It has been frequently observed that inhibition or genetic deficiency of lysosomal cathepsins delays tumor progression and reduces metastasis, although the underlying mechanisms remain elusive in most instances.
Periostin is a key component of the extracellular matrix at metastatic sites known to present growth factors to the lung-colonizing cancer cells during lung metastasis formation (Malanchi et al. 2011. Nature, 481:85-9). While exploring the role of lysosomal cathepsins during formation of lung metastasis in the MMTV-PyMT mouse model of metastasizing breast cancer, we found that the extent of TGFß-induced secretion of periostin correlates with cathepsin levels and activities, i.e. with cathepsins L and B. To explore the link between lysosomes, lysosomal proteases and periostin we studied a combination of gain- and loss-of-function approaches in cancer- and stromal cells.
The emerging signaling pathway sheds new light on how lysosomes and lysosomal proteases modulate oncogenic signaling pathways and contribute to the formation of the activated microenvironment of metastases. In addition, it adds a striking mechanistically explanation for the reduced metastasis formation reported in various mouse cancer models crossed with various cathepsin knock-out mice.