This is supported by our in vitro studies, in which MegaFasL is a potent apoptosis-inducing agent that is even more efficient in combination with imatinib. Acknowledgments This study was supported by personal grants from the http://www.selleckchem.com/products/Tipifarnib(R115777).html Dutch Cancer Society and the Netherlands Organisation for Health Research and Development to Bart Rikhof.
Colorectal cancer (CRC) development from benign precursor lesions, adenomatous polyps, following the accumulation of genetic and epigenetic changes, is one of the best-known examples of multistep carcinogenesis (Vogelstein et al, 1988; Fearon and Vogelstein, 1990; Chung, 2000). Recent evidence also suggests that a permissive tissue microenvironment is critical for the growth potential and spread of tumour cells (Kim et al, 2006; Reuter et al, 2009).

Specifically, tumour development is often driven by chronic inflammation. For example, the development of CRC is linked to the presence of inflammatory bowel disease (Xie and Itzkowitz, 2008). The majority of CRCs display one of two major genomic instability phenotypes, microsatellite instability (MSI) or chromosomal instability with microsatellite stability (MSS; Abdel-Rahman et al, 2001). About 85% of CRC exhibit MSS, aneuploidy, and loss of heterozygosity (LOH). Adenomatous polyposis coli (APC) and beta-catenin mutations are the most common early molecular aberrations in this phenotype category (Kinzler and Vogelstein, 1996; Polakis, 1997). These mutations lead to aberrant Wnt pathway activation, which is thought to initiate colon adenoma formation.

However, second-step activation of KRAS is also needed for adenoma progression to carcinoma (Phelps et al, 2009). The loss of functional APC also induces aneuploidy in vivo after a transient tetraploidy stage (Caldwell et al, 2007), which may enhance fitness of cells containing broken or rearranged chromosomes. We have previously shown that chromosome 12q21 aberrations, specifically allelic loss of the neuron navigator 3 (NAV3) gene, are associated with several subtypes of cutaneous T-cell lymphoma (CTCL; Karenko et al, 2005; Hahtola et al, 2008a), CTCL-associated lung cancers (Hahtola et al, 2008b), and ca. 25% of cutaneous basal and squamous cell cancers (Maliniemi et al, 2011). NAV3 mutations and copy number changes have thereafter been reported in melanoma (Bleeker et al, 2009) and in human glioblastomas, respectively (Nord et al, 2009).

In addition, NAV3 was the only differentially expressed gene in adrenal carcinoma relative to adrenocortical adenomas (Soon et al, 2009). In genomic landscaping, NAV3 Cilengitide belongs to the ��hill type’ candidate cancer gene group, which is commonly mutated in human breast and colon cancer (Wood et al, 2007). We now report that NAV3 copy number changes are found frequently in MSS type CRC, colon adenomas, and established CRC cell lines.