Endothelial activation in brain metastasis

Manuel Sarmiento Soto, Sébastien Serres, Alex M. Dickens, James R. Larkin, Daniel C. Anthony, Nicola R. Sibson

Poster at NCRI Cancer Conference, Liverpool, UK (2011)


Background: Brain metastasis affects 20-40% of cancer patients, yet the factors governing tumour development remain unclear. In lung and liver, endothelial adhesion molecules are implicated in both metastasis initiation and progression. However, little is known of their role in brain metastasis. The aim of this study was to quantify expression of key adhesion molecules and their ligands during pathogenesis of brain metastases in vivo and in metastasising cell lines in vitro.

Method: For the in vivo model, 4T1-GFP cells were microinjected into the striatum of BALB/c mice. Brains were perfusion-fixed at 5, 10, 21 and 35 days post-injection (n=3 per group). For the in vitro work, 4T1-GFP and MDA231BR-GFP cells were coated onto 96 well plates and incubated with/without mouse plasma for 6h. Tumour cells, adhesion molecules and their ligands were detected by immunohistochemistry or immunofluorescence.

Results: In vivo study showed that Tumour growth caused differential induction of adhesion molecules; for example, P-selectin showed a progressive activation over time, whilst E-selectin and ALCAM showed rapid upregulation followed by a gradual decline despite tumour growth. In vitro results showed expression of several adhesion molecule ligands and, in some cases (e.g. ALCAM), increase of protein expression in the cytoplasm after exposure to plasma.

Conclusion: This study demonstrates changing patterns of adhesion molecule expression during brain metastasis pathogenesis. Further studies will identify changes in endothelial activation during the earliest stages of induction via systemically-induced brain metastases. This work may reveal new therapeutic targets for brain metastasis, as well as potential diagnostic targets for molecular imaging.