Axl Expression is a Poor Prognostic Marker and Regulates Tumour Cell Invasion and Migration in Colorectal Cancer

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Abstract

Background
Colorectal cancer (CRC) is the third most common cancer in the UK with around 80% of patients undergoing surgery followed by adjuvant chemotherapy treatment. Among patients with clinicopathologically defined poor stage II and stage III CRC, there are subsets of patients who will not benefit from adjuvant 5-FU or 5-FU/oxaliplatin treatment. The aim of this study was to develop in vitro adjuvant models with the ultimate goal to identify novel treatment strategies for early stage CRC.

Method
Invasive populations were generated using invasion chambers. Analysis of migration and invasion was carried out using the xCELLigence system, protein activity/expression using receptor tyrosine kinase arrays and Western blotting.

Results
Six sublines of HCT116 cells were initially generated (I1-6) which displayed an increasing invasive/migratory phenotype compared to the parental cell line. Colony forming assays highlighted an increased ability to form colonies in the invasive sub-populations. At the molecular level, we found increases in basal activity of Axl and also in other kinases such as STAT3. Decreased activation of the EGFR and HER2 receptors was also noted in the invasive cell lines. In addition, exposure to sub-lethal 5-FU(IC20) doses resulted in significant increases in migration in these cell line models. Targeting of Axl by small molecule inhibitors or RNAi resulted in decreased migration and invasion rates across a panel of cell lines even in the presence of 5-FU. Axl targeting also resulted in reduced signalling via the JAK/STAT pathway. Analysis of a CRC stage II TMA by immunohistochemistry found that high Axl expression correlated with a poor prognosis.

Conclusion
Axl targeting with SMI or RNAi results in ablation of the invasive potential in our model and also in a panel of CRC cell lines. Combination of an Axl small molecule inhibitor could potentially be a novel treatment strategy for early stage CRC.
Original languageEnglish
Title of host publicationAxl Expression is a Poor Prognostic Marker and Regulates Tumour Cell Invasion and Migration in Colorectal Cancer
PublisherNational Cancer Research Institute
Publication statusPublished - Nov 2012

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