Matrikines are important components of tumor microenvironments that integrate communication between extracellular matricies and membrane-bound receptors thereby regulating cellular behaviors. One such matrikine that is differentially expressed in cancer microenvironments is the
extracellular matrix protein lumican; however its precise role in
cancer remains ambiguous. To study the effects of
lumican on
cancer cells, we created
lumican-overexpressing cell lines from murine
fibrosarcoma (MCA102) and pancreatic
adenocarcinoma (Pan02) cells.
Lumican overexpression in Pan02 cells increased invasiveness, decreased soft
agar colony size, and increased proliferation. Conversely in MCA102 cells,
lumican decreased invasiveness, increased soft
agar colony size, but did not influence proliferation. In contrast to these pleiotropic in vitro results,
lumican overexpression within the in vivo tumor microenvironment produced uniformly smaller
tumors. Importantly, reduced
tumor size was correlated with reduced vascular density. Consistent with
lumican's proposed anti-angiogenic activity,
lumican increased endothelial cell apoptosis. Importantly,
lumican was previously shown to influence Fas expression and our results show that
lumican enhanced Fas mediated endothelial cell apoptosis although we were unable to detect any difference in Fas or
Fas ligand expression between
lumican-overexpressing and control cells. Interestingly,
lumican had no effect on MCA102 apoptosis, suggesting that the observed reduction in
tumor size is specifically due to endothelial cell apoptosis rather than a direct effect on the cancerous cells themselves. Therefore, this study is the first to demonstrate a causal relationship between
tumor reduction and
lumican's effect on angiogenesis as opposed to an effect on the cancerous cells themselves.