Abstract 3444: The role of p75ntr and TIMP-1 in U251 malignant glioma cells

Abstract

Abstract The neurotrophin receptor p75NTR and trk receptors play an important role in the diverse functions of neurotrophins in the CNS. These include survival, differentiation, neurite outgrowth and development in the nervous system. More recently, an emerging role for the p75NTR has been described in tumor biology, both within the nervous system as well as in non-nervous system neoplasms. Investigative studies in vitro and in vivo have identified both tumor promoting and tumor inhibitory functions of p75NTR, related to specific tumor types. p75NTR has been implicated as a tumor and metastasis suppressor gene and in promoting apoptosis, particularly within the prostate. It has been suggested that p75NTR interactions in the microenvironment result in decreasing MMP2 and MMP9, with a concomitant increase in TIMP1 expression. These have a negative effect on tumor kinetics. However, these tumor promoting and tumor inhibitory functions of p75NTR have been reported in context of specific tumor types. Previously, we have shown that over-expressing TIMP1 in H2009, a lung adenocarcinoma cell line resulted in decreased expression of p75NTR in the clone HB1 compared to H2009. This clone was found to be more aggressive in both in vitro and in vivo studies. Extending these studies to glial neoplasms we sought to define a role of TIMP1in the modulation of p75NTR activities. To this end, we over-expressed TIMP1 in U251 glioma cell line. The resulting stable clones expressed decreased levels of p75 RNA and again behaved more aggressively in vitro with increased tumorigenicity and angiogenesis as evidenced by enhanced colony formation in soft agar as well as increased capillary network formation on Matrigel when serum-free conditioned media was used from the clone compared to parental U251 cell line. We have utilized p75 siRNA to knockdown the levels of p75NTR in U251 glioma cell line. Stable clones expressing reduced levels of p75 showed an increase in the number as well as the size of colonies in soft agar assay compared to the parental cell line suggesting increased tumorigenicity. Collectively our studies appear to define a tumor suppressor function for p75NTR. Additional studies are ongoing to further define the role of p75NTR and TIMP1. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3444.