Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model
Sheila Alcantara Llaguno1, Jian Chen, Chang-Hyuk Kwon
1Department of Developmental Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Abstract:
Malignant astrocytomas are infiltrative and incurable brain tumors. Despite profound therapeutic implications, the identity of the cell (or cells) of origin has not been rigorously determined. We previously reported mouse models based on conditional inactivation of the human astrocytoma-relevant tumor suppressors p53, Nf1, and Pten, wherein through somatic loss of heterozygosity, mutant mice develop tumors with 100% penetrance. In the present study, we show that tumor suppressor inactivation in neural stem/progenitor cells is both necessary and sufficient to induce astrocytoma formation. We demonstrate in vivo that transformed cells and their progeny undergo infiltration and multilineage differentiation during tumorigenesis. Tumor suppressor heterozygous neural stem/progenitor cultures from presymptomatic mice show aberrant growth advantage and altered differentiation, thus identifying a pretumorigenic cell population.
Insights
Malignant astrocytomas originate from neural stem/progenitor cells. Inactivating tumor suppressors (p53, Nf1, Pten) in these cells is necessary and sufficient for astrocytoma development, revealing a pretumorigenic cell population.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Stem Cell Biology
Background:
- Malignant astrocytomas are aggressive brain tumors with unknown cell of origin.
- Identifying the cell of origin is crucial for developing effective therapies.
Purpose of the Study:
- To determine the cell of origin for malignant astrocytomas.
- To investigate the role of neural stem/progenitor cells in astrocytoma formation.
Main Methods:
- Utilized genetically engineered mouse models with conditional inactivation of p53, Nf1, and Pten tumor suppressors.
- Analyzed tumor development and cell behavior in vivo and in vitro using neural stem/progenitor cell cultures.
Main Results:
- Tumor suppressor inactivation in neural stem/progenitor cells was sufficient to induce astrocytoma formation.
- Transformed cells infiltrated tissues and exhibited multilineage differentiation during tumorigenesis.
- Presymptomatic neural stem/progenitor cell cultures showed aberrant growth and altered differentiation, indicating a pretumorigenic state.
Conclusions:
- Neural stem/progenitor cells are the cell of origin for malignant astrocytomas.
- Early genetic alterations in these cells lead to aberrant growth and differentiation, initiating tumor development.
