Biomarker in the Spotlight: VCAM-1
VCAM-1 is one of our favorite biomarkers. The levels of this clinical biomarker are increased in patients with diseases as diverse as Parkinson’s disease and arthritis. The regulation of VCAM-1 is complicated. This has led to some interesting uses of VCAM-1 as an endpoint in phenotypic assays.
What is VCAM-1?
VCAM-1 (CD106 or vascular cell adhesion molecule-1) is a cell surface adhesion receptor that mediates the migration of white blood cells into tissues. VCAM-1 binds to adhesion molecules from the integrin family, α4β1 or VLA-4 and α4β7 integrins, on the surface of white blood cells. VCAM-1 is upregulated on a wide variety of cell types including endothelial cells when activated by inflammatory mediators. VCAM-1 can be shed from the cell surface and measured in serum.
Why is VCAM-1 important?
By controlling the localization and activation of white blood cells, VCAM-1 can contribute to inflammation-based tissue damage. Increased levels of VCAM-1 on endothelial cells or in tissues from patients have been observed in inflammatory bowel disease (Zurawski, et al., 2007; Gulubova et al., 2007; Danese et al., 2006), psoriasis (Rottman et al., 2001; Veale et al., 1995; Petzelbauer et al., 1997), graft-versus-host disease (Norton et al, 1992), atopic dermatitis (McAleer et al., 2018) and contact dermatitis (Das et al., 1994). Increased levels of soluble VCAM-1 have been found in sera from patients with rheumatoid arthritis (Klimek et al., 2014), Parkinson’s disease (Perner et al., 2019), chronic uticaria (itch) (Puxeddu et al., 2013) and peripheral artery disease (Edlinger et al., 2019). In rheumatoid arthritis patients, soluble VCAM-1 levels are reduced by anti-TNFalpha therapeutics, infliximab and etanercept (Klimiuk et al., 2004; Klimiuk et al, 2009). In patients with systemic lupus erythematosus, soluble VCAM-1 levels have been shown to correlate with disease severity (SLEDAI score) (Spronk et al., 1994). In coronary artery disease patients, soluble VCAM-1 levels were found to be associated with increased risk of death (Blankenberg et al., 2001). Soluble VCAM-1 levels were also found to be an independent predictor of death in patients with chronic heart failure (Savic-Radojevic et al., 2013).
How is VCAM-1 regulated?
The regulation of VCAM-1 expression is complicated. VCAM-1 expression can be induced by many different inflammatory mediators including IL-1, TNF-α, IFN-γ, IL-4 and IL-13 as well as bacterial-derived endotoxins such as LPS. Expression levels are further regulated by a variety of inflammatory and growth factor pathways including NF-κB, p38 MAPK, PKC, MAPK, JAK, HDAC, BET, and others. Regulation depends on the cell type and assay conditions or tissue setting.
We discovered an interesting feature of VCAM-1 regulation many years ago (Berg et al., 2005). When testing combinations of inflammatory mediators (IL-1, TNF-α, and IFN-γ) over large concentration ranges of each, synergistic effects were observed at very low concentrations while attenuated levels of VCAM-1 expression were observed at very high concentrations. This suggests that the individual pathways were interacting (through feedback or feed forward control mechanisms) to keep the level of VCAM-1 relatively stable over a wide range of mediator concentrations. This feature, robustness is characteristic of complex systems (read more here).
VCAM-1 as an endpoint in phenotypic assays.
The biological importance of VCAM-1 and its’ intriguing regulatory patterns led us to explore VCAM-1 as an endpoint in various human primary cell-based phenotypic assays (Berg, 2017). In these assays the regulation of VCAM-1 expression differs depending on the cell type and activation conditions (see the interactive case study here). One of the more interesting results came from testing a large set of reference drugs in a fibroblast-based model of wound healing, the BioMAP® HDF3CGF system. In this system, cells are stimulated with a cocktail of activators (IL-1β, TNF-α, IFN-γ, EGF, bFGF and PDGF-BB). From these experiments, a small number of reference drugs, all associated with a skin rash side effect, were found to further increase the levels of cell surface VCAM-1. These drugs include MEK inhibitors trametinib, pimasertib and selumetinib, p38 MAPK inhibitors, the IL-1receptor antagonist anakinra and IFN-β-1b. This work led to the development of a “toxicity signature” for MEK-associated skin rash (Berg et al., 2019).
This unexpected finding with VCAM-1 encouraged us to continue systematic efforts to study the regulation of clinical biomarkers in phenotypic assays. These studies are building our understanding of disease and toxicity mechanisms and can help in the design of safer medicines and the selection of safer drug combinations.
Image created in Canva by author.
