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

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Key Points</jats:title> <jats:p>1. ALCAM expression associates with poor prognosis and brain metastasis in NSCLC.</jats:p> <jats:p>2. ALCAM mediates interaction of NSCLC tumor cells with brain vascular endothelium.</jats:p> <jats:p>3. ALCAM might represent a novel preventive target to reduce the occurrence of BM in NSCLC.</jats:p> </jats:sec>

Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress

“…This was associated with PDAC tissue upregulation of the RAGE homologue CD166/activated leukocyte cell adhesion molecule (ALCAM), which shares with RAGE some endogenous ligands [ 200 ]. Consistent with this finding, CD166/ALCAM was previously found to be upregulated after genetic deletion of RAGE in the context of tissue inflammation driven by RAGE-ligands [ 200 ] and associated with tumor spread and recurrence in human cancers [ 201 , 202 ], including PDAC [ 202 ]. Overall, these results support the concept that AGEs promote invasive PDAC through receptor-mediated mechanisms and might be an important mediator of the increased risk of PDAC conferred by diabetes.…”

Treatment of Alectinib in NSCLC with Brain Metastasis Patient Refractory to Radiotherapy after Resistance to Crizotinib: A Case Report and Literature Review

“…BM, which are a frequent complication in patients with NSCLC, is associated with poor survival outcomes and poses clinical challenges for oncologists [8]. At initial diagnosis, 10% of NSCLC patients have BM, and the brain is the only site of tumor relapse in 50% NSCLC patients [9]. However, in NSCLC patients harboring ALKr, the risk of BM is higher.…”

CD9, a tetraspanin target for cancer therapy?

“…49 Thus, CD9-mediated ALCAM-ALCAM interactions modulate interactions between leukocytes (or cancer cells) with endothelial cells, and hence participate in physiological and pathological cell migration, the latter being an important step in cancer and in the development of metastases. 50,51 CD9 associates also with transmembrane transforming growth factor (TGF)-α and regulates TGF-α-induced EGFR activation and cell proliferation. 52 Notably, the association of CD9 with transmembrane protein TGF-α decreases the ectodomain shedding and the release of soluble TGF-α, and their co-expression confers changes (i) in cytoskeletal organization such as a decrease in actin stress fibers and focal adhesions and (ii) in RhoA and Rac1 GTPase activities.…”