22 February 2011
Pathology researchers publish in Nature Cell Biology exciting breakthrough for the understanding of cell death and the treatment of cancers that are resistant to cell death.
The work was carried out primarily by two PhD students in Christine Watson’s lab; the first author Peter Kreuzaler was funded by a department of Pathology PhD studentship and is now funded by a Trinity College fellowship and Anna D. Staniszewska, a current graduate student funded by the Breast Cancer Campaign.
Billions of cells in our body die every day. Damaged, infected or superfluous cells are thus disposed of to keep our bodies healthy. It is thought that most of these cells die by a process called apoptosis. However, we have shown that cells in the breast, following lactation, do not die by apoptosis but by a novel mechanism that requires organelles called lysosomes. These tend to be thought of as cellular waste bins since they digest cellular components and recycle them. However, we have discovered that during regression of the breast, enzymes called cathepsins leak out of the lysosomes into the cell and induce a process that we call lysosomal-mediated programmed cell death (LM-PCD). This is the first time that this type of cell death has been shown to occur in a normal mammalian organism. Furthermore, we have shown that a transcription factor, Stat3, that is often associated with breast cancer, is responsible for executing LM-PCD as it induces high levels of cathepsins while suppressing expression of a naturally occurring cathepsin inhibitor, a protein called Spi2a. Since a common feature of all cancers is their ability to evade cell death, our work will be of major importance in the design of treatments for cancers by targeting this new death mechanism.
Top : Our findings have led us to establish a multi-step model for the execution of LM-PCD during involution. We hypothesise that in late lactation cells become sensitized to cell death insults. When breast feeding is stopped, leakiness is induced. This however is not enough to induce cell death and the action of Stat3, which upregulates the cathepsins while downregulating a potent cathepsin inhibitor (Spi2a), is needed to execute cell death.
Bottom (left): An electron-microscopic picture of a single cell that has been expelled from the alveolus, the milk-producing unit of the breast, and is now undergoing lysosomal-mediated programmed cell death.
Bottom (right): Microscopic image of an alveolus. The dots are cells that were expelled and are now undergoing programmed cell death.
The full article can be read at http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb2171.html