SAGE and MPSS profiling of stroma to identify regulators of prostate development and tumourigenesis


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Brigid Orr1, Griet Vanpoucke1, Oliver Grace1, Raymond Chan1, George Ashley1, Karin Williams2, Omar Franco2, Simon Hayward2, Richard Anderson1, Axel Thomson1

1Medical Research Council, Edinburgh, Lothian, UK, 2Vanderbilt University, Nashville, USA

Abstract

Introduction

Stromal cells and the microenvironment play key roles in prostate cancer initiation and progression and cancer associated fibroblasts stimulate tumourigenesis. Similarly, the stroma controls organogenesis, and embryonic stroma (mesenchyme) can re-differentiate prostate tumours. It is clear that epithelia are regulated by powerful juxtacrine/paracrine signaling from the stroma, in both development and disease.

Methods

We have applied SAGE and MPSS gene profiling to prostatic developmental and tumour stroma to identify signalling pathways active in the stroma. Our focus has been on developmental pathways that function as extracellular signals which regulate organ growth and differentiation. These are frequently mis-expressed in prostate cancer.

Results

Comparative statistical analyses of the gene profiling libraries has identified genes that show significantly different (P<0.05) expression levels in embryonic, and normal adult and cancer stroma. One of the molecules we have identified is Scube1, which is expressed in embryonic mesenchyme and appears downregulated in cancer associated fibroblasts. Scube1 is located at chromosome 22q13 which is often lost during prostate cancer progression. Further molecules and signalling pathways identified are being followed up; we are investigating mRNA and protein expression, and functional activity in the cancer microenvironment.

Conclusion

The stroma is an attractive target for future therapies as it may be more genetically stable than epithelial tumour cells. Stromal signaling is likely to act early in tumour evolution and may be involved in tumour initiation, thus the stroma is a promising target for chemoprevention.

Introduction

Stromal cells and the microenvironment play key roles in prostate cancer initiation and progression and cancer associated fibroblasts stimulate tumourigenesis. Similarly, the stroma controls organogenesis, and embryonic stroma (mesenchyme) can re-differentiate prostate tumours. It is clear that epithelia are regulated by powerful juxtacrine/paracrine signaling from the stroma, in both development and disease.

Methods

We have applied SAGE and MPSS gene profiling to prostatic developmental and tumour stroma to identify signalling pathways active in the stroma. Our focus has been on developmental pathways that function as extracellular signals which regulate organ growth and differentiation. These are frequently mis-expressed in prostate cancer.

Results

Comparative statistical analyses of the gene profiling libraries has identified genes that show significantly different (P<0.05) expression levels in embryonic, and normal adult and cancer stroma. One of the molecules we have identified is Scube1, which is expressed in embryonic mesenchyme and appears downregulated in cancer associated fibroblasts. Scube1 is located at chromosome 22q13 which is often lost during prostate cancer progression. Further molecules and signalling pathways identified are being followed up; we are investigating mRNA and protein expression, and functional activity in the cancer microenvironment.

Conclusion

The stroma is an attractive target for future therapies as it may be more genetically stable than epithelial tumour cells. Stromal signaling is likely to act early in tumour evolution and may be involved in tumour initiation, thus the stroma is a promising target for chemoprevention.

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