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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

Pten dosage with EGFR overexpression affected enlarged dorsal root ganglia tumor multiplicity. (a) Left: representative of an early-onset peripheral nervous system phenotype observed in a 38-day Dhh-Cre; Ptenflox/flox; Cnp-EGFR (ΔPten/C-EGFR) experimental mouse. Brachial plexus: majority of the dorsal root ganglia and trigeminal nerves were enlarged. Middle: representative of a late-onset peripheral nervous system phenotype observed in a 104-day Dhh-Cre; Ptenflox/flox (ΔPten) control mouse. Brachial plexus: several dorsal root ganglia and trigeminal nerves were enlarged. Right: representative of a late-onset peripheral nervous system phenotype observed in a 274-day Dhh-Cre; Ptenflox/+; Cnp-EGFR (Pten-het/C-EGFR) control mouse. Brachial plexus: several dorsal root ganglia and trigeminal nerves were enlarged. Top panels: brachial plexi; middle panels: dorsal root ganglia; bottom panels: brain with trigeminal nerves; arrows indicate peripheral nervous system phenotype; scale bars, 2 mm. (b) Statistically significant differences in the number of enlarged dorsal root ganglia isolated from ΔPten/C-EGFR experimental cohort compared with control cohorts (ΔPten and Pten-het/C-EGFR). Mean ± standard deviation; P: unpaired t-test; n: number of mice evaluated in each cohort; N.S.: nonsignificant.
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fig2: Pten dosage with EGFR overexpression affected enlarged dorsal root ganglia tumor multiplicity. (a) Left: representative of an early-onset peripheral nervous system phenotype observed in a 38-day Dhh-Cre; Ptenflox/flox; Cnp-EGFR (ΔPten/C-EGFR) experimental mouse. Brachial plexus: majority of the dorsal root ganglia and trigeminal nerves were enlarged. Middle: representative of a late-onset peripheral nervous system phenotype observed in a 104-day Dhh-Cre; Ptenflox/flox (ΔPten) control mouse. Brachial plexus: several dorsal root ganglia and trigeminal nerves were enlarged. Right: representative of a late-onset peripheral nervous system phenotype observed in a 274-day Dhh-Cre; Ptenflox/+; Cnp-EGFR (Pten-het/C-EGFR) control mouse. Brachial plexus: several dorsal root ganglia and trigeminal nerves were enlarged. Top panels: brachial plexi; middle panels: dorsal root ganglia; bottom panels: brain with trigeminal nerves; arrows indicate peripheral nervous system phenotype; scale bars, 2 mm. (b) Statistically significant differences in the number of enlarged dorsal root ganglia isolated from ΔPten/C-EGFR experimental cohort compared with control cohorts (ΔPten and Pten-het/C-EGFR). Mean ± standard deviation; P: unpaired t-test; n: number of mice evaluated in each cohort; N.S.: nonsignificant.

Mentions: ΔPten/C-EGFR experimental animals displayed multiple enlarged dorsal root ganglia and enlarged peripheral nerves: brachial plexi, sacral plexi, trigeminal and sciatic nerves (Figure 2(a), left and Table 1). ΔPten control animals displayed a similar peripheral nervous system phenotype but with delayed latency and at a significantly reduced tumor multiplicity (Figure 2(a), middle and Table 1). Pten-het/C-EGFR animals displayed a similar peripheral nervous system phenotype with ΔPten control animals but with a latency of 415 days (Figure 2(a), right). The enlargement of peripheral nerves and dorsal root ganglia has been described for C-EGFR [13].


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)

Pten dosage with EGFR overexpression affected enlarged dorsal root ganglia tumor multiplicity. (a) Left: representative of an early-onset peripheral nervous system phenotype observed in a 38-day Dhh-Cre; Ptenflox/flox; Cnp-EGFR (ΔPten/C-EGFR) experimental mouse. Brachial plexus: majority of the dorsal root ganglia and trigeminal nerves were enlarged. Middle: representative of a late-onset peripheral nervous system phenotype observed in a 104-day Dhh-Cre; Ptenflox/flox (ΔPten) control mouse. Brachial plexus: several dorsal root ganglia and trigeminal nerves were enlarged. Right: representative of a late-onset peripheral nervous system phenotype observed in a 274-day Dhh-Cre; Ptenflox/+; Cnp-EGFR (Pten-het/C-EGFR) control mouse. Brachial plexus: several dorsal root ganglia and trigeminal nerves were enlarged. Top panels: brachial plexi; middle panels: dorsal root ganglia; bottom panels: brain with trigeminal nerves; arrows indicate peripheral nervous system phenotype; scale bars, 2 mm. (b) Statistically significant differences in the number of enlarged dorsal root ganglia isolated from ΔPten/C-EGFR experimental cohort compared with control cohorts (ΔPten and Pten-het/C-EGFR). Mean ± standard deviation; P: unpaired t-test; n: number of mice evaluated in each cohort; N.S.: nonsignificant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Pten dosage with EGFR overexpression affected enlarged dorsal root ganglia tumor multiplicity. (a) Left: representative of an early-onset peripheral nervous system phenotype observed in a 38-day Dhh-Cre; Ptenflox/flox; Cnp-EGFR (ΔPten/C-EGFR) experimental mouse. Brachial plexus: majority of the dorsal root ganglia and trigeminal nerves were enlarged. Middle: representative of a late-onset peripheral nervous system phenotype observed in a 104-day Dhh-Cre; Ptenflox/flox (ΔPten) control mouse. Brachial plexus: several dorsal root ganglia and trigeminal nerves were enlarged. Right: representative of a late-onset peripheral nervous system phenotype observed in a 274-day Dhh-Cre; Ptenflox/+; Cnp-EGFR (Pten-het/C-EGFR) control mouse. Brachial plexus: several dorsal root ganglia and trigeminal nerves were enlarged. Top panels: brachial plexi; middle panels: dorsal root ganglia; bottom panels: brain with trigeminal nerves; arrows indicate peripheral nervous system phenotype; scale bars, 2 mm. (b) Statistically significant differences in the number of enlarged dorsal root ganglia isolated from ΔPten/C-EGFR experimental cohort compared with control cohorts (ΔPten and Pten-het/C-EGFR). Mean ± standard deviation; P: unpaired t-test; n: number of mice evaluated in each cohort; N.S.: nonsignificant.
Mentions: ΔPten/C-EGFR experimental animals displayed multiple enlarged dorsal root ganglia and enlarged peripheral nerves: brachial plexi, sacral plexi, trigeminal and sciatic nerves (Figure 2(a), left and Table 1). ΔPten control animals displayed a similar peripheral nervous system phenotype but with delayed latency and at a significantly reduced tumor multiplicity (Figure 2(a), middle and Table 1). Pten-het/C-EGFR animals displayed a similar peripheral nervous system phenotype with ΔPten control animals but with a latency of 415 days (Figure 2(a), right). The enlargement of peripheral nerves and dorsal root ganglia has been described for C-EGFR [13].

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