Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Cathepsin D is required for tumour stroma development. (#165)

Floriane M Imhoff 1 , Chloe Squires 1 , Mitchell Clarke 1 , Sarah K Baird 1
  1. University of Otago, Dunedin, Otago, New Zealand

Formation of tumour stroma involves the migration and homing of bone marrow mesenchymal stem cells (MSCs) to the tumour site1. The migratory process requires proteolysis of the extracellular matrix to allow MSCs to exit the bloodstream and reach the tumour2. Cathepsin D is the most widely expressed member of the aspartic acid protease family and is upregulated in invasive breast cancer cells. It has therefore been indirectly linked to an increase in metastasis3. This raises the possibility that cathepsin D protease activity may be involved in the migration of MSCs towards tumours. We have shown that pepstatin A, an aspartic acid protease inhibitor, decreases the migration and invasion of the immortalized MSC line RCB2157 towards the breast cancer line MDA-MB-231 through Boyden chambers as measured by MTT assay. Cathepsin D is synthesized as a pre-pro-enzyme, which is cleaved to give rise to procathepsin D, the immature form of cathepsin D. Finally, the cleavage of procathepsin D releases the mature cathepsin D4. Our Western blot analysis showed high levels of all three forms of cathepsin D in MDA-MB-231 cells whereas expression in MSCs was only weak. Furthermore, migration of MSCs towards MDA-MB-231 conditioned medium was reduced by 30% when compared to the migration towards MDA-MB-231 cells themselves. These results suggest that cathepsin D, synthesized by cancer cells as a result of crosstalk during co-culture is involved in the migration of MSCs towards tumours. Targeting cathepsin D inhibition may therefore allow the prevention of tumour stroma development. 

  1. Kidd S. et al., PLoS One. 2012; 7(2):e30563
  2. Hess DA. and Allan AL., Methods Mol Biol., 2011; 750:25-44
  3. Rochefort H, Acta Oncol., 1992; 31(2):125-30
  4. Koelsh G et al., FEBS Lett. 1994 Apr 18;343(1):6-10