Computational models to explore the complexity of the epithelial to mesenchymal transition in cancer

The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.

Malignant cancer cells utilize their intrinsic migratory ability to invade adjacent tissues and the vasculature, and ultimately to metastasize. Cell migration is the sum of multi-step processes initiated by the formation of membrane protrusions in response to migratory and chemotactic stimuli. The driving force for membrane protrusion is localized polymerization of submembrane actin filaments. Recently, several studies revealed that molecules that link migratory signals to the actin cytoskeleton are upregulated in invasive and metastatic cancer cells. In this review, we summarize recent progress on molecular mechanisms of formation of invasive protrusions used by tumor cells, such as lamellipodia and invadopodia, with regard to the functions of key regulatory proteins of the actin cytoskeleton; WASP family proteins, Arp2/3 complex, LIM-kinase, cofilin, and cortactin.

Cell signaling systems that contain positive-feedback loops or double-negative feedback loops can, in principle, convert graded inputs into switch-like, irreversible responses. Systems of this sort are termed "bistable". Recently, several groups have engineered artificial bistable systems into Escherichia coli and Saccharomyces cerevisiae, and have shown that the systems exhibit interesting and potentially useful properties. In addition, two naturally occurring signaling systems, the p42 mitogen-activated protein kinase and c-Jun amino-terminal kinase pathways in Xenopus oocytes, have been shown to exhibit bistable responses. Here we review the basic properties of bistable circuits, the requirements for construction of a satisfactory bistable switch, and the recent progress towards constructing and analysing bistable signaling systems.