Abstract

In recent years the classic subdivision of apoptotic (programmed) cell death on one side and necrotic (accidental) cell death on the other has been enriched by an ever growing number of alternative pathways of cell death that can act in conjunction with or independently from apoptosis.

Amongst these alternative pathways of cell death, the lysosomal mediated pathway, which relies on partial lysosomal membrane permeabilization (LMP), has elicited increasing interest. Nevertheless, this type of cell death was believed to be confined to pathological conditions such as tumour cells or neurons after brain injury, and was seen as a backup mechanism when classical apoptosis fails to be activated.

Contrary to this view, recent findings from our group have shown that the regression of the mammary gland after lactation (involution), is carried out by non-classical, executioner caspase independent, lysosomal mediated programmed cell death (LM-PCD). This is the first time LM-PCD has been described under physiological circumstances. Furthermore we could show that Stat3 is indispensable for LM-PCD and regulates this pathway in at least two ways: 1) by upregulating lysosomal proteases such as cathepsins, while 2) downregulating the cytosolic cathepsin inhibitor Spi2A. Stat3 is also known to be commonly hyperactivated in breast cancers and is a marker of poor prognosis. We thus studied the impact of active Stat3 on the size, localisation and stability of lysosomes.

Previously our group could show that during lineage determination of the mammary gland several pathways known to be involved in lineage commitment of T-cells, such as the IL4 /IL13/Stat6 pathway, have been hijacked by mammary epithelial cells. Interestingly further parallels can be found during the execution of cell death in involution. To suit the occasion, on the basis of these examples some common characteristics of these two cellular systems will be discussed.