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Greater than 80% of all cancer cases are carcinomas, formed by the transformation of epithelial cells. During the initial stages of carcinogenesis, the cancer cells are confined to the primary site by a network of cell-cell adhesion molecules and an intact basal lamina; however, in some cases, a few cells along the edge of the primary tumor eventually break these bonds and complete the complex multistep process that leads to the formation of secondary tumors, or metastasis. For this to occur, a primary tumor cell must first invade the surrounding extracellular matrix, penetrate the basement membrane and intravasate a blood or lymphatic vessel. The cancer cell then disseminates to a distant organ via the circulation. If the cell survives the journey through the circulation, it attaches to the endothelium and extravasates into the surrounding tissue, where it may eventually generate a metastatic tumor (Fig-1). Based on the complexity of metastasis, one might assume that non-metastatic tumor cells must accumulate multiple genetic alterations before they successfully metastasize. However, recent studies from many groups have produced compelling evidence for an alternative, mechanistic, model, in which the carcinoma cells utilize a normally latent embryonic program, called epithelial-mesenchymal transition (EMT), to facilitate the initiation and progression of metastasis. |
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| Epithelial-Mesenchymal Transition and Cancer Metastasis |
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Epithelial–mesenchymal transition (EMT) is an important process during normal development. During EMT, epithelial cells lose cell-cell contacts and cell polarity, acquire mesenchymal gene expression, and undergo major changes in their cytoskeleton, thereby acquiring a mesenchymal appearance with increased motility and invasiveness. EMT has been shown to play an important role in various normal processes during, and after, the development of many organisms. For example, during embryo development, the mesoderm is derived from ectoderm by EMT, and the neural crest cells are also derived from the neural tube by EMT. In adults, EMT plays an important role during wound healing and tissue fibrosis. During tumor progression, EMT has been proposed to allow non-metastatic tumor cells to acquire the capacity to infiltrate the surrounding tissue (invasion) and ultimately metastasize to distant sites. The similarity between the histology of metastatic nodules and the corresponding primary tumor indicates that EMT-mediated metastatic progression must be a transient, reversible process. Studies of embryonic development have demonstrated that the mesenchymal cells in the mesoderm give rise to epithelial organs, including the kidney and ovary, by undergoing a reversible process known as mesenchymal-to-epithelial transition (MET). Therefore it would seem that cancer cells probably utilize this reversible process (MET) during the later stage of metastasis. |
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While Dr. Mani was a postdoctoral fellow in the Robert Weinberg lab, in collaboration with Jing Yang, he identified Twist and FOXC2, two master regulators of breast cancer metastasis, by utilizing an innovative mouse mammary tumor model Yang & Mani et al., 2004; Mani & Yang et al, 2007).
Suppressing Twist and FOXC2 expression using shRNA in highly metastatic cancer cells significantly decreased their ability to metastasize from the mammary gland to the lung. If the gene encoding Twist is mutated, mesoderm does not form during Drosophila embryogenesis. Therefore, Yang & Mani speculated that Twist might play an important role during EMT. Interestingly, they found that Twist not only played a role during EMT, but that over-expressing Twist in immortalized epithelial cells induced an EMT.
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The other gene, FOXC2, is a member of the winged helix/forkhead family of transcription factors and is known toplay an essential role during normal embryonic development. Unlike Twist, over-expression of FOXC2 increased the metastatic abilities of poorly metastatic cancer cells. In addition, FOXC2 is over-expressed in the highly invasive and metastatic basal-like subtype of breast cancer, which further supports the idea that FOXC2 plays a key role in cancer metastasis. Interestingly, FOXC2 is not expressed in any normal adult epithelial cells; however epithelial cells that have undergone EMT express FOXC2. Mani and Yang also showed that FOXC2 induced EMT in Maden-Darby canine kidney (MDCK) epithelial cells and that this increased the migratory and invasive behavior of the MDCK cells. Expression of FOXC2 in MDCK cells also caused the cells to secrete higher levels of MMP2 and MMP9. These observations established that FOXC2 is an important mediator of EMT, which can program cellular traits associated with malignancy and metastasis Mani & Yang et al 2007. |
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| EMT generates stem cells |
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During tumor metastasis, disseminated cancer cells would seem to require the ability to self-renew, similar to the ability of stem cells, in order to spawn macroscopic metastases. This raises the possibility that EMT, which promotes migration and invasion of cancer cells, may also endow cancer cells with a self-renewal capability. These observations suggested a possible link between stem cells and the cells generated by EMT. |
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Indeed, Dr. Mani in collaboration with Drs. Liao and Guo in the Weinberg Lab found that induction of EMT by over-expressing Snail or Twist in human mammary epithelial cells (HMLE), or exposing the HMLE cells to TGF-β1, caused these cells to exhibit cell surface markers similar to those of cancer stem cells, such as CD44 high/CD24 low, compared to the control cells. Another well-established property of stem cells is their ability to form mammospheres in suspension culture, and these mesenchymal-looking epithelial cells formed 30-fold more mammospheres than did the control cells. Furthermore, they found that CD44 high/CD24low cells isolated from human mammary epithelial cells and primary mouse mammary tissues exist in a mesenchymal state and express markers associated with EMT. Likewise, CD44 high/CD24 low cells isolated from human reduction tissues, acetis or invasive ductal carcinomas were found to express many markers associated with cells that have undergone EMT. These results suggests that EMT not only generates cancer cells with the increased motility and invasiveness needed for metastasis but also imparts on these cells the ability to self-renew, which would seem to be necessary for the establishment of secondary tumors. |
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If you have any question or comments, please contact K. Evans |
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