Abstract
Over 20% of cancer patients will suffer metastatic spread to the brain, and prognosis remains poor. Communication between tumour cells and host tissue is essential during metastasis, yet little is known of the processes underlying such interactions in the brain.Here we test the hypothesis that cross-talk between tumour cells and host brain cells, through tumour cell leukocyte function associated protein-1 (LFA-1), is critical in metastasis development. Temporal expression of LFA-1 and its major ligand intercellular adhesion molecule-1 (ICAM-1) was determined in two different mouse models of brain metastasis. Marked upregulation of both proteins was found, co-localising with astrocytes, microglia and tumour cells themselves. Silencing of LFA-1 expression in MDA231Br-GFP cells prior to intracerebral injection resulted in > 70% reduction in tumour burden compared to control MDA231Br-GFP cells (p < 0.005, n = 5). Subsequent qRT-PCR analysis of brain tissue revealed significant reductions in COX-2, VEGF and eNOS from host brain tissue, but not tumour cells, in mice injected with LFA-1 knockdown cells (p < 0.0001, n = 5). Finally, expression of both LFA-1 and ICAM-1 was demonstrated in human brain metastasis samples.The results of this study suggest LFA-1 as a new target in brain metastasis therapy and highlight the potential synergy with current anti-COX-2 and anti-NOS therapies.
Highlights
Despite advances in the treatment of primary tumours, the incidence of secondary tumours is increasing, in the brain [1]
Similar expression of leukocyte function associated protein-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) was observed in the MDA231BR-GFP model at 14 days after tumour induction to that seen at 10 days after tumour induction in the 4T1-GFP model (Figure 1D–1I); expression of both cell adhesion molecules (CAMs) was evident within the tumour area, and spreading beyond the tumour margins throughout the striatum (Figure 1D–1E)
In lung adenocarcinoma samples, LFA-1 expression was clearly upregulated in metastatic regions (Figure 2G–2H and 2J–2K), whereas ICAM-1 was detected primarily at the intersection between tumour cells and brain parenchyma (Figure 2I and 2L)
Summary
Despite advances in the treatment of primary tumours, the incidence of secondary tumours (metastases) is increasing, in the brain [1]. We have previously reported the development of in vivo models of breast cancer brain metastasis that enable investigation of the mechanisms involved in both the initial stages of seeding to the brain and downstream proliferation stages within the brain parenchyma [2, 3]. In those studies we have shown marked and early upregulation of specific subsets of cell adhesion molecules (CAMs) [3]. In particular, that showed marked and consistent upregulation in our experimental models was intercellular cell adhesion molecule-1 (ICAM-1) [3]. Leukocyte www.impactjournals.com/oncotarget function associated protein 1 (LFA-1, known as CD11aCD18 and αLβ2), a cognate ligand to ICAM-1 [5], was strongly upregulated, on tumour cells [3]
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