Oral Presentation 6th Australian Health and Medical Research Congress 2012

Insights into intra-cellular tension and the inter-cellular microenvironment in tumourigenesis (#73)

Michael S Samuel 1
  1. Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia

Cancers and their associated stroma manifest distinct tissue micro-environments that modulate tumour progression. We have previously shown using a gene-targeted mouse model expressing conditionally active Rho kinase (ROCK), the major Rho-effector protein downstream of RhoA and RhoC, that increased intra-cellular actomyosin tension within the epidermis causes inter-cellular collagen deposition, elevated tissue stiffness and perturbed tissue homeostasis by the stabilisation of β-catenin.  β-catenin is a key element of mechano-transcription pathways and its stabilisation results in hyper-activation of the Wnt signalling pathway, increased Tcf/Lef target gene activation and hyper-proliferation of keratinocytes. Activation of Rho kinase within the epidermis also leads to an increased susceptibility to epidermal papillomagenesis and squamous cell carcinoma (SCC). Tumour number, growth and progression in a SCC cancer model were increased by ROCK activation, while its blockade was inhibitory, implicating actomyosin-mediated cellular tension and consequent collagen deposition as significant tumour promoters.

Further analysis of the conditional Rho kinase mice revealed that not only collagen, but other constituents of the extracellular matrix (ECM) such as fibronectin were upregulated upon Rho kinase activation within the epidermis. Tumour promoting ability has been previously attributed to these ECM components in various cancers. We postulate that increased actomyosin tension mediated by activated ROCK within tumour cells, sets up a transcriptional program that moulds a tumour promoting microenvironment characterised by the increased production of ECM proteins and increased tissue density. This increased tissue density in turn fosters the establishment of cancers and their progression to invasive and metastatic forms. Expression analysis carried out on ROCK-activated versus control skin supports our hypothesis.