Metastasis – a transition from order to disorder
Epithelial cancers account for 85% of human cancers. They are found in the cells that line our organs and tissues, or make up the lining of the cavities inside our bodies. Epithelial cells undergo many changes during cancerous transformation. One of these changes involves the loss of epithelial characteristics, the features of the cell that keep them attached, ordered, and stationary in the epithelium. The cell instead gains mesenchymal characteristics that allows the cell to start moving away from the epithelium and invade surrounding tissue.
This Epithelial to Mesenchymal Transition, or EMT, allows the cancer cells to spread, or metastasise, to other tissues and organs. Metastasis is one of the six Hallmarks of Cancer, capabilities that cancer cells must acquire in order to survive and form tumours, as described by Douglas and Weinberg in 2000.
This series will look at each of the hallmarks of cancer by looking at a recent paper published in each of these areas:
Today we look at the role of an EMT in tissue invasion and metastasis using the example of pancreatic ductal adenocarcinoma (PDAC). PDAC is a very aggressive type of pancreatic cancer with a 5-year survival rate of only 6%. It is a leading cause of morbidity in Europe and the US. 85% of patients with PDAC will show metastasis at the time of diagnosis. The EMT seen in these cells is one of the most important factors leading to metastasis. Scientists are targeting EMT as a treatment for this cancer.
Notch signalling is one of many signalling pathways that allow cells to respond to there environment. Cell communication through Notch signalling is required for tumour growth and allows the cells to undergo an EMT to become more invasive.
Top Notch research
Research published last month by Palagani and colleagues at the Medical University Hospital in Tuebingen, Germany, investigated the role of inhibiting Notch signalling to prevent an EMT.
Notch induces an EMT by activating a protein called SLUG, which is responsible for the loss of epithelial protein E-cadherin and gain of mesenchymal protein N-cadherin seen during this transition. Cadherin proteins are responsible for binding cells together in the epithelium – it is this switch in the type of cadherin, which occurs during the EMT, that allows cells to become more invasive and spread.
Palagani used a Notch inhibitor, γ-secretase inhibitor IX (GSI), to turn off Notch signalling and found that levels of SLUG and mesenchymal protein N-cadherin were reduced. This means, by inhibiting Notch signalling, they were able to stop an EMT and prevent the cells from becoming more invasive. Also, they found that GSI treatment reduced cancer cell growth and prevented tumour formation. The future for the GSI drug as a anti-cancer treatment looks promising.
Palagani V, El Khatib M, Kossatz U, Bozko P, Müller MR, et al. (2012) Epithelial Mesenchymal Transition and Pancreatic Tumor Initiating CD44+/EpCAM+ Cells Are Inhibited by γ-Secretase Inhibitor IX. PLoS ONE 7(10): e46514. doi:10.1371/journal.pone.0046514 (open access)