Deciphering the molecular signalling underpinning early-dissemination and metastasis from stage I colorectal cancer


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Philip Dunne1,Maurice Loughrey2,Helen Coleman2,Aoife McCooey2,Susan Richman3,Andrew Blake4,Keara Redmond2,Dion Morton5,Ian Tomlinson5,Simon Leedham4,Rachael McBride2,Jeffrey Campbell2,Tim Maughan4,Mark Lawler2,S:cort Consortium6
1Centre for Cancer Research & Cell Biology Queen's University Belfast, Belfast, UK ,2Queen's University Belfast, Belfast, UK,3University of Leeds, Leeds, UK,4University of Oxford, Oxford, UK,5University of Birmingham, Birmingham, UK,6S:CORT Consortium, Oxford, UK

Abstract

Background

Reduction in colorectal cancer (CRC) mortality will largely involve prevention, earlier detection and treatment optimisation. Bowel cancer screening (BCS), detects asymptomatic tumours much earlier, with stage I CRC (T1/2, N0, M0) now accounting for 48% of BCS-detected tumours, compared to 9% outside screening.

We hypothesise that within early lesions detected by BCS, there are highly aggressive early-disseminating tumours that would otherwise be detected at later stage, but due to BCS they are being caught earlier while potentially curable. We propose that molecular profiling can discriminate between lesions based on their probability of developing lymph node (LN+) and/or distant metastasis (dM+).

Method

To identify factors associated with early-dissemination, we have molecularly profiled a feasibility cohort (n=41) of T1 CRC, enriched for aggressive tumours (N+ and/or dM+ T1’s). Sample collection to expand this cohort to n=300 is ongoing.

Results

Histological factors (including immune/fibroblast content) that are prognostic in stage II/III CRC are not significantly associated with eventual metastatic relapse in T1 CRC. Molecular profiling revealed a significant shift in transcriptional signalling between aggressive and non-aggressive tumours. Intrinsic stem-like biology in combination with stress-response activation and, intriguingly, signalling normally associated with development of Parkinson’s disease is elevated in CRC tissue from aggressive lesions. Preliminary analysis with in vitro and in vivo models of CRC have confirmed the ability of these intrinsic factors to promote early-dissemination and metastatic spread, which reflects the aggressive clinical phenotype.

Conclusion

In order to find any effective treatment you have to first understand the biology underpinning disease. Our data indicates that the ability to undergo early-dissemination, leading to either LN+ or dM+, is established and, most importantly, detectable, even in the earliest pathologically staged T1 tumours. This study may ultimately enable the development of tailored disease management plans for the increasing numbers of early-stage patients being diagnosed as a result of BCS.