ALCAM contributes to brain metastasis formation in non-small-cell lung cancer through interaction with the vascular endothelium

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Justine Münsterberg - , University of Hamburg (Author)
  • Desirée Loreth - , University of Hamburg (Author)
  • Laura Brylka - , University of Hamburg (Author)
  • Stefan Werner - , University of Hamburg (Author)
  • Jana Karbanová - , Research Group Tissue Engineering, Tissue Engineering (Research Group), Biotechnology Center (Author)
  • Monja Gandrass - , University of Hamburg (Author)
  • Svenja Schneegans - , University of Hamburg (Author)
  • Katharina Besler - , University of Hamburg (Author)
  • Fabienne Hamester - , University of Hamburg (Author)
  • José Ramon Robador - , University Hospital Heidelberg (Author)
  • Alexander Thomas Bauer - , University Hospital Heidelberg (Author)
  • Stefan Werner Schneider - , University Hospital Hamburg Eppendorf, University of Hamburg (Author)
  • Michaela Wrage - , University of Hamburg (Author)
  • Katrin Lamszus - , University of Hamburg (Author)
  • Jakob Matschke - , University of Hamburg (Author)
  • Yogesh Vashist - , University of Hamburg (Author)
  • Güntac Uzunoglu - , University of Hamburg (Author)
  • Stefan Steurer - , University of Hamburg (Author)
  • Andrea Kristina Horst - , University of Hamburg (Author)
  • Leticia Oliveira-Ferrer - , University of Hamburg (Author)
  • Markus Glatzel - , University of Hamburg (Author)
  • Thorsten Schinke - , University of Hamburg (Author)
  • Denis Corbeil - , Research Group Tissue Engineering, Tissue Engineering (Research Group), Biotechnology Center (Author)
  • Klaus Pantel - (Author)
  • Cecile Maire - , University of Hamburg (Author)
  • Harriet Wikman - (Author)

Abstract

BACKGROUND: Brain metastasis (BM) in non-small-cell lung cancer (NSCLC) has a very poor prognosis. Recent studies have demonstrated the importance of cell adhesion molecules in tumor metastasis. The aim of our study was to investigate the role of activated leukocyte cell adhesion molecule (ALCAM) in BM formation in NSCLC.

METHODS: Immunohistochemical analysis was performed on 143 NSCLC primary tumors and BM. A correlation between clinicopathological parameters and survival was developed. Biological properties of ALCAM were assessed in vitro by gene ablation using CRISPR/Cas9 technology in the NCI-H460 NSCLC cell line and in vivo by intracranial and intracardial cell injection of NCI-H460 cells in NMRI-Foxn1nu/nu mice.

RESULTS: ALCAM expression was significantly upregulated in NSCLC brain metastasis (P = 0.023) with a de novo expression of ALCAM in 31.2% of BM. Moderate/strong ALCAM expression in both primary NSCLC and brain metastasis was associated with shortened survival. Functional analysis of an ALCAM knock-out (KO) cell line showed a significantly decreased cell adhesion capacity to human brain endothelial cells by 38% (P = 0.045). In vivo studies showed significantly lower tumor cell dissemination in mice injected with ALCAM-KO cells in both mouse models, and both the number and size of BM were significantly diminished in ALCAM depleted tumors.

CONCLUSIONS: Our findings suggest that elevated levels of ALCAM expression promote BM formation in NSCLC through increased tumor cell dissemination and interaction with the brain endothelial cells. Therefore, ALCAM could be targeted to reduce the occurrence of BM.

KEY POINTS: 1. ALCAM expression associates with poor prognosis and brain metastasis in NSCLC.2. ALCAM mediates interaction of NSCLC tumor cells with brain vascular endothelium.3. ALCAM might represent a novel preventive target to reduce the occurrence of BM in NSCLC.

Details

Original languageEnglish
Pages (from-to)955-966
Number of pages12
JournalNeuro-oncology
Volume22
Issue number7
Publication statusPublished - 7 Jul 2020
Peer-reviewedYes

External IDs

PubMedCentral PMC7339886
Scopus 85084426929
ORCID /0000-0003-1181-3659/work/142252253
ORCID /0000-0001-7687-0983/work/142253731

Keywords

Sustainable Development Goals

Keywords

  • Activated-Leukocyte Cell Adhesion Molecule, Animals, Brain Neoplasms/secondary, Carcinoma, Non-Small-Cell Lung, Endothelial Cells, Endothelium, Vascular, Female, Humans, Lung Neoplasms, Male, Mice

Library keywords