There exist a number of well-defined markers of the
epithelial to mesenchymal transition (EMT), a process crucial for the outgrowth
of tumours to new areas of the body (metastasis), and now a signalling protein
Pyk2 has been welcomed into the fold.
Focal Adhesion Kinase (FAK) is an established regulator of
EMT in response to the pro-EMT signalling protein Tumour Growth Factor Beta
(TGFβ), a recent
study has revealed that some of FAK’s functions also require Pyk2 and suggests
important roles for Pyk2 in tumour metastasis. A previous
study by Sun et al. from The University of Hong Kong has also described a
role for Pyk2 in driving EMT in liver cancer (hepatocellular carcinoma).
Normal human breast cells transformed to be cancer-like and
cells from patients with aggressive (invasive ductal cell carcinoma, with
reaccurance after 5 years) show high levels of Pyk2 protein. One breast cancer cell
line is a mixture of less aggressive and more aggressive cancer cells, within
these different cell populations the group observed vastly different levels of
Pyk2 protein.
This increased Pyk2 expression was associated with
increased growth of cells in a three dimensional tumour-like environment. In
fact, growth of cells in this 3D model can enhance Pyk2 expression in breast
cancer cell lines in a manner that is independent of the pro-EMT factor TGFβ. When growing two dimensionally (i.e. on a plastic culture surface) breast
cancer cells show low levels of Pyk2, however treatment TGFβ could increase
Pyk2 levels, but not to the same extent as observed in the 3D model. The group
suggest that the 3D model exhibits autocrine TGFβ signalling (where TGFβ
released by one cell acts directly upon the same cell). Importantly, not only
do the cells make more Pyk2, but there are higher levels of the active form of
Pyk2 (phosphorylated Pyk2). The signalling mechanism which links TGFβ to the
increased Py2k levels observed was shown to involve the actions of a
transcription factor called Smad4, this pathway was observed clearest in
aggressive breast cancer cells.
Metastasis requires a dramatic change in the shape of cells (a
novel mechanism of this was previously described in a past
post); the classical EMT shape change is induced by TGFβ, however this was
independent of Pyk2. It appears that FAK is the key protein involved here.
The group went on to show that whilst up-regulation of Pyk2
in breast cancer cells is required along with FAK for acquisition of an EMT
signature, Pyk2 alone is indispensable for their ability to outgrow their initial
“primary” tumour site and metastasise to the lung. Pyk2 could therefore present a therapeutic target for the treatment of invasive, pre-metastatic breast cancer.
Mentioned Articles
Wendt MK, Schiemann
BJ, Parvani JG, Lee YH, Kang Y, Schiemann WP.
Oncogene. 2012 Jun
18. doi: 10.1038/onc.2012.230. [Epub ahead of print]
Sun CK, Ng KT, Lim
ZX, Cheng Q, Lo CM, Poon RT, Man K, Wong N, Fan ST.
PLoS One. 2011 Apr
20;6(4):e18878. doi: 10.1371/journal.pone.0018878.