The International Journal of Biochemistry & Cell Biology 39 (2007) 2153–2160 Medicine in focus Epithelial–mesenchymal transition and tumour invasion Marcello Guarino * Department of Anatomical Pathology, Hospital of Vimercate, via C. Battisti 23, 20059 Vimercate (MI), Italy Received 14 April 2007; received in revised form 17 July 2007; accepted 20 July 2007 Available online 31 July 2007 Abstract Carcinoma invasion implies potentiality to metastasize distantly but, despite its clinical importance, it is still a poorly understood process. There is increasing evidence pointing to a role of epithelial–mesenchymal transition by which tumour cells would weaken E-cadherin-dependent intercellular adhesion and enhance motility, thus becoming able to penetrate into surrounding tissues. The activated tissue microenvironment at the advancing tumour front seems to provide the appropriate stimuli for triggering this change. The binding of growth factors and extracellular matrix molecules to tumour cell membrane receptors generates cascades of intracel- lular signals that could ultimately promote the down-regulation of E-cadherin and the activation of the cytoskeleton. Therefore, cells lose intercellular junctions and emanate cytoplasmic extensions that protrude from the basal surface into the stromal compartment through interruptions of the basement membrane. These protrusions establish new contacts with the interstitial matrix and, finally, the contraction of the cytoskeleton allows cell translocation into the stroma. Here, repeated cycles of spatially and temporally coordinated protrusive and contractile events ensure the locomotion of invading cells. Invasion predicts the ability to generate metastasis, therefore epithelial–mesenchymal transition could provide new insights on the mechanisms underlying this detrimental process. Furthermore, since deregulated proteins known to be involved in epithelial–mesenchymal transition seem associated with cancer progression, they could potentially be utilized as prognostic markers or therapeutic targets. Thus, in addition to increasing our knowledge of tumour invasion biology, studying epithelial–mesenchymal transition will, in the future, offer novel opportunities to define clinical parameters and pharmacological treatment. © 2007 Elsevier Ltd. All rights reserved. Keywords: Epithelial–mesenchymal transition; Tumour invasion; Signalling pathway; Rho GTPases 1. Introduction Carcinoma is the most frequent type of cancer in humans, and the occurrence of metastasis accounts Abbreviations: EMT, epithelial–mesenchymal transition; ECM, extracellular matrix; SH2, Src-homology 2; PI3K, phosphoinositide- 3-kinase; PIP3, phosphatidylinositol-3,4,5-trisphosphate; GSK-3, glycogen synthase kinase-3; FAK, focal adhesion kinase; MLC, myosin light chain; TGF, transforming growth factor-; ILK, integrin-linked kinase; PAK, p21-activated kinase; LIMK, LIM kinase; ROCK, Rho kinase * Tel.: +39 0396654362. E-mail address: guarino.marcello@alice.it. for most cancer-related deaths. Invasion is the first of the cascade of events leading to development of metastasis, but it is at present the less understood. It occurs by transfer of malignant cells from the primi- tive neoplastic focus into surrounding host tissues and implicates acquisition of ability to migrate (Christofori, 2006). Carcinomas are comprised of cohesive epithe- lial cells linked to one another by E-cadherin-based cell–cell junctions and are initially separated from the stroma by the basement membrane, a specialized extracellular matrix (ECM) structure providing correct information for epithelial functions and stability. Thus, to gain access into the stromal compartment and become 1357-2725/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2007.07.011