Investigation of the role of mesoderm inducing genes in a cell culture model for the progression of colorectal cancer

Abstract

Cancer stem cells (CSC) are initiating cells in many cancer types that have
similar prope1ties like normal embryonic stem cells. Colorectal tumours can undergo epithelial to mesenchymal transition (EMT)-like processes at the invasive front, rendering them capable of invasion and metastasis. Recently, a possible link between cells undergoing EMT and cells with stem cell like properties has been identified in mammary Cancer stem cells (CSC). It is of fundamental importance to understand molecular events leading to establishment and maintenance of cancer initiating cells and how these relate to cellular transitions during tumourigenesis. However it is difficult to observe these processes in vivo, not least due to the transient nature of events during tumourigenesis.
We used an in vitro system to recapitulate changes occuring in CRC cells at
the invasive front (mesenchymal-like cells) and central mass (epithelial-like cells) of tumours. We show for the first time, that the mesoderm inducer BRACHYURY
differentially influences expression of the pluripotency gene NANOG, through
association of BRACHYURY with upstream regulatory e lements in the NANOG
promoter in CRC cells. Binding ofBRACHYURY to the NANOG promoter directly
influences expression of NANOG and is predominant in mesenchymal-like cancer
cells. We also demonstrate that the oncogene, ~-catenin is upstream of both
BRACHYURY and NANOG and influences the expression of markers of CSCs in the
mesenchymal-like cells, whose presence has previously been linked to poor patient prognosis. Finally, we show that a similar pathway exists in two other cell lines (NTERA-2 and T84).

Date of Award	May 2010
Original language	English
Awarding Institution	Bangor University
Sponsors	Tenovus Cancer Researc & Gwynedd Haematology and Cancer Research Fund