Direct orthotopic transplantation of fresh surgical specimen preserves CD133+ tumor cells in clinically relevant mouse models of medulloblastoma and glioma.
Recent identification of cancer stem cells in medulloblastoma (MB) and high-grade glioma has stimulated an urgent need for animal models that will not only replicate the biology of these tumors, but also preserve their cancer stem cell pool. We hypothesize that direct injection of fresh surgical specimen of MB and high-grade glioma tissues into anatomically equivalent locations in immune-deficient mouse brains will facilitate the formation of clinically accurate xenograft tumors by allowing brain tumor stem cells, together with their non-stem tumor and stromal cells, to grow in a microenvironment that is the closest to human brains. Eight of the 14 MBs (57.1%) and two of the three high-grade gliomas (66.7%) in this study developed transplantable (up to 12 passages) xenografts in mouse cerebellum and cerebrum, respectively. These xenografts are patient specific, replicating the histopathologic, immunophenotypic, invasive/metastatic, and major genetic (analyzed with 10K single nucleotide polymorphism array) abnormalities of the original tumors. The xenograft tumor cells have also been successfully cryopreserved for long-term preservation of tumorigenicity, ensuring a sustained supply of the animal models. More importantly, the CD133(+) tumor cells, ranging from 0.2%-10.4%, were preserved in all the xenograft models following repeated orthotopic subtransplantations in vivo. The isolated CD133(+) tumor cells formed neurospheres and displayed multi-lineage differentiation capabilities in vitro. In summary, our study demonstrates that direct orthotopic transplantation of fresh primary tumor cells is a powerful approach in developing novel clinical relevant animal models that can reliably preserve CD133(+) tumor cell pools even during serial in vivo subtransplantations. Disclosure of potential conflicts of interest is found at the end of this article.
Shu
Qin
Q
Laboratory of Molecular Neuro-Oncology, Texas Children's Cancer Center, Texas Children's Hospital, 6621 Fannin St, MC 3-3320, Houston, Texas 77030, USA.
Wong
Kwong Kwok
KK
Su
Jack M
JM
Adesina
Adekunle M
AM
Yu
Li Tian
LT
Tsang
Yvonne T M
YT
Antalffy
Barbara C
BC
Baxter
Patricia
P
Perlaky
Laszlo
L
Yang
Jianhua
J
Dauser
Robert C
RC
Chintagumpala
Murali
M
Blaney
Susan M
SM
Lau
Ching C
CC
Li
Xiao-Nan
XN
D000071916:AC133 Antigen; D000293:Adolescent; D000818:Animals; D015703:Antigens, CD / Q000032:analysis*; D001932:Brain Neoplasms / Q000473:pathology* / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D015925:Cryopreservation; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000473:pathology* / Q000601:surgery; D006023:Glycoproteins / Q000032:analysis*; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000473:pathology* / Q000601:surgery; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000473:pathology; D010455:Peptides / Q000032:analysis*; D020641:Polymorphism, Single Nucleotide; D014183:Transplantation, Heterologous
D000071916:AC133 Antigen; D015703:Antigens, CD; D004273:DNA, Neoplasm; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse