Serpin expression in tumors facilitates brain metastasis by blocking the effects of plasmin.
Major finding: Serpin expression in tumors facilitates brain metastasis by blocking the effects of plasmin.
Concept: Plasmin induces FasL-mediated cancer cell death and blocks L1CAM-mediated spreading along capillaries.
Impact: Serpin-mediated cancer cell survival and outgrowth may facilitate brain metastasis in several cancer types.
Lung and breast cancers are the most frequent sources of brain metastases, but most cancer cells that invade the brain die prior to successful metastatic outgrowth. To investigate how cancers overcome barriers to metastatic colonization of the brain, Valiente and colleagues examined gene expression in human or mouse tumor lung and breast cell lines with brain metastatic phenotypes and noted elevated expression of one or more members of the serpin family, particularly plasminogen activator (PA)– inhibitory serpins. Expression of the two most frequently upregulated anti-PA serpins, neuroserpin and serpin B2, was also associated with brain relapse in patients with lung adenocarcinoma and was elevated in brain metastasis samples. Knockdown of one or more serpins in metastatic lung or breast cancer cell lines reduced their ability to colonize the brain, whereas ectopic serpin expression in nonmetastatic parental cells induced brain metastasis. Given that PA converts plasminogen into plasmin, an endopeptidase involved in brain stromal responses, these findings raised the possibility that PA-inhibitory serpins facilitate tumor cell brain colonization by preventing plasmin accumulation in the brain stroma. Consistent with this idea, plasminogen and plasmin were detected in murine brain stroma after cancer cell extravasation, and plasmin killed infiltrating cancer cells in brain-slice cultures. Plasmin blocked brain metastasis in part by triggering FasL-dependent apoptosis in invading cancer cells and by preventing cancer cells from adhering to and spreading along brain capillaries by cleaving the cellular adhesion molecule L1CAM. However, both the apoptotic and antiadhesive effects of plasmin were mitigated in highly metastatic cells in a serpin-dependent manner. Thus, increased expression of PA-inhibitory serpins in lung and breast cancer cells may facilitate metastatic colonization of the brain by promoting cancer cell survival and metastatic outgrowth, a finding that may provide insight into metastatic progression in other organs.