The Role of Stroma Microenvironments in Prostate Cancer Cell Migration and Metastasis

Terminal prostate cancer is the result of metastatic spread of the tumour from the prostate and is the 2nd leading cause of cancer deaths in men. Although in vitro assays have been developed to screen for inhibitors of prostate cancer metastasis and cell migration, they routinely utilise 2- Demensional (2-D) culture of prostate cancer cell lines. Current assays do not simulate complexity of the in vivo human tumour microenvironment which contains a mixture of normal and transformed epithelial cells and stromal cells. Therefore there is a requirement to develop novel 3-D models to recapitulate the in vivo tumour microenvironment to understand tumour stroma function. Utilising a 3-D co-culture spheroid model incorporating primary human tumour stroma with prostate cancer cells we have shown that the stroma has a key role in prostate cancer epithelial cell migration and motility. By utilising 4-D two-photon imaging and gene expression analysis we have analysed the molecular mechanisms of stromal cell mediated prostate cancer cell migration, identifying genes that regulate the migration process. Analysis of human tumour stroma indicates a key role in the immune system in driving tumour stroma to express a lymphoid stromal phenotype that provides the microenvironment for active tumour cell migration. This offers an interesting dichotomy that the formation of lymphoid like stroma in aggressive tumours may paradoxically deliver help to drive the immune response to the tumour whilst simultaneously providing the microenvironment for tumour cell migration and metastasis. The molecular mechanism of prostate cancer cell migration and metastasis and stroma-epithelial cell interactions involves a complex balance between the adhesion molecule VCAM-1 and two counter ligands VLA-4 and SPARC, also known as osteonectin or BM-40. The utilisation of shRNA knockdown, Fc chimeric proteins and blocking antibodies, indicates a key role for stromal-epithelia adhesion and detachment dependent cell migration mediated by VCAM-1, VLA-4 and SPARC.