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FP6

COLORECTAL CANCER Report Summary

Project ID: 6357
Funded under: FP6-MOBILITY
Country: Spain

Final Activity Report Summary - COLORECTAL CANCER (beta-catenin/TCF target gene programs driving intestinal Stem Cell maintenance, colorectal cancer initiation and progression)

The project 'Beta-catenin/TCF target gene programs driving intestinal stem cell maintenance, colorectal cancer initiation and progression' was part of ongoing research carried out by Dr Elena Sancho. The overall goal of this project was to further define the genetic programme controlled by Wnt signalling mutations at the onset of Colorectal cancer (CRC) tumorigenesis and to study how this initial set of instructions was further modulated by the interaction with other signalling pathways during CRC progression. In particular, our research focussed on the role of Transforming growth factor (TGF) beta signalling on CRC progression. The ultimate aim was to identify molecules susceptible of being targeted by the pharmaceutical industry.

The project attempted to compare the genetic programme controlled by Wnt signalling in normal tissue and CRC using two complementary experimental approaches involving microdissected tumour samples as well as CRC cells engineered to block Wnt signalling. Microarray chip analysis of these samples would yield information regarding the differences between normal proliferating progenitors and tumour cells at the onset of tumorigenesis, and changes occurring to this original set of instructions imposed by Wnt signalling mutations during tumour progression. During the initial phases of this study most of our efforts were directed towards the establishment of the necessary collaborations with the pathology departments of Hospital del Mar and Hospital Vall d' Hebron in Barcelona in order to select and obtain CRC patient samples at different stages of the disease, as well as to the optimisation of the involved techniques, such as microdissection and ribonucleic acid (RNA) extraction. At the same time, efforts were placed in gathering 10 CRC cell lines and engineering of derivatives in which Wnt signalling could be blocked by the induction of a dominant negative form of the transcription factor four (TCF4) in the CRC cell lines.

Nevertheless, most of the effort during the European reintegration grant (ERG) was directed towards the study of the interaction and impact of other signalling pathways on Wnt signalling, specifically focussing on the TGF beta pathway. To this end, we restored TGF beta signalling in CRC cell lines that had lost responsiveness and used this cellular model to dissect the effects of TGF beta on CRC cells. Following an extensive characterisation of the model system that we generated, it was clearly shown that TGF beta could override Wnt signalling in terms of CRC proliferation. Microarray chip analysis demonstrated that it also interfered with a specific set of instructions imposed by Wnt signalling mutations, mainly with those specifying proliferative or undifferentiated cells. These results led us to propose that in CRC carcinogenesis TGF beta signals might have counter effects in comparison to Wnt signals, explaining the high incidence of mutations in components of the TGF beta pathway in CRC. A manuscript containing these results was under preparation by the time of the ERG completion.

In addition, the data extracted from the microarray analysis of CRC cells with restored TGF beta signalling was used to study a collection of colorectal adenomas and carcinomas for which there was available microarray information. The genetic profile controlled by TGF beta in our cell system containing no more than 400 genes, the so-called TGF beta signature, clustered this collection of tumours in two perfectly identified branches, one containing only adenomas and one containing only carcinomas. Moreover, a small group of 100 genes within the TGF beta signature was capable of clustering the tumours into two branches adenoma versus carcinoma. These results implied that the difference between a benign adenoma and a potentially fatal carcinoma lay in the TGF beta signature of no more than 100 genes. By the time of the project completion these results were scrutinised in more detail and new animal and in vitro models were developed to carefully dissect the molecules playing an executive role in the adenoma or carcinoma transition.

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