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Teratoma Growth Retardation by HDACi Treatment of the Tumor Embryonal Source
Jure Krasic1,2,3, Lucija Skara1,2,3, Monika Ulamec2,3,4,5
1Department of Medical Biology, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia.
Abstract:
Among testicular germ cell tumors, teratomas may often be very aggressive and therapy-resistant. Our aim was to investigate the impact of histone deacetylase inhibitors (HDACi) on the in vitro growth of experimental mouse teratoma by treating their embryonic source, the embryo-proper, composed only of the three germ layers. The growth of teratomas was measured for seven days, and histopathological analysis, IHC/morphometry quantification, gene enrichment analysis, and qPCR analysis on a selected panel of pluripotency and early differentiation genes followed. For the first time, within teratomas, we histopathologically assessed the undifferentiated component containing cancer stem cell-like cells (CSCLCs) and differentiated components containing numerous lymphocytes. Mitotic indices were higher than apoptotic indices in both components. Both HDACi treatments of the embryos-proper significantly reduced teratoma growth, although this could be related neither to apoptosis nor proliferation. Trichostatin A increased the amount of CSCLCs, and upregulated the mRNA expression of pluripotency/stemness genes as well as differentiation genes, e.g., T and Eomes. Valproate decreased the amount of CSCLCs, and downregulated the expressions of pluripotency/stemness and differentiation genes. In conclusion, both HDACi treatments diminished the inherent tumorigenic growth potential of the tumor embryonal source, although Trichostatin A did not diminish the potentially dangerous expression of cancer-related genes and the amount of CSCLC.
Insights
Histone deacetylase inhibitors (HDACi) reduced teratoma growth by targeting the embryo-proper. However, Trichostatin A increased cancer stem cells, while Valproate decreased them, impacting tumor growth differently.
Area of Science:
- Developmental Biology
- Cancer Research
- Epigenetics
Background:
- Teratomas, aggressive and therapy-resistant testicular germ cell tumors, originate from pluripotent embryonic cells.
- Histone deacetylase inhibitors (HDACi) are epigenetic modifiers with potential anti-cancer properties.
- Understanding HDACi effects on teratoma precursors is crucial for novel therapeutic strategies.
Purpose of the Study:
- To investigate the impact of HDAC inhibitors on the in vitro growth of experimental mouse teratomas.
- To analyze the effects of HDAC inhibition on the embryonic source (embryo-proper) of teratomas.
- To assess the influence of HDACi on cancer stem cell-like cells (CSCLCs) and gene expression within teratomas.
Main Methods:
- Treatment of mouse embryo-proper with HDAC inhibitors (Trichostatin A and Valproate).
- Measurement of teratoma growth over seven days.
- Histopathological analysis, IHC/morphometry, gene enrichment, and qPCR analysis of pluripotency and differentiation genes.
Main Results:
- Both HDACi treatments significantly reduced teratoma growth without affecting apoptosis or proliferation.
- Trichostatin A increased CSCLCs and upregulated pluripotency/stemness and differentiation genes.
- Valproate decreased CSCLCs and downregulated pluripotency/stemness and differentiation genes.
Conclusions:
- HDACi diminish the inherent tumorigenic growth potential of the teratoma embryonal source.
- Trichostatin A's effect on CSCLCs and cancer-related gene expression warrants further investigation.
- Valproate demonstrates a more favorable impact by reducing CSCLCs and key gene expressions.
