An Overview of CD133 as a Functional Unit of Prognosis and Treatment Resistance in Glioblastoma

Abstract

Biomarkers for resistance in Glioblastoma multiforme (GBM) are lacking, and progress in the clinic has been slow to arrive. CD133 (prominin-1) is a membrane-bound glycoprotein on the surface of cancer stem cells (CSCs) that has been associated with poor prognosis, therapy resistance, and tumor recurrence in GBM. Due to its connection to CSCs, to which tumor resistance and recurrence have been partially attributed in GBM, there is a growing field of research revolving around the potential role of CD133 in each of these processes. However, despite encouraging results in vitro and in vivo, the biological interplay of CD133 with these components is still unclear, causing a lack of clinical application. In parallel, omic data from biospecimens that include CD133 are beginning to emerge, increasing the importance of understanding CD133 for the effective use of these highly dimensional data sets. Given the significant mechanistic overlap, prioritization of the most robust findings is necessary to optimize the transition of CD133 to clinical applications using patient-derived biospecimens. As a result, this review aims to compile and analyze the current research regarding CD133 as a functional unit in GBM, exploring its connections to prognosis, the tumor microenvironment, tumor resistance, and tumor recurrence.

Keywords: CD133; chemo/radioresistance; glioblastoma; omics; recurrence; stem cell marker.

Figure A1

CD133 interaction network in all diseases and biospecimen types based on IPA ((QIAGEN Inc., https://www.qiagenbioinformatics.com/products/ingenuitypathway-analysis) accessed on 24 July 2023) [32].

Figure A2

Extended CD133 (PROM1) interaction network limiting interaction to molecules in cancer based on IPA molecule activity prediction when (A) HIF1A is activated causing downstream activation and (B) STAT3 is inhibited causing downstream inhibition ((QIAGEN Inc., https://www.qiagenbioinformatics.com/products/ingenuitypathway-analysis) accessed on 24 July 2023) [32].

Figure A3

CD133 interaction network based on IPA ((QIAGEN Inc., https://www.qiagenbioinformatics.com/products/ingenuitypathway-analysis) accessed on 24 July 2023) [32]. Network comparison analysis with tissue expression dataset files based on IPA, (A) normal cerebral cortex and (B) cultured cancer stem cells [33]. (C) tumor sample analysis GBM secondary tumor vs. BS149 cell line (normal human astrocytes) [34]. (D) TCRseq and RNA-Seq of tumor tissue, non-neoplastic brain tissue, and peripheral blood from patients [35].

Figure 1

Modified Sankey diagram sorting the publications used into publication type, year, and subgroup [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31].

Figure 2

CD133 (PROM1) interaction network limiting interaction to molecules in cancer based on the IPA molecule activity prediction ((QIAGEN Inc., https://www.qiagenbioinformatics.com/products/ingenuitypathway-analysis) accessed on 24 July 2023) [32]. Network comparison analysis with (A) Activation of HIF1A (e.g., under hypoxia conditions) results in increased predicted expression of PROM1 and the hypothesis is that this drives tumor recurrence. (B) Inhibition of STAT3 results in decreased predicted expression of PROM1 and the hypothesis is that this can lead to tumor response. The same downstream mediators appear to be involved, given current evidence, with PROM1 activation or inhibition driving activation/inhibition of downstream molecules. The extended interaction network is presented in Figure A2.

Figure 3

Alternative promoters (tissue specific) and the downstream effects of CD133 activation on the Akt pathway with implications for pluripotency, tumorigenesis, cell cycle effects, apoptosis and cell survival, protein synthesis, and angiogenesis based on IPA molecule activity prediction ((QIAGEN Inc., https://www.qiagenbioinformatics.com/products/ingenuitypathway-analysis) accessed on 24 July 2023) [32].

Figure 4

CD133 interaction network based on IPA ((QIAGEN Inc., https://www.qiagenbioinformatics.com/products/ingenuitypathway-analysis) accessed on 24 July 2023) [32]. Network comparison analysis with tissue expression dataset files obtained from IPA, (A) normal cerebral cortex and (B) cultured cancer stem cells [33].