Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model.
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.
Alcantara Llaguno
Sheila
S
Department of Developmental Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Chen
Jian
J
Kwon
Chang-Hyuk
CH
Jackson
Erica L
EL
Li
Yanjiao
Y
Burns
Dennis K
DK
Alvarez-Buylla
Arturo
A
Parada
Luis F
LF
D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000502:physiology; D000818:Animals; D001254:Astrocytoma / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000235:genetics; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011230:Precancerous Conditions / Q000473:pathology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D025521:Tumor Suppressor Proteins; C045073:Cre recombinase; D019426:Integrases