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.