Cell type-dependent pathogenic functions of overexpressed human cathepsin B in murine breast cancer progression
30.09.2013
Bengsch F, Buck A, Günther SC, Seiz JR, Tacke M, Pfeifer D, von Elverfeldt D, Sevenich L, Hillebrand LE, Kern U, Sameni M, Peters C, Sloane BF, Reinheckel T.
Oncogene. 2014 Sep 4;33(36):4474-84.
Cathepsins are ubiquitously expressed cysteine proteases. In cancers they are abundant and frequently overexpressed in the cancer cells as well as in cells of the tumor microenvironment, i.e. tumor-associated macrophages. By gain and loss of function studies in the MMTV-PyMT mouse model of metastasizing breast cancer we could demonstrate that genetic ablation or transgenic overexpression of cathepsins B results in attenuated or enhanced cancer phenotypes, respectively.
In order to mimic the clinical situation of overexpressed cathepsin B, we studied overexpression of cathepsin B in cancer- or stroma cells alone or in combination. Although co-culture with macrophages supports invasive sprouting of PyMT cell spheroids, macrophage expressed cathepsin B did not further affect sprout formation. In contrast, cathepsin B overexpression in tumor cells fostered invasive strand formation. These in vitro results were corroborated by orthotopic injection of syngenic breast cancer cells in mammary glands: overexpression of cathepsin B in the injected cancer cells resulted in enhanced tumor growth, while injection of PyMT cells into the mammary glands of transgenic mice ubiquitously expressing cathepsin B did not alter the growth kinetics as compared to wild-type recipients.
