Cancers of epithelial origin account for 90% of cancer deaths worldwide. Their behavior has been compared to an uncontrolled wound healing process for over a century [1]. In more recent times Dvorak developed this comparison further, describing the differences and similarites between physiologic wound healing and the cancer induced formation of tumor stroma [2].
A distinct cellular behavior observed during wound repair and tissue regeneration is epithelial mesenchymal transition or EMT. An EMT is not a single phenotype, but a general description of a cellular plasticity that can vary from a transient increase in cellular mobility to a complete molecular reprogramming [3]. It occurs in response to different physiologic challenges, including during embryonic development, tissue regeneration, and cancer progression [4]. An EMT can be understood as a biologic process enabling an epithelial cell to assume a mesenchymal-like phenotype, providing that cell with distinct capabilities. These include an enhanced ability to migrate effectively; invade and degrade tissue through matrix metalloproteinase (MMP) expression; an ability to synthesize extracellular matrix components; and a resistance to apoptosis during the anchorage independent conditions associated with migration.
Fundamentally, EMT is a cellular alteration permitting enhanced migration (Figure 1). Normally, epithelial cells are held together tightly at junctions containing E-cadherin in complexes with catenins linked to the actin cytoskeleton, limiting their migration. The dissolution of these adhesive E-cadherin junctions is the hallmark of EMT. This can occur through the down regulation of E-cadherin expression via negative transcriptional activators such as Snail and Twist [5, 6], as well as through a growth factor induced relocalization of E-cadherin [7, 8].
A good example of an EMT like process occurring during wound healing is re-epithelialization. After incisional injury keratinocytes undergo transient phenotypic changes similar to the more complete EMT changes noted during developmental processes such as gastrulation [9]. These changes include an enhanced migratory ability through the disruption of cadherens junctions and the ability to degrade tissue through metalloproteinase expression. Another good example of an EMT like process occurring during wound healing is the transformation of ovarian epithelial cells to a mesenchymal phenotype under the influence of EGF during the post-ovulatory repair of the damaged surface epithelium [10].
The molecular signals inducing EMT during wound repair appear to emanate from damaged tissue microenvironments. Tissue injury triggers an acute inflammatory response resulting in activation of the coagulation cascade; platelet aggregation; and the proliferation of activated fibroblasts/inflammatory cells at the injury site [11]. This induces the release of numerous soluble inflammatory molecules and growth factors [12]. TGF beta signaling, in cooperation with activation of various receptor tyrosine kinases, is particularly important to the induction of EMT in both physiologic and pathologic settings [13]. The growth factors recognizing these receptors with the strongest links to EMT induction include EGF [10], FGF [14], HGF [15], PDGF [16], and IGF [17].
Closely aligned with wound healing is tissue regeneration. Tissue specific stem cells are responsible for tissue maintenance during the life of the organism, and they can self-renew and produce daughter cells that can differentiate into the more specialized cells comprising the bulk of the tissue [18]. The molecular signals inducing stem cell activation/proliferation are only now being discovered, but similar to EMT induction, tissue damage appears to be an important trigger. In the adult Drosophila intestine, which is an excellent model to study stem cell behavior because intestinal stem cells are the only mitotically active cell, tissue damage triggers a rapid intestinal stem cell activation and proliferation [19]. The mouse intestine is more complicated. The three specialized cell types that comprise colonic epithelium (enterocytes, goblet, and enteroendocrine cells) are replenished by a population of colonic stem cells located in distinct niches in the subepithelium known as the crypts of Lieberkuhn. Tissue injury induces proliferation and expansion of this cell population represented by an elongation of these crypts [20]. Similarly, in the lungs of mice suffering inhalational injury, the rapid generation of large clonal cell patches representing active stem cell proliferation is observed [21].
