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Modulation of cell adhesion and migration through regulation of the immunoglobulin superfamily member ALCAM/CD166.

ABSTRACT: In epithelial-derived cancers, altered regulation of cell-cell adhesion facilitates the disruption of tissue cohesion that is central to the progression to malignant disease. Although numerous intercellular adhesion molecules participate in epithelial adhesion, the immunoglobulin superfamily (IgSF) member activated leukocyte cell adhesion molecule (ALCAM), has emerged from multiple independent studies as a central contributor to tumor progression. ALCAM is an archetypal member of the IgSF with conventional organization of five Ig-like domains involved in homo- and heterotypic adhesions. Like many IgSF members, ALCAM is broadly expressed and involved in cellular adhesion across many cellular processes. While the redundancy of intercellular adhesion molecules (CAMs) could diminish the impact of any single CAM, consistent correlation between ALCAM expression and patient outcome for multiple cancers underscores its role in tumor progression. Unlike most oncogenes and tumor suppressors, ALCAM is neither mutated nor amplified or deleted. Experimental disruption of ALCAM-mediated adhesions implies that this IgSF member contributes to tumor progression through dynamic turnover of the protein at the cell surface. Since ALCAM is not frequently altered at the gene level, it appears to promote malignant behavior through regulation of its availability rather than its specific activity. These observations help explain its heterogeneous expression within malignant disease and the drastic changes in protein levels across tumor progression. To reveal how ALCAM contributes to tumor progression, we review regulation of its gene expression, alternative splicing, targeted proteolysis, binding partners, and surface shedding within the context of cancer. Studying ALCAM regulation has led to a novel understanding of the fine-tuning of cell adhesive state through the utilization of otherwise normal regulatory processes, which thereby enable tumor cell invasion and metastasis.

SUBMITTER: von Lersner A

PROVIDER: S-EPMC6639050 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Modulation of cell adhesion and migration through regulation of the immunoglobulin superfamily member ALCAM/CD166.

von Lersner Ariana A Droesen Lenny L Zijlstra Andries A

Clinical & experimental metastasis 20190218 2

In epithelial-derived cancers, altered regulation of cell-cell adhesion facilitates the disruption of tissue cohesion that is central to the progression to malignant disease. Although numerous intercellular adhesion molecules participate in epithelial adhesion, the immunoglobulin superfamily (IgSF) member activated leukocyte cell adhesion molecule (ALCAM), has emerged from multiple independent studies as a central contributor to tumor progression. ALCAM is an archetypal member of the IgSF with c ...[more]

PMID: 30778704

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Project description:Activated leukocyte cell adhesion molecule (ALCAM, or CD166) is a cell adhesion molecule and one of potential tumour metastasis 'soil' receptors that via homotypic and heterotypic interactions, mediates cancer cell adhesion. The present study investigated clinical, pathological and prognostic values of ALCAM in patients with pancreatic cancer. Human pancreatic cancer (PANC-1 and Mia PaCa-2) and human vascular endothelial cell lines were used to construct cell models differentially expressing levels of ALCAM. Tumour-endothelial interaction and tumour migration were assessed by a DiI-based method and electric cell-substrate impedance sensing (ECIS) assay. Pancreatic cancer tissues (n=223), collected immediately after surgery, were analysed for levels of the ALCAM transcripts, which were also analysed against clinical, pathological and clinical outcomes of the patients. ALCAM protein was assessed by immunohistochemistry on a tissue array. Our study demonstrate that pancreatic cancer tissues had significantly higher levels of ALCAM transcripts than normal tissues (P<0.00001). There were no significant differences with staging, differentiation and tumour locations. Tumours from patients who died of pancreatic cancer had significantly high levels of ALCAM compared with those who lived (P=0.018), and this finding was further supported by ROC analysis (P=0.016). Multivariant analysis showed that ALCAM is an independent prognosis factor for overall survival (HR=5.485), with both nodal status and TNM staging contributing to the model (HR=2.578 and 3.02, respectively). A surprising finding was the relationship between ALCAM expression and microvessel embolism of tumour cells (P=0.021, with vs without tumour embolism). Levels of ALCAM were found to be a determinant factor to adherence of the pancreatic cancer cells to vascular endothelial cells, as demonstrated by pancreatic cancer cell models genetically engineered to express differential levels of ALCAM. The tumour-endothelial interaction mediated by ALCAM was readily blocked by addition of soluble ALCAM. Our data supports the conclusion that ALCAM expression is aberrant in pancreatic cancer and its raised expression is an independent prognostic factor for the survival of the patients and the microvascular embolism by cancer cells. Our results suggest that ALCAM plays a key role in mediating tumour-endothelial cell interactions and enhancing tumour embolism in pancreatic cancer, and targeting ALCAM represents a potential therapeutic strategy for treating human pancreatic cancer.

Dataset Information

Modulation of cell adhesion and migration through regulation of the immunoglobulin superfamily member ALCAM/CD166.

Publications

Modulation of cell adhesion and migration through regulation of the immunoglobulin superfamily member ALCAM/CD166.

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