Editors' ChoiceCancer

Blocking Brain Metastasis

Sci. Signal.  18 Mar 2014:
Vol. 7, Issue 317, pp. ec72
DOI: 10.1126/scisignal.2005281

The brain appears to have exceptional defenses beyond the blood-brain barrier against cancer cell colonization. Valiente et al. searched for factors that enable some types of cancers to establish metastases in the brain in the transcriptome of brain-metastatic (BrM) subpopulations of lung (H2030 and PC) and breast (MDA-MB-231 and CN34) cancer cell lines. Compared with parental cells, bone- or lung-metastatic subpopulations of MDA-MB-231 cells, the BrM subpopulation showed increased mRNA abundance for at least one of four genes encoding the serpin family of protease inhibitors. BrM cells had increased protein abundance of serpins B2 and I1 (also known as neuroserpin), which inhibit plasminogen activator (which converts plasminogen to plasmin), and SERPINB2 and SERPINI1 expression were associated with brain metastasis in human primary lung adenocarcinomas. After intracardiac injection in mice or seeding onto brain slices, parental H2030 cells had a high rate of apoptosis in brain tissue, whereas BrM-H2030 cells bound, coated, and proliferated along the abluminal surface of brain capillaries. The only serpin that was more abundant in BrM-H2030 cells than in parental cells was neuroserpin, and knockdown of SERPINI1 did not affect cell proliferation in culture but inhibited metastasis in mice and colonization (and increased apoptosis) in brain slices. In BrM-PC9 cells injected into mice, overexpression of wild-type neuroserpin, but not a catalytically inactive form, promoted brain but not bone metastasis. Plasmin cleaves the cytokine FasL, which activates apoptosis through the adaptor protein FADD. FasL was enriched in reactive astrocytes in BrM-H2030–derived brain metastatic lesions in mice. Addition of neuroserpin or serpin B2 decreased the amount of soluble FasL in mouse brain slices, indicating that serpins inhibit the production of FasL. However, although inhibition of FasL signaling through a dominant-negative FADD blocked apoptosis in neuroserpin-deficient BrM-H2030 cells, it did not restore their metastatic capacity. Plasmin also cleaves L1CAM, a cell adhesion protein that is associated with cell invasion and poor prognosis in various cancers. L1CAM was abundant in brain metastasis samples from nonsmall-cell lung cancer patients and was concentrated at the interfaces between BrM-H2030 cells and capillaries, as well as between adjacent BrM-H2030 cells in brain lesions in mice. L1CAM knockdown prevented BrM-H2030 and BrM-MDA-MB-231 cells from spreading and proliferating over capillaries in mouse brain slices and prevented the metastasis of neuroserpin-overexpressing BrM-PC9 cells. Addition of plasmin to cultured BrM-H2030 cells decreased the surface abundance of L1CAM as well as their cell adhesion capacity. Together, these findings suggest that targeting serpins in lung and breast cancer cells may prevent brain metastasis.

M. Valiente, A. C. Obenhauf, X. Jin, Q. Chen, X. H.-F. Zhang, D. J. Lee, J. E. Chaft, M. G. Kris, J. T. Huse, E. Brogi, J. Massagué, Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014). [Online Journal]

Related Content