The return of Dr Jekyll in cancer metastasis.

Metastasis, the process whereby tumour cells disseminate and colonize distant organs, is the primary cause of cancer mortality. Diverse models have been proposed to explain how tumour cells acquire metastatic competency. Calon et al (2012) now provide insight into the molecular underpinnings of metastasis by describing a key stromal, non-cell autonomous role for Transforming Growth Factorbeta (TGFb) in promoting the initiation of colonization in otherwise TGFb-resistant colorectal cancer (CRC) cells. Growing tumour cells are surrounded by stroma, a heterogenous population of cells that includes fibroblasts, endothelial precursors and cells of the immune system (Sethi and Kang, 2011; Valastyan and Weinberg, 2011). This stroma engages in an active dialogue with the tumour cells to create a unique microenvironment that is conducive to the survival and progression of a growing tumour. In late stage tumours, productive metastases arise when the tumour cells leave the primary site to disseminate throughout the body and seed new secondary tumours in distant organs. How tumour cells leave behind their primary microenvironment to establish and successfully colonize secondary sites that might harbour tumour-hostile environments has been the subject of extensive research and speculation. A recent study by Calon et al (2012) provides new insights into this long-standing question with the discovery that Transforming Growth Factor-beta (TGFb) produced by tumour cells critically promotes colorectal cancer (CRC) cell colonization through its actions on the stroma (Figure 1). The secreted factor, TGFb has been called the ‘Dr Jekyll and Mr Hyde’ of cancer (Bierie and Moses, 2006) due to paradoxical function as both a tumour suppressor and a tumour promoter. For instance, TGFb inhibits the proliferation of epithelial cells, an activity that most tumour cells must learn to overcome during cancer progression. However, TGFb also promotes the metastatic phenotype by enhancing tumour cell migration and promoting epithelialto-mesenchymal transition (EMT). In human CRC, the majority of tumour cells display constitutive Wnt signalling, typically because of mutations in either the adenomas polyposis gene (APC) or b catenin.