The human tumour micro-environment modelled in in vitro biomatrices and applied to cancer drug discovery


Session type:

Teresa Coughlan1, Suzanne Underwood1, Phil Clarke1, Elizabeth Whelband1, Richard Argent1, Anna Grabowska1, Snow Stolnik2, Brett Hall3, Rajendra Kumari1, Sue Watson1
1Division of Pre-Clinical Oncology, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom,2School of Pharmacy, University Of Nottingham, Nottingham, United Kingdom,3OrthoBiotech, Oncology Research & Development, Beerse, Belgium


The importance of the micro-environment in supporting tumour growth is becoming increasingly apparent. Classical murine models used to study tumour development may not mimic the human micro-environment well, since the tumours become infiltrated with mouse stromal cells; this may prevent modelling of certain key paracrine ligand-receptor interactions important for cancer development, such as HGF/c-met, since the human receptor does not recognise the mouse ligand.


We have used novel 3-D cell-culture biomatrix models of human colorectal tumours such as those made by polyelectrolyte complexation (PEC) or cell suspension in basal membrane extract to develop authentic representations of tumour tissue. We have used fluorescent and bioluminescent reporter genes, in order to label and thus track specific tumour cell types such as epithelial cells and fibroblasts throughout formation and growth of these 3-D models.


We have shown that these models are highly reproducible and that cells grown in this way behave more as they do in vivo than is the case for growth in standard 2-D plastic vessels, with regard to epithelial cell shape/polarity, cell-cell adhesions and molecular profile. In addition, 3-D models faithfully replicate tumour conditions such as hypoxia, epithelial-to-mesenchymal transition (EMT) and anti-cancer drug resistance.


Reporter genes driven by constitutive and inducible promoters enable tracking of individual cell populations and provide a real-time read-out for cell proliferation, hypoxia, EMT and apoptosis in complex 3D models. Ultimately, the models will provide systems for screening of new drugs that specifically target the tumour microenvironment.