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Conditional Inactivation of Pten with EGFR Overexpression in Schwann Cells Models Sporadic MPNST.

Keng VW, Watson AL, Rahrmann EP, Li H, Tschida BR, Moriarity BS, Choi K, Rizvi TA, Collins MH, Wallace MR, Ratner N, Largaespada DA - Sarcoma (2012)

Bottom Line: The genetic mechanisms involved in the transformation from a benign neurofibroma to a malignant sarcoma in patients with neurofibromatosis-type-1- (NF1-)associated or sporadic malignant peripheral nerve sheath tumors (MPNSTs) remain unclear.It is hypothesized that many genetic changes are involved in transformation.We tested if these two genes cooperate in the evolution of PNSTs.

View Article: PubMed Central - PubMed

Affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA ; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA ; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA ; Brain Tumor Program, University of Minnesota, Minneapolis, MN 55455, USA ; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.

ABSTRACT
The genetic mechanisms involved in the transformation from a benign neurofibroma to a malignant sarcoma in patients with neurofibromatosis-type-1- (NF1-)associated or sporadic malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. It is hypothesized that many genetic changes are involved in transformation. Recently, it has been shown that both phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) play important roles in the initiation of peripheral nerve sheath tumors (PNSTs). In human MPNSTs, PTEN expression is often reduced, while EGFR expression is often induced. We tested if these two genes cooperate in the evolution of PNSTs. Transgenic mice were generated carrying conditional floxed alleles of Pten, and EGFR was expressed under the control of the 2',3'-cyclic nucleotide 3'phosphodiesterase (Cnp) promoter and a desert hedgehog (Dhh) regulatory element driving Cre recombinase transgenic mice (Dhh-Cre). Complete loss of Pten and EGFR overexpression in Schwann cells led to the development of high-grade PNSTs. In vitro experiments using immortalized human Schwann cells demonstrated that loss of PTEN and overexpression of EGFR cooperate to increase cellular proliferation and anchorage-independent colony formation. This mouse model can rapidly recapitulate PNST onset and progression to high-grade PNSTs, as seen in sporadic MPNST patients.

No MeSH data available.


Related in: MedlinePlus

Expression microarray analysis of PTEN and EGFR in human peripheral nerve tumors. (a) Purified human Schwann cells from normal sciatic nerve (N-SC), dermal neurofibroma cell lines (dNF-SC), and plexiform neurofibroma cell lines (pNF-SC). Transformed cells from malignant peripheral nerve sheath cell lines (MPNST-C). Asterisks indicate sporadic MPNST samples. (b) Solid dermal neurofibromas (dNF), plexiform neurofibromas (pNF), and malignant peripheral nerve sheath tumors (MPNST). Four different probes for EGFR were used. Red, increase in red intensity as expression increases; Blue, increase in blue intensity as expression decreases. (c) Conditional inactivation of Pten and EGFR overexpression in Schwann cells resulted in high-grade PNST initiation and/or progression due to the upregulation of both Ras/Mapk/Erk and Pi3k/Akt/mTor signaling pathways (right). Inactivation of Pten alone resulted in reduced latency with low-grade PNST tumorigenesis at low penetrance (middle). Conditional inactivation of Pten alone can result in low-grade PNST tumorigenesis via the upregulation of the Pi3k/Akt/mTor signaling pathway. Partial conditional inactivation of Pten in the context of EGFR overexpression in Schwann cells resulted in prolonged latency with hyperplasia to low-grade PNST tumorigenesis at low penetrance (left), resulting in upregulation of Ras/Mapk/Erk and slight upregulation of the Pi3k/Akt/mTor signaling pathways. SOS1: son of sevenless homolog 1; GRB2: growth factor receptor-bound protein 2; IRS2: insulin receptor substrate 2; Dhh-Cre; Ptenflox/flox; EGFR (ΔPten/C-EGFR), Dhh-Cre; Ptenflox/+; EGFR (Pten-het/C-EGFR) and Dhh-Cre; Ptenflox/flox (ΔPten) animals.
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fig4: Expression microarray analysis of PTEN and EGFR in human peripheral nerve tumors. (a) Purified human Schwann cells from normal sciatic nerve (N-SC), dermal neurofibroma cell lines (dNF-SC), and plexiform neurofibroma cell lines (pNF-SC). Transformed cells from malignant peripheral nerve sheath cell lines (MPNST-C). Asterisks indicate sporadic MPNST samples. (b) Solid dermal neurofibromas (dNF), plexiform neurofibromas (pNF), and malignant peripheral nerve sheath tumors (MPNST). Four different probes for EGFR were used. Red, increase in red intensity as expression increases; Blue, increase in blue intensity as expression decreases. (c) Conditional inactivation of Pten and EGFR overexpression in Schwann cells resulted in high-grade PNST initiation and/or progression due to the upregulation of both Ras/Mapk/Erk and Pi3k/Akt/mTor signaling pathways (right). Inactivation of Pten alone resulted in reduced latency with low-grade PNST tumorigenesis at low penetrance (middle). Conditional inactivation of Pten alone can result in low-grade PNST tumorigenesis via the upregulation of the Pi3k/Akt/mTor signaling pathway. Partial conditional inactivation of Pten in the context of EGFR overexpression in Schwann cells resulted in prolonged latency with hyperplasia to low-grade PNST tumorigenesis at low penetrance (left), resulting in upregulation of Ras/Mapk/Erk and slight upregulation of the Pi3k/Akt/mTor signaling pathways. SOS1: son of sevenless homolog 1; GRB2: growth factor receptor-bound protein 2; IRS2: insulin receptor substrate 2; Dhh-Cre; Ptenflox/flox; EGFR (ΔPten/C-EGFR), Dhh-Cre; Ptenflox/+; EGFR (Pten-het/C-EGFR) and Dhh-Cre; Ptenflox/flox (ΔPten) animals.

Mentions: Both PTEN and EGFR levels in purified Schwann cells taken from human peripheral nerve and neurofibroma cells; transformed cells taken from MPNST cell lines (Figure 4(a)) and solid tumors (Figure 4(b)) at various stages of disease were analyzed by microarray gene expression analysis.


Conditional Inactivation of Pten with EGFR Overexpression in Schwann Cells Models Sporadic MPNST.

Keng VW, Watson AL, Rahrmann EP, Li H, Tschida BR, Moriarity BS, Choi K, Rizvi TA, Collins MH, Wallace MR, Ratner N, Largaespada DA - Sarcoma (2012)

Expression microarray analysis of PTEN and EGFR in human peripheral nerve tumors. (a) Purified human Schwann cells from normal sciatic nerve (N-SC), dermal neurofibroma cell lines (dNF-SC), and plexiform neurofibroma cell lines (pNF-SC). Transformed cells from malignant peripheral nerve sheath cell lines (MPNST-C). Asterisks indicate sporadic MPNST samples. (b) Solid dermal neurofibromas (dNF), plexiform neurofibromas (pNF), and malignant peripheral nerve sheath tumors (MPNST). Four different probes for EGFR were used. Red, increase in red intensity as expression increases; Blue, increase in blue intensity as expression decreases. (c) Conditional inactivation of Pten and EGFR overexpression in Schwann cells resulted in high-grade PNST initiation and/or progression due to the upregulation of both Ras/Mapk/Erk and Pi3k/Akt/mTor signaling pathways (right). Inactivation of Pten alone resulted in reduced latency with low-grade PNST tumorigenesis at low penetrance (middle). Conditional inactivation of Pten alone can result in low-grade PNST tumorigenesis via the upregulation of the Pi3k/Akt/mTor signaling pathway. Partial conditional inactivation of Pten in the context of EGFR overexpression in Schwann cells resulted in prolonged latency with hyperplasia to low-grade PNST tumorigenesis at low penetrance (left), resulting in upregulation of Ras/Mapk/Erk and slight upregulation of the Pi3k/Akt/mTor signaling pathways. SOS1: son of sevenless homolog 1; GRB2: growth factor receptor-bound protein 2; IRS2: insulin receptor substrate 2; Dhh-Cre; Ptenflox/flox; EGFR (ΔPten/C-EGFR), Dhh-Cre; Ptenflox/+; EGFR (Pten-het/C-EGFR) and Dhh-Cre; Ptenflox/flox (ΔPten) animals.
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Related In: Results  -  Collection

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fig4: Expression microarray analysis of PTEN and EGFR in human peripheral nerve tumors. (a) Purified human Schwann cells from normal sciatic nerve (N-SC), dermal neurofibroma cell lines (dNF-SC), and plexiform neurofibroma cell lines (pNF-SC). Transformed cells from malignant peripheral nerve sheath cell lines (MPNST-C). Asterisks indicate sporadic MPNST samples. (b) Solid dermal neurofibromas (dNF), plexiform neurofibromas (pNF), and malignant peripheral nerve sheath tumors (MPNST). Four different probes for EGFR were used. Red, increase in red intensity as expression increases; Blue, increase in blue intensity as expression decreases. (c) Conditional inactivation of Pten and EGFR overexpression in Schwann cells resulted in high-grade PNST initiation and/or progression due to the upregulation of both Ras/Mapk/Erk and Pi3k/Akt/mTor signaling pathways (right). Inactivation of Pten alone resulted in reduced latency with low-grade PNST tumorigenesis at low penetrance (middle). Conditional inactivation of Pten alone can result in low-grade PNST tumorigenesis via the upregulation of the Pi3k/Akt/mTor signaling pathway. Partial conditional inactivation of Pten in the context of EGFR overexpression in Schwann cells resulted in prolonged latency with hyperplasia to low-grade PNST tumorigenesis at low penetrance (left), resulting in upregulation of Ras/Mapk/Erk and slight upregulation of the Pi3k/Akt/mTor signaling pathways. SOS1: son of sevenless homolog 1; GRB2: growth factor receptor-bound protein 2; IRS2: insulin receptor substrate 2; Dhh-Cre; Ptenflox/flox; EGFR (ΔPten/C-EGFR), Dhh-Cre; Ptenflox/+; EGFR (Pten-het/C-EGFR) and Dhh-Cre; Ptenflox/flox (ΔPten) animals.
Mentions: Both PTEN and EGFR levels in purified Schwann cells taken from human peripheral nerve and neurofibroma cells; transformed cells taken from MPNST cell lines (Figure 4(a)) and solid tumors (Figure 4(b)) at various stages of disease were analyzed by microarray gene expression analysis.

Bottom Line: The genetic mechanisms involved in the transformation from a benign neurofibroma to a malignant sarcoma in patients with neurofibromatosis-type-1- (NF1-)associated or sporadic malignant peripheral nerve sheath tumors (MPNSTs) remain unclear.It is hypothesized that many genetic changes are involved in transformation.We tested if these two genes cooperate in the evolution of PNSTs.

View Article: PubMed Central - PubMed

Affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA ; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA ; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA ; Brain Tumor Program, University of Minnesota, Minneapolis, MN 55455, USA ; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.

ABSTRACT
The genetic mechanisms involved in the transformation from a benign neurofibroma to a malignant sarcoma in patients with neurofibromatosis-type-1- (NF1-)associated or sporadic malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. It is hypothesized that many genetic changes are involved in transformation. Recently, it has been shown that both phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) play important roles in the initiation of peripheral nerve sheath tumors (PNSTs). In human MPNSTs, PTEN expression is often reduced, while EGFR expression is often induced. We tested if these two genes cooperate in the evolution of PNSTs. Transgenic mice were generated carrying conditional floxed alleles of Pten, and EGFR was expressed under the control of the 2',3'-cyclic nucleotide 3'phosphodiesterase (Cnp) promoter and a desert hedgehog (Dhh) regulatory element driving Cre recombinase transgenic mice (Dhh-Cre). Complete loss of Pten and EGFR overexpression in Schwann cells led to the development of high-grade PNSTs. In vitro experiments using immortalized human Schwann cells demonstrated that loss of PTEN and overexpression of EGFR cooperate to increase cellular proliferation and anchorage-independent colony formation. This mouse model can rapidly recapitulate PNST onset and progression to high-grade PNSTs, as seen in sporadic MPNST patients.

No MeSH data available.


Related in: MedlinePlus