Abstract 503: Investigating the role of Tks5 and invadopodia in prostate tumor progression

Abstract

Much of the morbidity and mortality in prostate cancer patients occurs strictly in response to metastatic disease. While ongoing efforts are examining the therapeutic value of Src kinase inhibitors, the mechanism by which Src activates invasive cell behavior within the context of this disease are not well-understood. Invadopodia are cytoskeletal structures formed by cancer cells that enable binding to, proteolytic degradation of, and invasion through the extracellular matrix. We and others have previously demonstrated that the Src tyrosine kinase substrate and adaptor protein Tks5 is important for invadopodia formation and function. Here we demonstrate that Src is activated and Tks5 up-regulated in prostate tumor specimens and invasive cell lines. Remarkably, overexpression of Tks5 alone is sufficient to form invadopodia structures and enhance invadopodia-associated gelatin degradation and invasion in the LNCaP cell line. We further show that this increase in invasive behavior likely depends on Src kinase activity and Tks5 phosphorylation. Our results predict a role for Src-Tks5 signaling in prostate tumor progression. This hypothesis will be tested in future studies using (i) mouse xenografts to monitor tumor development from Tks5-modified prostate cancer cell lines, and (ii) human prostate tumor tissue sections to measure Tks5 staining relative to tumor grade. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 503. doi:1538-7445.AM2012-503

Evidence for the Possible Biological Significance of the igf-1 Gene Alternative Splicing in Prostate Cancer

“…However, there is also evidence that does not support a causal association between serum IGF-I (or IGFBP-3, discussed below) and the risk of PCa (Woodson et al, 2003), and it was hypothesized that high-grade PCas are more autonomous and less sensitive to the action of IGF-I than low-grade cancers (Nimptsch et al, 2011). Moreover, the results from a recent study, which provides the largest assessment of the role of the IGF system in the development of prostate-specific antigen (PSA)-detected PCa, suggested that circulating IGF-I has a limited role in the development of early PCa but it may remain an important risk factor for disease progression (Rowlands et al, 2012). Furthermore, IGFBP-3 levels have been inversely associated with prostate carcinogenesis and the negative correlation between IGFBP-3 levels and cancer risk is consistent with a protective role of IGFBP-3, i.e., high IGFBP-3 concentrations may lead to reduced IGF-I bioavailability (Koutsilieris et al, 1995; Bogdanos et al, 2003; Papatsoris et al, 2005; Werner and Bruchim, 2009).…”