Application of advances in molecular biology to the treatment of brain tumors
ABSTRACT Recent advances in molecular biology have substantially improved our understanding of the molecular genetics of primary brain
neoplasms. Soon each histopathologic category of glioma will be further divided into subgroups according to similar genetic
background, gene expression profile, and similarity of biologic responses to radiotherapy or chemotherapy. Identification
of key molecules that are specifically altered in neoplastic cells will provide candidate molecular targets for tumor treatment.
Novel therapeutic tools for targeting tumor cells, such as viral vectors for gene therapy, have been created. In the near
future, the accumulation of new knowledge in brain tumor biology and genetics, combined with rational drug design, will revolutionize
the treatment of malignant gliomas, which are among the most lethal human cancers.
- [Show abstract] [Hide abstract]
ABSTRACT: Aberrant PDGF-PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR-β activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR-β and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR-β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT. Moreover, PDK1 interacted with ACK1 during PDGF stimulation, which is required for the binding of ACK1 to PDGFR-β. Further mutational analysis showed that T325 of ACK1 was crucial for the ACK1 and PDK1 interaction. ACK1 Y635F or T325A mutants abolished PDGFR-β-induced AKT activation, the subsequent nuclear translocation of β-catenin and the expression of cyclin D1. Glioma cell cycle progression, proliferation, and tumorigenesis were accordingly blocked by ACK1 Y635F or T325A. In glioblastoma multiforme samples from 51 patients, increased ACK1 tyrosine phosphorylation correlated with upregulated PDGFR-β activity and AKT activation. Taken together, our data demonstrate that ACK1 plays a pivotal role in PDGF-PDGFR-induced AKT signaling in glioma tumorigenesis. This knowledge contributes to our understanding of glioma progression and may facilitate the identification of novel therapeutic targets for future glioma treatment. © 2014 Wiley Periodicals, Inc.International Journal of Cancer 04/2015; 136(8). DOI:10.1002/ijc.29234 · 5.01 Impact Factor
- Supplements to Clinical neurophysiology 02/2006; 59:61-6. DOI:10.1016/S1567-424X(09)70013-3
- [Show abstract] [Hide abstract]
ABSTRACT: Molecular anatomic pathology represents the blend of traditional morphological methods and the multigene approach to determine cancer-related gene alterations for diagnostic and prognostic purposes. Microdissection genotyping was utilized to characterize 197 gliomas with targeted microdissection of 2–7 areas spanning the spectrum of histologic types and grades. The methodology described herein is complementary to the existing realities of pathology practice. The technique utilizes paraffin-embedded fixative-treated tissue of small sample size after the primary morphological examination by the pathologist. Molecular information derived from microdissection genotyping in combination with the traditional histological information, results in an enhanced understanding of glioma formation and biological progression leading to improvements in diagnosis and prediction of prognosis. In all, 100% or 32 of 32 cases with at least partial treatment response was observed in neoplasms possessing the 1p or 1p/19q loss. The 19q loss alone without coexisting 1p showed no improvement in treatment response. Gliomas lacking 1p loss with only allelic loss involving 3p, 5q, 9p, 10q and 17p showed unfavorable outcome of only 35%, or six of 17 cases with treatment response. In addition, the determination of fractional allelic loss (favorable/unfavorable), was a very good independent predictor of biological behavior. These findings emphasize the importance of determining the cumulative pattern of mutational damage on 16 distinct sites or more, especially in the presence of 1p loss which in isolation or in combination with 19q is a favorable prognostic factor for therapeutic response.Keywords: microdissection genotyping, molecular anatomic pathology, glioma, loss of heterozygosity, fractional allelic loss, 1p/19qModern Pathology 06/2004; 17(11):1346-1358. DOI:10.1038/modpathol.3800194 · 6.36 Impact Factor