Cancer genetics: mouse models of intestinal cancer

Abstract

The capacity to model cancer within the mouse has advanced significantly in recent years. Perhaps the most notable technical gains have been in the development of techniques that allow the temporal and spatial control of gene expression, so that it is now possible to regulate target genes in the tissue of choice and at a given time [Maddison and Clarke (2005) J. Pathol. 205, 181-193; Shaw and Clarke (2007) DNA Repair 6, 1403-1412; Marsh and Clarke (2007) Expert Rev. Anticancer Ther. 7, 519-531]. We have used these approaches to study tumorigenesis in the murine intestine. Loss of function of the tumour-suppressor gene Apc (adenomatous polyposis coli) has been associated with the development of both human and murine neoplasia, principally those of the intestinal epithelium. However, as Apc has been implicated in multiple cellular functions, the precise mechanisms underlying these associations remain somewhat unclear. I review here the use of an inducible strategy to co-ordinately delete genes from the adult murine epithelium. This approach has allowed a characterization of the direct consequences of inactivation of gene function. For Apc, these include failure in the differentiation programme, failure to migrate, aberrant proliferation and the aberrant induction of apoptosis. Transcriptome analysis of this model has also identified potential new targets for therapeutic intervention, such as Sparc (secreted protein acidic and rich in cysteine), deficiency of which, we have now shown, suppresses adenoma formation. Finally, we have been able to address how other genes modulate the consequences of Apc loss. Thus we show that there is little effect following loss of cyclin D1, Tcf-1 and p53, but that there are marked differences following loss of either c-Myc or Mbd2. The models therefore allow us to define the earliest events associated with carcinogenesis in the intestine.

Characterization and In Vivo Validation of a Three-Dimensional Multi-Cellular Culture Model to Study Heterotypic Interactions in Colorectal Cancer Cell Growth, Invasion and Metastasis

“…The multi-cellular nature of the TME and its multitude of soluble factors contributing to heterotypic communication, the changes in the extracellular matrix and the dynamic evolution of tumor-host complicate the in vivo study of the TME. In addition, animal models are expensive, time consuming, and subjected to higher variability (Heijstek et al, 2005 ; Clarke, 2007 ). Based on these considerations, we set up to develop a 3D heterotypic co-culture model allowing the study of the interactions between cancer cells and cells of the TME.…”

“…Studying heterotypic cellular interaction in vivo is limited due to constrains in accessing the tissue, the simultaneous presence of multiple cell types, and the difficulty in selectively modulating specific cell types or intercellular interactions. In addition, in vivo monitoring requires invasive procedures and time-course experiments necessitate large amounts of animals (Taketo, 2006 ; Clarke, 2007 ; Golovko et al, 2015 ).…”