The receptor tyrosine kinase/PI3K/Akt/mammalian target of rapamycin (RTK/PI3K/Akt/mTOR) pathway is frequently altered in tumors. Inactivating mutations of either the TSC1 or the TSC2 tumor-suppressor genes cause tuberous sclerosis complex (TSC), a benign tumor syndrome in which there is both hyperactivation of mTOR and inhibition of RTK/PI3K/Akt signaling, partially due to reduced PDGFR expression. We report here that activation of PI3K or Akt, or deletion of phosphatase and tensin homolog (PTEN) in mouse embryonic fibroblasts (MEFs) also suppresses PDGFR expression. This was a direct effect of mTOR activation, since rapamycin restored PDGFR expression and PDGF-sensitive Akt activation in Tsc1 -/-and Tsc2 -/-cells. Akt activation in response to EGF in

The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated but not in well-differentiated human breast cancers. Both human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors with hyperactive mTOR due to tumor suppressor TSC1 or TSC2 deficiency exhibited enhanced STAT3/p63/Notch signaling. Furthermore, tumorigenic potential of cells with uncontrolled mTOR signaling was suppressed by Notch inhibition. Our data therefore suggest that perturbation of cell differentiation by augmented Notch signaling might be responsible for the underdifferentiated phenotype displayed by certain tumors with an aberrantly activated RTK/PI3K/AKT/mTOR pathway. Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling.

Extracranial metastasis is a unique but rare manifestation of glioblastoma multiforme. It is thought to arise from glioblastoma cells disseminated into the blood stream. We undertook a comprehensive analysis of 88 cases of extracranial glioblastoma (5 were gliosarcomas) published between 1928 and 2009. Cases included in the analysis were primary or secondary glioblastomas that subsequently invaded organs outside the brain or spinal cord. The median age was 38 years and the median overall survival time was 10.5 months (range 0.0-60.0 months). The median time from symptom onset to diagnosis of primary glioblastoma was 2.5 months, from diagnosis to detection of extracranial metastasis was 8.5 months, and from metastasis to death was 1.5 months. From 1940 to 2009, there has been progressive lengthening of the interval from detection of extracranial metastasis to death, at a rate of 0.7 months per decade (95% confidence interval 0.5-1.0 month). Use of magnetic resonance imaging correlates with an increase in overall survival but not age, gender, or site of primary glioblastoma. Patients treated with surgery + radiation + chemotherapy + cerebrospinal fluid shunting had the longest average survival interval from metastasis to death when compared to those treated with surgery alone, radiation alone, surgery + radiation, and surgery + radiation + chemotherapy. Lung metastasis is a prognostic factor of extremely poor outcomes. We conclude that patients with glioblastoma extracranial metastasis have poor prognosis, but there has been a progressive lengthening of survival in each successive decade from 1940 to 2000.

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