Limits...
A mouse model of human primitive neuroectodermal tumors resulting from microenvironmentally-driven malignant transformation of orthotopically transplanted radial glial cells.

Malchenko S, Sredni ST, Hashimoto H, Kasai A, Nagayasu K, Xie J, Margaryan NV, Seiriki K, Lulla RR, Seftor RE, Pachman LM, Meltzer HY, Hendrix MJ, Soares MB - PLoS ONE (2015)

Bottom Line: These results are significant for several reasons.First, they show that malignant transformation of radial glial cells can occur in the absence of specific mutations or inherited genomic alterations.Second, they demonstrate that the same radial glial cells may either give rise to brain tumors or differentiate normally depending upon the microenvironment of the specific region of the brain to which the cells are transplanted.

View Article: PubMed Central - PubMed

Affiliation: Cancer Biology and Epigenomics Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.

ABSTRACT
There is growing evidence and a consensus in the field that most pediatric brain tumors originate from stem cells, of which radial glial cells constitute a subtype. Here we show that orthotopic transplantation of human radial glial (RG) cells to the subventricular zone of the 3rd ventricle--but not to other transplantation sites--of the brain in immunocompromised NOD-SCID mice, gives rise to tumors that have the hallmarks of CNS primitive neuroectodermal tumors (PNETs). The resulting mouse model strikingly recapitulates the phenotype of PNETs. Importantly, the observed tumorigenic transformation was accompanied by aspects of an epithelial to mesenchymal transition (EMT)-like process. It is also noteworthy that the tumors are highly invasive, and that they effectively recruit mouse endothelial cells for angiogenesis. These results are significant for several reasons. First, they show that malignant transformation of radial glial cells can occur in the absence of specific mutations or inherited genomic alterations. Second, they demonstrate that the same radial glial cells may either give rise to brain tumors or differentiate normally depending upon the microenvironment of the specific region of the brain to which the cells are transplanted. In addition to providing a prospect for drug screening and development of new therapeutic strategies, the resulting mouse model of PNETs offers an unprecedented opportunity to identify the cancer driving molecular alterations and the microenvironmental factors that are responsible for committing otherwise normal radial glial cells to a malignant phenotype.

No MeSH data available.


Related in: MedlinePlus

The tumor cells invade the ventricular system.A- Septo-Striatal section, phase contrast (tissue slides, 1X); B- The same Septo-Striatal section: Ki-67 (red) overlay with GFP (green) and DAPI (blue) (LC25-R—8 weeks post-injection) (tissue slides, 1X); C- (LC26-R—12 weeks post-injection), D- (LC35TR-R—12 weeks post-injection), and E- (LCAS-R—12 weeks post-injection)—tumor growing within the parenchyma of the subventricular zone protruding to the ventricle (HE- 5X, 20X and 10X respectively); F- tumor growing within the parenchyma and invading lateral ventricle (LC26-R—12 weeks post-injection) (HE- 5X); G- tumor growing within the parenchyma, Ki-67 staining (LC26-R—12 weeks post-injection) (HE- 20X); H- tumor growing within the ventricular system including forth ventricle and subarachnoid space permeating the cerebellum (LC26-R—12 weeks post-injection) (HE- 5X); I- Tumor growing inside the parenchyma and protruding into the ventricular space. (CM14R - 8 weeks post-injection) (HE- 10X, inserts- 4X digital); J- and K- poorly differentiated neuroblastic tumor with rosette formation (LC26-R—12 weeks post-injection) (HE- 40X), rosettes—orange arrows; L- and N- frequent atypical mitoses—yellow arrows and inserts (LC26-R—12 weeks post-injection) (HE- 40X, inserts- 6X digital); M- tumor perivascular invasion (LCAS-R—12 weeks post-injection) (HE— 40X); N- and O—prominent angiogenesis—red arrows and insert (LC26-R—12 weeks post-injection) (HE- 40X, insert- 5X digital); P- geographic necrosis with pseudo-palisades (LCAS-R—12 weeks post-injection) (HE— 10X).TU—tumor; P—parenchyma; V—ventricle; CP—choroid plexus; CBL—cerebellum; N—necrosis.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4380339&req=5

pone.0121707.g002: The tumor cells invade the ventricular system.A- Septo-Striatal section, phase contrast (tissue slides, 1X); B- The same Septo-Striatal section: Ki-67 (red) overlay with GFP (green) and DAPI (blue) (LC25-R—8 weeks post-injection) (tissue slides, 1X); C- (LC26-R—12 weeks post-injection), D- (LC35TR-R—12 weeks post-injection), and E- (LCAS-R—12 weeks post-injection)—tumor growing within the parenchyma of the subventricular zone protruding to the ventricle (HE- 5X, 20X and 10X respectively); F- tumor growing within the parenchyma and invading lateral ventricle (LC26-R—12 weeks post-injection) (HE- 5X); G- tumor growing within the parenchyma, Ki-67 staining (LC26-R—12 weeks post-injection) (HE- 20X); H- tumor growing within the ventricular system including forth ventricle and subarachnoid space permeating the cerebellum (LC26-R—12 weeks post-injection) (HE- 5X); I- Tumor growing inside the parenchyma and protruding into the ventricular space. (CM14R - 8 weeks post-injection) (HE- 10X, inserts- 4X digital); J- and K- poorly differentiated neuroblastic tumor with rosette formation (LC26-R—12 weeks post-injection) (HE- 40X), rosettes—orange arrows; L- and N- frequent atypical mitoses—yellow arrows and inserts (LC26-R—12 weeks post-injection) (HE- 40X, inserts- 6X digital); M- tumor perivascular invasion (LCAS-R—12 weeks post-injection) (HE— 40X); N- and O—prominent angiogenesis—red arrows and insert (LC26-R—12 weeks post-injection) (HE- 40X, insert- 5X digital); P- geographic necrosis with pseudo-palisades (LCAS-R—12 weeks post-injection) (HE— 10X).TU—tumor; P—parenchyma; V—ventricle; CP—choroid plexus; CBL—cerebellum; N—necrosis.

Mentions: All RG cell lines exhibit normal karyotypes and express Sox2-, Nestin-, and BLBP (Fig 1). Surprisingly, all RG cell lines, including those derived from the healthy child, the psychiatric patient, and the hESC line, gave rise to tumor masses (Fig 2A and 2B) [12].


A mouse model of human primitive neuroectodermal tumors resulting from microenvironmentally-driven malignant transformation of orthotopically transplanted radial glial cells.

Malchenko S, Sredni ST, Hashimoto H, Kasai A, Nagayasu K, Xie J, Margaryan NV, Seiriki K, Lulla RR, Seftor RE, Pachman LM, Meltzer HY, Hendrix MJ, Soares MB - PLoS ONE (2015)

The tumor cells invade the ventricular system.A- Septo-Striatal section, phase contrast (tissue slides, 1X); B- The same Septo-Striatal section: Ki-67 (red) overlay with GFP (green) and DAPI (blue) (LC25-R—8 weeks post-injection) (tissue slides, 1X); C- (LC26-R—12 weeks post-injection), D- (LC35TR-R—12 weeks post-injection), and E- (LCAS-R—12 weeks post-injection)—tumor growing within the parenchyma of the subventricular zone protruding to the ventricle (HE- 5X, 20X and 10X respectively); F- tumor growing within the parenchyma and invading lateral ventricle (LC26-R—12 weeks post-injection) (HE- 5X); G- tumor growing within the parenchyma, Ki-67 staining (LC26-R—12 weeks post-injection) (HE- 20X); H- tumor growing within the ventricular system including forth ventricle and subarachnoid space permeating the cerebellum (LC26-R—12 weeks post-injection) (HE- 5X); I- Tumor growing inside the parenchyma and protruding into the ventricular space. (CM14R - 8 weeks post-injection) (HE- 10X, inserts- 4X digital); J- and K- poorly differentiated neuroblastic tumor with rosette formation (LC26-R—12 weeks post-injection) (HE- 40X), rosettes—orange arrows; L- and N- frequent atypical mitoses—yellow arrows and inserts (LC26-R—12 weeks post-injection) (HE- 40X, inserts- 6X digital); M- tumor perivascular invasion (LCAS-R—12 weeks post-injection) (HE— 40X); N- and O—prominent angiogenesis—red arrows and insert (LC26-R—12 weeks post-injection) (HE- 40X, insert- 5X digital); P- geographic necrosis with pseudo-palisades (LCAS-R—12 weeks post-injection) (HE— 10X).TU—tumor; P—parenchyma; V—ventricle; CP—choroid plexus; CBL—cerebellum; N—necrosis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380339&req=5

pone.0121707.g002: The tumor cells invade the ventricular system.A- Septo-Striatal section, phase contrast (tissue slides, 1X); B- The same Septo-Striatal section: Ki-67 (red) overlay with GFP (green) and DAPI (blue) (LC25-R—8 weeks post-injection) (tissue slides, 1X); C- (LC26-R—12 weeks post-injection), D- (LC35TR-R—12 weeks post-injection), and E- (LCAS-R—12 weeks post-injection)—tumor growing within the parenchyma of the subventricular zone protruding to the ventricle (HE- 5X, 20X and 10X respectively); F- tumor growing within the parenchyma and invading lateral ventricle (LC26-R—12 weeks post-injection) (HE- 5X); G- tumor growing within the parenchyma, Ki-67 staining (LC26-R—12 weeks post-injection) (HE- 20X); H- tumor growing within the ventricular system including forth ventricle and subarachnoid space permeating the cerebellum (LC26-R—12 weeks post-injection) (HE- 5X); I- Tumor growing inside the parenchyma and protruding into the ventricular space. (CM14R - 8 weeks post-injection) (HE- 10X, inserts- 4X digital); J- and K- poorly differentiated neuroblastic tumor with rosette formation (LC26-R—12 weeks post-injection) (HE- 40X), rosettes—orange arrows; L- and N- frequent atypical mitoses—yellow arrows and inserts (LC26-R—12 weeks post-injection) (HE- 40X, inserts- 6X digital); M- tumor perivascular invasion (LCAS-R—12 weeks post-injection) (HE— 40X); N- and O—prominent angiogenesis—red arrows and insert (LC26-R—12 weeks post-injection) (HE- 40X, insert- 5X digital); P- geographic necrosis with pseudo-palisades (LCAS-R—12 weeks post-injection) (HE— 10X).TU—tumor; P—parenchyma; V—ventricle; CP—choroid plexus; CBL—cerebellum; N—necrosis.
Mentions: All RG cell lines exhibit normal karyotypes and express Sox2-, Nestin-, and BLBP (Fig 1). Surprisingly, all RG cell lines, including those derived from the healthy child, the psychiatric patient, and the hESC line, gave rise to tumor masses (Fig 2A and 2B) [12].

Bottom Line: These results are significant for several reasons.First, they show that malignant transformation of radial glial cells can occur in the absence of specific mutations or inherited genomic alterations.Second, they demonstrate that the same radial glial cells may either give rise to brain tumors or differentiate normally depending upon the microenvironment of the specific region of the brain to which the cells are transplanted.

View Article: PubMed Central - PubMed

Affiliation: Cancer Biology and Epigenomics Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.

ABSTRACT
There is growing evidence and a consensus in the field that most pediatric brain tumors originate from stem cells, of which radial glial cells constitute a subtype. Here we show that orthotopic transplantation of human radial glial (RG) cells to the subventricular zone of the 3rd ventricle--but not to other transplantation sites--of the brain in immunocompromised NOD-SCID mice, gives rise to tumors that have the hallmarks of CNS primitive neuroectodermal tumors (PNETs). The resulting mouse model strikingly recapitulates the phenotype of PNETs. Importantly, the observed tumorigenic transformation was accompanied by aspects of an epithelial to mesenchymal transition (EMT)-like process. It is also noteworthy that the tumors are highly invasive, and that they effectively recruit mouse endothelial cells for angiogenesis. These results are significant for several reasons. First, they show that malignant transformation of radial glial cells can occur in the absence of specific mutations or inherited genomic alterations. Second, they demonstrate that the same radial glial cells may either give rise to brain tumors or differentiate normally depending upon the microenvironment of the specific region of the brain to which the cells are transplanted. In addition to providing a prospect for drug screening and development of new therapeutic strategies, the resulting mouse model of PNETs offers an unprecedented opportunity to identify the cancer driving molecular alterations and the microenvironmental factors that are responsible for committing otherwise normal radial glial cells to a malignant phenotype.

No MeSH data available.


Related in: MedlinePlus