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Mechanisms of Tumor Cell Invasiveness and Metastasis.
Carcinomas constitute ~80% of the tumors encountered in the oncology clinic, and metastases are responsible for ~90% of all cancer-associated deaths. These figures have focused our attentions on the mechanisms that enable carcinoma cells to invade and metastasize. In fact, the ability to invade and metastasize is a complex, multistep process that involves a number of distinct changes in cell phenotype. Thus, the invasion-metastasis cascade has been proposed to be constituted of the following discrete steps: local invasiveness, intravasation (invasion into blood and lymphatic vessels), transport through the circulation, extravasation (escape from blood vessels into the surrounding tissue parenchyma), formation of a micrometastasis, and finally, colonization (growth of a micrometastasis into a macroscopic metastasis).
The biological complexity of this cascade rivals that of the initial steps of tumorigenesis, raising the question of whether a number of distinct mutations must occur within tumor cells in order to enable them to execute this series of complex biological processes. At the same time, it provokes the question of how cancer cells are able to acquire these multiple abilities in a relatively short period of time.
We have been working over the past several years with a series of transcription factors that are normally active during early embryogenesis and during wound healing. These transcription factors all are capable of inducing epithelial cells (the progenitors of carcinomas) to undergo the epithelial-mesenchymal transition (EMT), a transdifferentiation process that allows epithelial cells to acquire many of the attributes of motile, invasive stromal cells such as fibroblasts. Each of these transcription factors is capable of acting pleiotropically to induce the multiple cellular changes that are associated with the EMT. These include the acquisition of fibroblastic morphology, the downregulation of E-cadherin and cytokeratins, the induction of N-cadherin and vimentin, (often) the secretion of matrix metalloproteinases (MMPs), and the acquisition of invasive behavior.
To date, we have studied in some detail the actions of four of these transcription factors, which play key roles in specific steps of embryogenesis involving EMTs, such as gastrulation and the emigration of cells from the neural crest. The Twist, FOXC2, Goosecoid, and Slug transcription factors all seem capable of programming much, if not all, of the EMT program when expressed ectopically in epithelial cells. We have arrived at these transcription factors through a variety of experimental routes. Twist and FOXC2 were uncovered through an expression array screen of genes that were expressed in highly metastatic mouse breast cancer cells but not in their non-invasive, non-metastatic counterparts. Goosecoid was identified because of its known role in specifying the Spemann organizer, which helps to program gastrulation. And Slug was identified because of its known role in enabling neural crest cells to become motile and invasive.
The role of several of these transcription factors in facilitating metastasis has been demonstrated by inhibiting their expression in otherwise metastatic cells. Thus, shutdown of Twist and Slug expression in metastatic mouse breast cancer cells and human melanoma cells respectively results in suppression of their metastatic behavior. Unproven by these experiments is whether ectopic expression of one or another of these transcription factors in normally non-invasive cancer cells enables the latter to acquire all of the capabilities needed to execute the entire invasion-metastasis cascade.
Significantly, the expression of several of these transcription factors is associated with specific subtypes of human malignancies. For example, Twist is expressed preferentially in invasive lobular carcinomas of the breast, which are known to be highly invasive and carry a poor clinical prognosis, while rarely being expressed in invasive ductal carcinomas, which have a far more favorable clinical course. Similarly, FOXC2 is expressed in almost half of the basaloid subclass of human breast cancers, which carry a poor prognosis, while being rarely expressed in the epithelioid tumors that generally have a good prognosis for the breast cancer patient.
