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Importance of activated leukocyte cell adhesion molecule (ALCAM) in prostate cancer progression and metastatic dissemination.

ABSTRACT: Activated Leukocyte Cell Adhesion Molecule (ALCAM) has been linked to the progression of numerous human cancers, where it appears to play a complex role. The current study aims to further assess the importance of ALCAM in prostate cancer and the prognostic potential of serum ALCAM as a biomarker for prostate cancer progression. Here we demonstrate enhanced levels of tissue ALCAM are associated with metastasis. Additionally, elevated serum ALCAM is indicative of progression and poorer patient outlook, and demonstrates comparable prognostic ability to PSA in terms of metastasis and prostate cancer survival. ALCAM suppression enhanced proliferation and invasiveness in PC-3 cells and motility/migration in PC-3 and LNCaP cells. ALCAM suppressed PC-3 cells were generally less responsive to HGF and displayed reduced MET transcript expression. Furthermore a recombinant human ALCAM-Fc chimera was able to inhibit LNCaP cell attachment to HECV and hFOB1.19 cells. Taken together, ALCAM appears to be a promising biomarker for prostate cancer progression, with enhanced serum expression associated with poorer prognosis. Suppression of ALCAM appears to impact cell function and cellular responsiveness to certain micro environmental factors.

SUBMITTER: Sanders AJ

PROVIDER: S-EPMC6824871 | biostudies-other | 2019 Oct

REPOSITORIES: biostudies-other

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Importance of activated leukocyte cell adhesion molecule (ALCAM) in prostate cancer progression and metastatic dissemination.

Sanders Andrew J AJ Owen Sioned S Morgan Liam D LD Ruge Fiona F Collins Ross J RJ Ye Lin L Mason Malcolm D MD Jiang Wen G WG

Oncotarget 20191029 59

Activated Leukocyte Cell Adhesion Molecule (ALCAM) has been linked to the progression of numerous human cancers, where it appears to play a complex role. The current study aims to further assess the importance of ALCAM in prostate cancer and the prognostic potential of serum ALCAM as a biomarker for prostate cancer progression. Here we demonstrate enhanced levels of tissue ALCAM are associated with metastasis. Additionally, elevated serum ALCAM is indicative of progression and poorer patient out ...[more]

PMID: 31695844

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Project description:BackgroundAn altered expression of the activated leukocyte cell adhesion molecule (ALCAM) is associated with cancer progression in various cancer types. In some cancers ALCAM has a prognostic value or is predictive for the benefit of therapeutic interventions. To date there are no data on the role of ALCAM in cervical cancer available.MethodsIn this study, ALCAM expression was analysed by immunohistochemistry (IHC) in tissue samples of 233 patients with cervical cancer, among them 178 with complete follow-up information. In addition, soluble (s-)ALCAM was measured in sera of a subset of the included patients (n = 55) by enzyme-linked immunosorbent assay (ELISA).ResultsALCAM overexpression was detected (immunoreactive score (IRS) 2-12) in 58.4% of the cervical cancer samples. The normal ectocervical or endocervical epithelium showed no ALCAM reactivity. In untreated patients, ALCAM overexpression in tumor tissue tended to be associated with shorter cancer-specific survival (CSS) and disease-free survival (DFS). Patients, whose tumor samples showed ALCAM overexpression receiving a cytotoxic therapy like radiotherapy or chemoradiation, however, had a favourable prognosis compared to those patients, whose cancers showed no or minimal ALCAM staining. This effect was particularly apparent in patients receiving chemoradiation where the CSS was significantly longer in patients with ALCAM-positive tumors (p = 0.038; cumulative incidence rates at 96 months 8%, 95% CI 0%-23%, and 26%, CI 3%-43% in ALCAM-positive and ALCAM-negative cases, respectively).Median preoperative s-ALCAM concentration in sera from tumor patients was 27.6 ng/ml (range 17.5-55.1 ng/ml, mean 28.9 ng/ml), serum levels did not correlate with intratumoral ALCAM expression.ConclusionsThe data of our retrospective study suggest that the prognostic value of ALCAM expression in cervical carcinoma might be therapy-dependent, and that ALCAM might function as a predictive marker for the response to chemoradiation. This should be confirmed in further, prospective studies.

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.

Project description:Multiple sclerosis is a chronic neuroinflammatory disorder characterized by demyelination, oligodendrocyte damage/loss and neuroaxonal injury in the context of immune cell infiltration in the central nervous system. No neuroprotective therapy is available to promote the survival of oligodendrocytes and protect their myelin processes in immune-mediated demyelinating diseases. Pro-inflammatory CD4 T helper (Th)17 cells can directly interact with oligodendrocytes in multiple sclerosis and its animal model, causing injury to myelinating processes and cell death through direct contact. However, the molecular mechanisms underlying the close contact and subsequent detrimental interaction of Th17 cells with oligodendrocytes remain unclear. In this study we conducted single cell RNA sequencing of human primary oligodendrocytes cultured alone, in contact or separated by an insert with primary Th17 polarized T cells and identified several cell adhesion molecules that may modulate T cell contact mediated damage of oligodendrocytes. Furthermore, we used flow cytometry and immunofluorescence studies on central nervous system tissue from multiple sclerosis subjects, its animal model and controls to characterize the expression of cell adhesion molecules by mature oligodendrocytes. We found that a significant proportion of human and murine mature oligodendrocytes express melanoma cell adhesion molecule and activated leukocyte cell adhesion molecule in multiple sclerosis, EAE and controls although their regulation differ between human and mouse. We observed that exposure to pro-inflammatory cytokines or to human activated T cells are associated with a marked downregulation of the expression of melanoma cell adhesion molecule but not activated leukocyte cell adhesion molecule at the surface of human primary oligodendrocytes. Furthermore, we used in vitro live-imaging, immunofluorescence, and flow cytometry to determine the contribution of these molecules to Th17-polarized cell adhesion and cytotoxicity towards human oligodendrocytes. Silencing and blocking activated leukocyte cell adhesion molecule but not melanoma cell adhesion molecule limited prolonged interactions between oligodendrocytes and Th17-polarized cells, resulting in decreased adhesion of Th17-polarized cells to oligodendrocytes and conferred significant protection of oligodendrocytic processes.

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Importance of activated leukocyte cell adhesion molecule (ALCAM) in prostate cancer progression and metastatic dissemination.

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Importance of activated leukocyte cell adhesion molecule (ALCAM) in prostate cancer progression and metastatic dissemination.

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