Glioblastomas are the most common and aggressive primary brain tumor in adults, with a median survival of only fourteen months with the best available treatments. Much needed novel therapies may arise from increased appreciation of the biological and molecular properties of subset of tumor cells which can self-renew and recapitulate the parental tumor. These cancer stem cells remain controversial due to the evolving understanding of their nature: however, a number of reports have demonstrated that glioblastomas contain cancer stem cells and that these glioma stem cells contribute to therapeutic resistance and tumor angiogenesis. We now demonstrate that the cell survival regulator A20/Tumor Necrosis Factor a Inducible Protein 3 is a glioma stem cell target which contributes to glioma growth. Although very limited and often contradictory data exists regarding the expression and function of A20 in brain tumors, we find that GSCs consistently express elevated levels of A20 in comparison to non-stem glioma cells. Targeting the expression of A20 in GSCs reduces their growth in association with increased cell cycle arrest, elevated apoptosis, and decreased self-renewal. Targeting A20 in GSCs increased the survival of mice bearing human glioma xenografts, and analysis of a glioma expression database indicates that increased A20 mRNA correlates with poor glioma patient survival. Based on this background, we hypothesize that A20 promotes glioma growth and recurrence due, in part, to maintenance of a cancer stem cell phenotype. We propose to elucidate the molecular and biological role of A20 in glioma stem cell biology in an effort to determine novel targets for glioma patient therapies.
In some cancers, a subfraction of tumor cells called cancer stem cells may contribute to tumor growth and recurrence. Our studies identify A20, or Tumor Necrosis Factor Alpha Inducible Protein 3 (TNFAIP3), as a novel cancer stem cell target in glioma linked to poor patient survival. Targeting A20 decreases glioma stem cell survival and reduces glioma formation in animal models, indicating anti-A20 therapies may be beneficial for glioma patients.
|Rowse, Amber L; Gibson, Sara A; Meares, Gordon P et al. (2017) Protein kinase CK2 is important for the function of glioblastoma brain tumor initiating cells. J Neurooncol 132:219-229|
|Boyd, Nathaniel H; Walker, Kiera; Fried, Joshua et al. (2017) Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo. JCI Insight 2:|
|Tran, Anh N; Boyd, Nathaniel H; Walker, Kiera et al. (2017) NOS Expression and NO Function in Glioma and Implications for Patient Therapies. Antioxid Redox Signal 26:986-999|
|Gilbert, Ashley N; Walker, Kiera; Tran, Anh Nhat et al. (2017) Modeling Physiologic Microenvironments in Three-Dimensional Microtumors Maintains Brain Tumor Initiating Cells. J Cancer Stem Cell Res 5:|
|Hjelmeland, Anita; Zhang, Jianhua (2016) Metabolic, autophagic, and mitophagic activities in cancer initiation and progression. Biomed J 39:98-106|
|Rivera, M; Wu, Q; Hamerlik, P et al. (2015) Acquisition of meiotic DNA repair regulators maintain genome stability in glioblastoma. Cell Death Dis 6:e1732|
|Moskwa, Patryk; Zinn, Pascal O; Choi, Young Eun et al. (2014) A functional screen identifies miRs that induce radioresistance in glioblastomas. Mol Cancer Res 12:1767-78|
|Scott, Jacob G; Hjelmeland, Anita B; Chinnaiyan, Prakash et al. (2014) Microenvironmental variables must influence intrinsic phenotypic parameters of cancer stem cells to affect tumourigenicity. PLoS Comput Biol 10:e1003433|
|Walker, Kiera; Hjelmeland, Anita (2014) Method for Efficient Transduction of Cancer Stem Cells. J Cancer Stem Cell Res 2:|
|Yan, Kenneth; Wu, Qiulian; Yan, Diana H et al. (2014) Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy. Genes Dev 28:1085-100|
Showing the most recent 10 out of 26 publications