Activated Leukocyte Cell Adhesion Molecule (ALCAM), a Potential ‘Seed’ and ‘Soil’ Receptor in the Peritoneal Metastasis of Gastrointestinal Cancers

Abstract

Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166) is a cell–cell adhesion protein conferring heterotypic and homotypic interactions between cells of the same type and different types. It is aberrantly expressed in various cancer types and has been shown to be a regulator of cancer metastasis. In the present study, we investigated potential roles of ALCAM in the peritoneal transcoelomic metastasis in gastrointestinal cancers, a metastatic type commonly occurred in gastro-intestinal and gynaecological malignancies and resulting in poor clinical outcomes. Specifically, we studied whether ALCAM acts as both a ‘seed’ receptor in these tumour cells and a ‘soil’ receptor in peritoneal mesothelial cells during cancer metastasis. Gastric cancer and pancreatic cancer tissues with or without peritoneal metastasis were compared for their levels of ALCAM expression. The impact of ALCAM expression in these tumours was also correlated to the patients’ clinical outcomes, namely peritoneal metastasis-free survival. In addition, cancer cells of gastric and pancreatic origins were used to create cell models with decreased or increased levels of ALCAM expression by genetic knocking down or overexpression, respectively. Human peritoneal mesothelial cells were also genetically transfected to generate cell models with different profiles of ALCAM expression. These cell models were used in the tumour-mesothelial interaction assay to assess if and how the interaction was influenced by ALCAM. Both gastric and pancreatic tumour tissues from patients who developed peritoneal metastases had higher levels of ALCAM transcript than those without. Patients who had tumours with high levels of ALCAM had a much shorter peritoneal metastasis free survival compared with those who had low ALCAM expression (p = 0.006). ALCAM knockdown of the mesothelial cell line MET5A rendered the cells with reduced interaction with both gastric cancer cells and pancreatic cancer cells. Likewise, levels of ALCAM in both human gastric and pancreatic cancer cells were also a determining factor for their adhesiveness to mesothelial cells, a process that was likely to be triggered the phosphorylation of the SRC kinase. A soluble ALCAM (sALCAM) was found to be able to inhibit the adhesiveness between cancer cells and mesothelial cells, mechanistically behaving like a SRC kinase inhibitor. ALCAM is an indicator of peritoneal metastasis in both gastric and pancreatic cancer patients. It acts as not only a potential peritoneal ‘soil’ receptor of tumour seeding but also a ‘soil’ receptor in peritoneal mesothelial cells during cancer metastasis. These findings have an important therapeutic implication for treating peritoneal transcoelomic metastases.

Inhibition of miR-214 expression by small molecules alleviates head and neck cancer metastasis by targeting ALCAM/TFAP2 signaling

“…The cell adhesion molecule ALCAM been reported to have an important role in tumor progression and is abundantly expressed in mesenchymal cells. Aberrant changes in ALCAM have also been reported in myeloma, prostate, esophagus, colon, pancreatic, and endometrial cancer [32,[45][46][47][48][49][50][51][52]. ALCAM is also a regulator of cadherin-mediated adherens junctions in uveal melanoma cells [53].…”

“…Cell-adhesion molecules have been reported for their significant contribution to the malignant phenotypes of human cancer cells and play an important role in cell proliferation, migration, invasion, and metastasis [31][32][33]. The ALCAM is a marker of mesenchymal cells and is involved in cancer metastasis [34].…”

Claudin-10 in the Blood Brain Barrier Function of Cerebral Endothelial Cells and Transendothelial Invasion of Breast Cancer Cells

“…Brain endothelial cells are an important components of the blood-brain barrier, and the claudin protein family in brain endothelial cells plays an important role in the strength of the blood-brain barrier, which can seriously affect substance diffusion (e.g. drug delivery) and brain metastasis of tumours including breast cancer (4,22,23). However, the role of CLDN10 in TJs of the blood brain barrier and brain metastasis of breast cancer has not been reported.…”

State-of-the-Art Molecular Oncology in UK

“…Yang et al [4] conducted a study to investigate the potential role of the activated leukocyte cell adhesion molecule (ALCAM) in the peritoneal metastasis of gastrointestinal cancers. Specifically, they aimed to determine whether ALCAM expression in gastrointestinal cancers, including gastric and pancreatic cancers, has a predictive value in the development of peritoneal metastasis.…”