Human Malignant Rhabdoid Tumor Antigens as Biomarkers and Potential Therapeutic Targets

Abstract

Introduction: Atypical teratoid rhabdoid tumor (ATRT) is a lethal type of malignant rhabdoid tumor in the brain, seen mostly in children under two years old. ATRT is mainly linked to the biallelic inactivation of the SMARCB1 gene. To understand the deadly characteristics of ATRT and develop novel diagnostic and immunotherapy strategies for the treatment of ATRT, this study investigated tumor antigens, such as alpha-fetoprotein (AFP), mucin-16 (MUC16/CA125), and osteopontin (OPN), and extracellular matrix modulators, such as matrix metalloproteinases (MMPs), in different human malignant rhabdoid tumor cell lines. In addition, the roles of MMPs were also examined. Materials and methods: Five human cell lines were chosen for this study, including two ATRT cell lines, CHLA-02-ATRT and CHLA-05-ATRT; a kidney malignant rhabdoid tumor cell line, G401; and two control cell lines, human embryonic kidney HEK293 and HEK293T. Both ATRT cell lines were treated with a broad-spectrum MMP inhibitor, GM6001, to investigate the effect of MMPs on cell proliferation, viability, and expression of tumor antigens and biomarkers. Gene expression was examined using a reverse transcription polymerase chain reaction (RT-PCR), and protein expression was characterized by immunocytochemistry and flow cytometry. Results: All the rhabdoid tumor cell lines tested had high gene expression levels of MUC16, OPN, AFP, and MSLN. Low expression levels of neuron-specific enolase (ENO2) by the two ATRT cell lines demonstrated their lack of neuronal genotype. Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) and tissue inhibitor of metalloproteinases-2 (TIMP-2) were highly expressed in these malignant rhabdoid tumor cells, indicating their invasive phenotypes. GM6001 significantly decreased ATRT cell proliferation and the gene expression of MSLN, OPN, and several mesenchymal markers, suggesting that inhibition of MMPs may reduce the aggressiveness of rhabdoid cancer cells. Conclusion: The results obtained from this study may advance our knowledge of the molecular landscapes of human malignant rhabdoid tumors and their biomarkers for effective diagnosis and treatment. This work analyzed the expression of human malignant rhabdoid tumor antigens that may serve as biomarkers for the development of novel therapeutic strategies, such as cancer vaccines and targeted and immunotherapies targeting osteopontin and mesothelin, for the treatment of patients with ATRT and other malignant rhabdoid tumors.

Survival Benefit from Multimodal Treatment for Patients with Atypical Teratoid Rhabdoid Tumor in a Surveillance, Epidemiology, and End Results Database Analysis

“…However, this was not the case in univariate analysis. We believe this is probably due to the aggressive nature of ATRT [31, 35]. In addition, different genetic studies have shown that the supratentorial and infratentorial tumors have varying genetic profiles that might contribute to OS [35].…”

“…Research is also being conducted to investigate the benefits of molecular-based targeted therapies and immunomodulator therapies [29][30][31]. In a preclinical study conducted by Jayanthan et al [32], they explored the potential of multikinase inhibitors in treating ATRT.…”

Modeling human brain rhabdoid tumor by inactivating tumor suppressor genes in induced pluripotent stem cells

“…GLI1 protein expression was lower in Epi-iPSC-SP, EC6A-SP, and EC7A-SP when compared to the ATRT cell lines. Interestingly, GLI2, NPM, and Osteopontin proteins were expressed by all cells, which are putative ATRT biomarkers [ 34 , 35 ]. Finally, Pax-6 expression was higher in ATRT cell lines and EC7A-SP but lower in Epi-iPSC-SP and EC6A-SP ( Fig.…”

“…The approach used in this study did not require animals but the early-stage cerebellum differentiation protocol to generate spheroids [ 41 ]. The model's gene expression profile showed high similarity with that of patient-derived ATRT cell lines, including upregulated SHH and β-catenin pathway [ 4 ], higher expression of OCT4 and NANOG embryonic markers [ 42 ], higher OPN [ 34 ], as well as a lower level of specific neuronal marker ENO2 ( Fig. 8 ).…”

“…Other ATRT biomarkers such as GLI2, NPM, and Osteopontin were also expressed by the knockout spheroids ( Fig. 9 ) [ 34 , 35 , 42 ]. Taken together, the gene and protein expression profiles imply that EC6A- and EC7A-derived spheroids may serve as an ATRT-like model.…”