J Clin Invest. 2014;124:5466–80.
Hartwig T, Montinaro A, von Karstedt S, Sevko A, Surinova S, Chakravarthy A, et al. The TRAIL-induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2. Mol Cell. 2017;65:730–42.e735.
Wang X, Chen JX, Liu JP, You C, Liu YH, Mao Q. Gain of function of mutant TP53 in glioblastoma: prognosis and response to temozolomide. Ann Surg Oncol. 2014;21:1337–44.
Shiraishi S, Tada K, Nakamura H, Makino K, Kochi M, Saya H, et al. Influence of p53 mutations on prognosis of patients with glioblastoma. Cancer. 2002;95:249–57.
Pollack IF, Finkelstein SD, Woods J, Burnham J, Holmes EJ, Hamilton RL, et al. Expression of p53 and prognosis in children with malignant gliomas. N Engl J Med. 2002;346:420–7.
Lee SY. Temozolomide resistance in glioblastoma multiforme. Genes Dis. 2016;3:198–210.
Kyritsis AP, Bondy ML, Hess KR, Cunningham JE, Zhu D, Amos CJ, et al. Prognostic significance of p53 immunoreactivity in patients with glioma. Clin Cancer Res. 1995;1:1617–22.
Jin Y, Xiao W, Song T, Feng G, Dai Z. Expression and prognostic significance of p53 in glioma patients: a meta-analysis. Neurochem Res. 2016;41:1723–31.
Arimappamagan A, Somasundaram K, Thennarasu K, Peddagangannagari S, Srinivasan H, Shailaja BC, et al. A fourteen gene GBM prognostic signature identifies association of immune response pathway and mesenchymal subtype with high risk group. PLoS ONE. 2013;8:e62042.
Mostafa H, Pala A, Högel J, Hlavac M, Dietrich E, Westhoff MA, et al. Immune phenotypes predict survival in patients with glioblastoma multiforme. J Hematol Oncol. 2016;9:77.
Wang PF, Song HW, Cai HQ, Kong LW, Yao K, Jiang T, et al. Preoperative inflammation markers and IDH mutation status predict glioblastoma patient survival. Oncotarget. 2017;8:50117–23.
Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, et al. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell. 2017;32:42–56. e46.
van Horssen R, ten Hagen TL, Eggermont AM. TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist. 2006;11:397–408.
Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature. 2010;463:318–25.
Bhat Krishna PL, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, et al. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell. 2013;24:331–46.
Kim SH, Ezhilarasan R, Phillips E, Gallego-Perez D, Sparks A, Taylor D, et al. Serine/threonine kinase MLK4 determines mesenchymal identity in glioma stem cells in an NF-κB-dependent manner. Cancer Cell. 2016;29:201–13.
Han J, Chu J, Keung Chan W, Zhang J, Wang Y, Cohen JB, et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci Rep. 2015;5:11483.
Zhang J, Sarkar S, Cua R, Zhou Y, Hader W, Yong VW. A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis. Carcinogenesis. 2012;33:312–9.
Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ. CCL2 and interleukin-6 promote survival of human CD11b+peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem. 2009;284:34342–54.
Chang AL, Miska J, Wainwright DA, Dey M, Rivetta CV, Yu D, et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res. 2016;76:5671.
Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, et al. Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell. 2002;1:269–77.
Bowman RL, Wang Q, Carro A, Verhaak RGW, Squatrito M. GlioVis data portal for visualization and analysis of brain tumor expression datasets. Neuro Oncol. 2017;19:139–41.
Sturn A, Quakenbush J, Trajanoski Z. Genesis: cluster analysis of microarray data. Bioinformatics. 2002;18:207–8.
Acknowledgements
We thank Dr. Joonbeom Bae, Dr. Chang-Yong Choi, and Sang-Pil Choi from Korea University for their advice on experiments related to immune cells, and Ock Ran Kim (Seoul National University Hospital) for advice on histological analyses. This work was supported by grants to Hyunggee Kim from the National Research Foundation (NRF) (2015R1A5A1009024 and 2017M3A9A8031425), Next-Generation Biogreen 21 Program (PJ01107701), Brain Korea 21 Plus, and Korea University, from the Korea Health Industry Development Institute (KHIDI) (HI14C3418) to D-HN, and from the NRF (2016M3C7A1913844) to SHK. The bio-specimens for this study were provided by Samsung Medical Center Biobank.
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Ham, S.W., Jeon, HY., Jin, X. et al. TP53 gain-of-function mutation promotes inflammation in glioblastoma. Cell Death Differ 26, 409–425 (2019). https://doi.org/10.1038/s41418-018-0126-3
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DOI: https://doi.org/10.1038/s41418-018-0126-3
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