Heterozygosity for the neurofibromatosis 1 (NF1) tumor suppressor results in abnormalities in cell attachment, spreading and motility in astrocytes

Abstract

Individuals with the neurofibromatosis 1 (NF1) tumor predisposition syndrome develop low-grade pilocytic astrocytomas at an increased frequency. Previously, we demonstrated that astrocytes from mice heterozygous for a targeted mutation in the Nf1 gene (Nf1+/- astrocytes) exhibit a cell autonomous growth advantage associated with increased RAS pathway activation. In this report, we extend our initial characterization of the effect of reduced Nf1 gene expression on astrocyte function by demonstrating that Nf1+/- astrocytes exhibit decreased cell attachment, actin cytoskeletal abnormalities during the initial phases of cell spreading, and increased cell motility. Whereas these cytoskeletal abnormalities were also observed in Nf1-/- astrocytes, astrocytes expressing a constitutively active RAS molecule showed increased cell motility and abnormal actin cytoskeleton organization during cell spreading, but exhibited normal cell attachment. Based on ongoing gene expression profiling experiments on human astrocytoma tumors, we demonstrate increased expression of two proteins implicated in cell attachment, spreading and motility (GAP43 and T-cadherin) in Nf1+/- and Nf1-/- astrocytes. These results support the emerging notion that tumor suppressor gene heterozygosity results in abnormalities in cell function that may contribute to the pathogenesis of non-tumor phenotypes in NF1.

Comparative Oncogenomics Implicates the Neurofibromin 1 Gene (NF1) as a Breast Cancer Driver

“…However, there is accumulating evidence that haploinsufficiency or reduced expression of tumor suppressor genes can influence carcinogenesis (Berger et al 2011). Indeed heterozygosity for Nf1 causes cancer-like cellular phenotypes in astrocytes (Gutmann et al 1999;Bajenaru et al 2001;Gutmann et al 2001). We note that a recent cancer genome study did not report a high frequency of NF1 CNAs (Curtis et al 2012).…”

Ras Dependent Paracrine Secretion of Osteopontin by Nf1+/− Osteoblasts Promote Osteoclast Activation in a Neurofibromatosis Type I Murine Model

“…In this study, we observed an increased OPN expression in Nf1ϩ/Ϫ osteoblasts and an increased serum level of OPN in Nf1ϩ/Ϫ mice. It has been established that loss of NF1, a GTPase for p21Ras, results in an activation of Ras in a number of lineages (3,10,18,27). The increase in OPN expression in Nf1ϩ/Ϫ mice may be a result of the hyper Ras activity in osteoblasts.…”

Malignant Transformation in Skin is Associated with the Loss of T-Cadherin Expression in Human Keratinocytes and Heterogeneity in T-Cadherin Expression in Tumor Vasculature

“…T-cadherin overexpression was found to be a common feature of human invasive hepatocellular carcinomas (Riou et al, 2006) and high grade astrocytomas, where it was associated with malignant transformation of astrocytes. Hetezygosity for NF1 (neurofibromatosis 1) tumor suppressor resulting in reduced attachment and spreading and increased motility also coincided with upregulated T-cadherin expression (Gutmann et al, 2001).…”