Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression

Abstract

From the earliest stages of embryonic development, cells of epithelial and mesenchymal origin contribute to the structure and function of developing organs. However, these phenotypes are not always permanent, and instead, under the appropriate conditions, epithelial and mesenchymal cells convert between these two phenotypes. These processes, termed Epithelial-Mesenchymal Transition (EMT), or the reverse Mesenchymal-Epithelial Transition (MET), are required for complex body patterning and morphogenesis. In addition, epithelial plasticity and the acquisition of invasive properties without the full commitment to a mesenchymal phenotype are critical in development, particularly during branching morphogenesis in the mammary gland. Recent work in cancer has identified an analogous plasticity of cellular phenotypes whereby epithelial cancer cells acquire mesenchymal features that permit escape from the primary tumor. Because local invasion is thought to be a necessary first step in metastatic dissemination, EMT and epithelial plasticity are hypothesized to contribute to tumor progression. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in breast and other cancers contributes to tumor progression. For example, developmental EMT regulators including Snail/Slug, Twist, Six1, and Cripto, along with developmental signaling pathways including TGF-beta and Wnt/beta-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes. This review focuses on the parallels between epithelial plasticity/EMT in the mammary gland and other organs during development, and on a selection of developmental EMT regulators that are misexpressed specifically during breast cancer.

Figure 1

EMT and Epithelial Plasticity. During EMT, epithelial cells lose their apico-basal polarity. Tight junctions which typically maintain apico-basal polarity dissolve allowing the mixing of apical and basolateral membrane proteins. Adherens and gap junctions are disassembled and cell surface proteins such as E-cadherin and epithelial-specific integrins (green) are replaced by N-cadherin and integrins specific to extracellular components (blue). The actin cytoskeleton is remodeled into stress fibers which accumulate at areas of cell protrusions. The epithelial intermediate filaments, cytokeratins, are replaced by vimentin. Meanwhile, the underlying basement membrane is degraded and the cell invades and moves into the surrounding stroma, devoid of cell-cell contacts.

Figure 2

EMT promotes metastasis by enhancing local invasion. During primary tumor formation, the genetic and epigenetic changes in the tumor cells coupled with alterations in the tumor microenvironment promote EMT. EMT and epithelial plasticity enable the tumor cells to de-adhere from their neighboring cells, invade through the underlying basement membrane and move into the surrounding tissue either as single cells (blue) or as clusters (light blue) of cells. This local invasion sets the stage for metastatic dissemination and spread to the draining lymph nodes. In addition, migration of single cells and potentially clusters of cells also can access the bloodstream leading to hematogenous spread of tumor cells and the development of distant metastatic disease.

Figure 3

Developmental EMT. a During gastrulation, ectodermal cells (yellow) at the primitive streak undergo EMT (blue) as a result of signals produced by the Spemann-Mangold organizer. These cells ingress through the primitive streak and migrate into the underlying tissue. The newly ingressed cells either remain mesenchymal becoming the primary mesoderm (red) or undergo MET forming the endoderm (green) and together establish the trilaminar embryo. b The neural crest cells (blue) are formed from an EMT of cells at the border of the embryonic ectoderm and the neuroectoderm during closure of the neural tube. After invading from their site of origin, neural crest cells migrate throughout the developing embryo giving rise to diverse tissue including craniofacial structure, the adrenal medulla and the peripheral nervous system.

Figure 4

Epithelial Plasticity during development and wound healing. Sheet movement is a form of collective cell migration that occurs during wound healing. Cell polarity is determined by the edge of the sheet where cells of the leading edge maintain adhesion to neighboring cells while directing the movement of the sheet to close the wound. These leading or pioneer cells (light blue) do not undergo a full EMT but exhibit mesenchymal features such as directed movement, development of cell protrusions, and loss of apico-basal polarity. However, the epithelial phenotype is maintained and completely regained once the wound or gap is closed. Arrows portray directional movements.

Figure 5

Parallels between normal mammary development and breast cancer progression. a Mammary gland development begins during embryogenesis resulting in a rudimentary ductal system. After onset of puberty, ductal elongation and branching morphogenesis leads to extension and arborization of the ductal tree. As the ducts extend through the mammary fat pad, differentiation of precursor cells in the TEB gives rise to the luminal and myoepithelial cells. In addition, cap cells at the leading edge of the TEB exhibit features of epithelial plasticity that are critical to the normal branching process (Inset). During pregnancy, lobuloalveolar development and side branching occur in preparation for lactation. b Breast cancer begins with the primary lesion, however as breast cancer progresses, tumor cells acquire an invasive and motile phenotype analogous to the epithelial plasticity and EMT observed in development. The epithelial plasticity and EMT permits local spread of tumor cells. Genes/pathways implicated in EMT and epithelial plasticity and misexpressed in breast cancer progression include Cripto-1, Snail/Slug/Twist, Six1, Wnt and TGF-β signaling (Inset). Local invasion of both single cell and collective migration of the tumor cells sets the stage for metastatic dissemination to distant organ sites in late stage breast cancer.

Figure 6

The Functional Consequences of EMT. In addition to the well-characterized role for EMT in local spread of tumor cells, induction of EMT also correlates with numerous other properties including a tumor-initiating cell phenotype, resistance to chemotherapy and senescence, evasion of the immune system and induction of a basal gene expression profile.