A wide-ranging study pre-published on-line in Nature last month points the finger at the chemokine CCL2 (also known as MCP-1, or JE in mice) as a key regulator of tumour metastasis. Intriguingly, CCL2 seems to participate in the generation of clinically-relevant metastatic disease on multiple levels: it promotes seeding of the shed metastatic cells, but it also promotes establishment and growth of the micrometastases, a process that is dependent on VEGF production from a tissue macrophage subset that responds to CCL2. All this nicely suggests that CCL2 (and its signaling pathway) may be an attractive therapeutic avenue for reducing the risk of metastasis. The close links between the academic authors and the global pharmaceutical company Johnson & Johnson suggests that this avenue is already being aggressively pursued.
But what about CCL2 as a biomarker for detecting early metastasis and directing treatment? The study shows that the density of CCL2-expressing macrophages in the region of the metastasis is associated with disease progression, so it seems plausible that measuring CCL2 levels in appropriate biological samples (whether tissue or blood) might be a productive investigation.
All this has special resonance for scientists at Total Scientific. A decade ago, similar data (here and here) linking CCL2 to the mechanism of atherosclerosis and vascular restenosis prompted us, among others, to investigate whether circulating levels of CCL2 might be predictive of coronary heart disease.
The bottom-line finding (that CCL2 levels in serum are not linked to heart disease) was disappointing. But the process of getting to that conclusion was highly instructive. CCL2 binds to blood cells through both high affinity (receptor) interactions and lower affinity (matrix) associations. The amount of CCL2 bound to signaling receptors is essentially irrelevant for the measurement of CCL2 in blood, but the lower affinity associations turned out to be much more significant. As much as 90% of the CCL2 in blood is bound to the enigmatic Duffy antigen on red blood cells (enigmatic because this receptor seems to be related to chemokine receptors but lacks any kind of signaling function). Worse still, this equilibrium is readily disturbed during the processing of the blood sample: anticoagulants such as heparin or EDTA shift the equilibrium in one direction or the other altering apparent CCL2 levels. Minor variations in the sample preparation protocol can have dramatic effects on the measured levels – whether between studies or within a study – not a good sign for a biomarker to achieve clinical and commercial utility.
And it’s not only ex vivo variables that affect the equilibrium: red blood cell counts differ between subjects, with women typically having lower red blood cell counts and lower total CCL2 levels as a result. Since women also have lower rates of heart disease, a widespread failure to recognize the complexity of measuring CCL2 in blood fractions most likely contributed to a number of false-positive studies. Needless to say, almost a decade on from those positive studies, CCL2 has not found a place as a biomarker for heart disease probably because, as we discovered, the reported associations had their origins in a subtle measurement artifact.
Does this mean CCL2 is unlikely to be a useful biomarker for metastatic potential among cancer sufferers? Not at all. But it does mean that studies to investigate the possibility will have to be much more carefully designed than is typically the case. Learning from our previous experiences studying CCL2 levels in heart disease patients, the Total Scientific team has assembled the necessary tools to address this question in cancer.
However, an old adage among biomarker researchers comes to mind: “If it looks simple to measure, it probably means you don’t know enough about it”.
Dr. David Grainger
CBO, Total Scientific Ltd.
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