A developmental transition may be a useful model for tumor progression.
Until recently, the universally accepted dogma in cancer research stated that replicating cells accumulate several rounds of mutations before becoming cancerous. According to that dogma, the mutations that result in metastatic spread throughout the body occur late in tumor progression. This idea has recently been challenged by the identification of cancer stem cells (CSCs), which provide a new explanation for both the initiation and propagation of tumorigenesis. Rather than following a linear process that starts with unchecked replication and ends with the loss of adhesion molecules that drives metastasis, CSCs can self-renew, proliferate, differentiate, and even revert back to a stem cell state, producing metastatic cells at unexpected stages of the disease.
With a new understanding that cancer progression does not necessarily follow a particular order, researchers have been looking for models to help explain how and when cancers become aggressive. While the idea of CSCs helps explain some observations that do not fit within the accepted dogma, researchers have proposed another idea based on a normal process in embryonic development called the epithelial-to-mesenchymal transition (EMT). Embryonic development requires epithelial cells to change gene expression patterns, lose their adhesion molecules, and become motile, mesenchymal-like cells that invade the extracellular matrix and later differentiate to form the interior tissues of the body such as skeletal muscles and the heart. A similar process, which includes the loss of adhesion molecules and the activation of common genes by Wnt/β-catenin and other signaling pathways, is also a prerequisite for malignant tumor development, particularly the metastatic process. Studying the basic biology of EMT, therefore, could shed light on the processes that cancer cells undergo as they develop.
Although EMT can be a useful model, embryogenesis and tumorigenesis differ in important ways, and the precise role of an EMT (or EMT-like processes) in cancer progression and its relationship to CSCs, remain controversial.1
In normal cells, there is a tight coordination between cell adhesion and signaling, manifested by a dependence on anchorage for growth. Cancer cells can often grow without the restriction for attachment. The main question then is: what is the nature of the coordination between adhesion-related signaling and cancer cells, and how are these molecules involved in regulating cancer progression and metastasis?
EMT provides a window into the consequences of losing some and gaining other adhesion molecules. Sendurai Mani, together with Robert Weinberg and colleagues at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, induced an EMT-like state in epithelial cell cultures by overexpressing Snail and Twist, two key transcription factors that activate EMT, thereby decreasing the cell-adhesion molecule E-cadherin and increasing mesenchymal marker expression.2 Interestingly, this resulted in some of the engineered epithelial cells forming mammospheres (balls of nonadherent cells capable of differentiation), a property normally associated with stem cells. It also suggested that the loss of adhesion dependence may play a role in maintaining a stem cell-like state.
To test whether EMT with its characteristic loss of E-cadherin was important early in tumor progression, mice bred to express an E-cadherin gene whose function could be disrupted at will were crossed with mice that formed benign lung adenomas due to a ras mutation.3 When the E-cadherin expression was disrupted, the mice developed invasive carcinoma that metastasized into regional lymph nodes and bone marrow and promoted angiogenesis. This revealed a novel function of E-cadherin in angiogenesis. In addition, work by a different group demonstrated that breast cancer cells were found in the circulation of patients with small, noninvasive tumors, suggesting that metastasis occurred at an early stage of the disease.4
The loss of E-cadherin is not only caused by mutations within the cancer cell itself. Noncancerous cells in the tumor microenvironment may also contribute to the loss. Proteases secreted by tumor-associated macrophages cleave E-cadherin at the cancer cell surface and promote metastasis. Also, cells in the cancer microenvironment often secrete metalloproteases—enzymes that break down the extracellular matrix—and allow cancer cells to invade. Finally, growth factors secreted into the microenvironment can cause more differentiated cancer cells to revert back to cells displaying CSC properties.5
The EMT paradigm may be useful for understanding metastasis in the context of CSC, but the model is far from perfect. Pathologists rarely observe EMT in cancer tissues; in fact, invading cells appear epithelial rather than mesenchymal and for the most part do not express stem cell markers. Can we say that these cells have undergone a “radical change in cell identity”? The answer to this question is critical for a deeper understanding of the biology of cancer and remains one of the hotly debated issues in the cancer-EMT field. Controversy also surrounds the definition and identification of CSCs. Indeed, CSCs express markers common to nontransformed stem cells, but when CSCs are isolated and injected in small numbers they can initiate tumor formation in mice.
The biggest challenge facing cancer researchers today is the development of models that allow in vivo visualization and molecular analysis of the dynamic three-dimensional interactions between cancer cells and their environment, similar to models used to visualize cell motility and differentiation during embryogenesis. Only then will we be able to determine the significance of an EMT-like process for the progression of cancer. These and related questions will undoubtedly remain exciting research topics at the forefront of molecular cancer research for the near future.
Cell Biology Faculty Member References: