[Show abstract][Hide abstract] ABSTRACT: Metastasizing tumor cells undergo a transformation that resembles a process in normal development when non-migratory epithelial cells modulate the expression of cytoskeletal and adhesion proteins to promote cell motility. Here we find a mesenchymal cadherin, Cadherin-11 (CDH11), is increased in cells exiting the ventricular zone (VZ) neuroepithelium during normal cerebral cortical development. When overexpressed in cortical progenitors in vivo, CDH11 causes premature exit from the neuroepithelium and increased cell migration. CDH11 expression is elevated in human brain tumors, correlating with higher tumor grade and decreased patient survival. In glioblastoma, CDH11-expressing tumor cells can be found localized near tumor vasculature. Endothelial cells stimulate TGFβ signaling and CDH11 expression in glioblastoma cells. TGFβ promotes glioblastoma cell motility, and knockdown of CDH11 expression in primary human glioblastoma cells inhibits TGFβ-stimulated migration. Together, these findings show that Cadherin-11 can promote cell migration in neural precursors and glioblastoma cells and suggest that endothelial cells increase tumor aggressiveness by co-opting mechanisms that regulate normal neural development.
PLoS ONE 01/2013; 8(8):e70962. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acquired resistance to tyrosine kinase inhibitors (TKIs) in the treatment of chronic myelogenous leukemia (CML) is frequently caused by point mutations in the ABL kinase domain of the BCR-ABL fusion gene. The T315I mutation is the most common mutation found in the kinase domain and leads to complete resistance to existing TKIs. Sensitive and specific approaches for detecting this mutation in patient specimens can provide valuable information to guide treatment decisions and monitor their effectiveness. Here, we describe an allele-specific real-time polymerase chain reaction method to distinguish and quantify wild type or T315I mutant ABL transcripts. This approach has high specificity in identifying mutant transcripts and shows minimal interference from wild-type transcripts. As few as 5 copies of the T315I mutant transcript or 0.025% (2.5×10(-4)) T315I mutant transcripts could be detected by this method. This approach requires no additional specialized reagents other than those used in standard real-time polymerase chain reaction and therefore may be easily incorporated as an effective strategy for the early detection and monitoring of TKI resistance in patients with CML.
Diagnostic molecular pathology: the American journal of surgical pathology, part B 03/2012; 21(1):34-9. · 1.58 Impact Factor