by ecancer reporter Clare Sansom

Macrophages are white blood cells that engulf “foreign” materials and so play an important role in the innate immune system.

They are also found in solid tumours, where they promote tumour progression and metastasis.

These tumours release cytokines that attract monocytes, the precursors of macrophages, from the bloodstream to the site of the tumour: when they enter the tumour they differentiate into macrophages.

Several molecules that impair the processes involved in the recruitment, differentiation and retention of tumour-associated macrophages are being developed as drugs for cancer.

One of the cytokines involved is C–C chemokine ligand 2 (CCL2), which is expressed by several tumour types and recruits monocytes expressing its receptor CCR2 to the site of the tumour.

In mouse models of metastatic breast cancer, compounds that block the binding of CCL2 to CCR2 on monocytes and thus prevent their differentiation into macrophages can delay metastasis and prolong survival.

Similarly, CCL2 expression and macrophage infiltration are both correlated with poor survival in human breast cancer.

These findings suggest that CCL2 might be a useful therapeutic target for this tumour type.

However, research recently published by Mohamed Bentires-Alj of Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland and his co-workers¹ suggest an unexpected drawback to this approach.

Bentires-Alj and his colleagues treated mice bearing CCL2-secreting metastatic breast tumours with anti-CCL2 or control antibody and found, as expected, that the anti-CCL2 antibody alone reduced cancer cell invasion and metastasis development.

They then stopped the antibody treatment in order to monitor the extent to which the anti-CCL2 effect persisted.

Surprisingly, they found a “dramatic” increase in lung and liver metastases and in circulating tumour cells (CTCs) in the mice that had received the anti-CCL2 antibody 10 days after the treatment had stopped.

The mean survival time of these mice was also less than that of the mice that had been given control antibody.

Ten days after stopping treatment, the mice that had been treated with anti-CCL2 had fewer monocytes in their bone marrow but more in tumour metastases than the control mice, indicating that these were only released from the bone marrow after treatment.

The researchers then transferred monocytes from the bone marrow of untreated, tumour-bearing mice into similar mice treated with anti-CCL2 or control antibody.

Monocytes that were transferred during anti-CCL2 treatment were retained in the bloodstream, whereas those transferred after treatment cessation migrated to the sites of the primary tumour and metastases.

This recruitment of monocytes from the blood to the tumour increased the number of CTCs and enhanced metastasis.

Bentires-Alj and his co-workers then assessed the extent to which monocyte recruitment mediates the increase in metastasis by removing the primary tumour from mice on the last day of anti-CCL2 treatment and assessing the lung metastases 10 days later.

Metastasis still increased in these mice even though numbers of CTCs were reduced.

This suggests that it is the recruitment of monocytes and their differentiation into macrophages that enhances metastasis after the end of anti-CCL2 treatment.

Further experiments suggested that the macrophages promote growth in metastases through increased expression of IL-6 and therefore of the pro-angiogenic growth factor VEGF-A, which is induced by this cytokine.

Treating similar tumour-bearing mice with anti-CCL2 followed by anti-IL-6 antibodies reduced VEGF-A levels; decreased angiogenesis, tumour cell proliferation and growth within the lung metastases; and increased the survival time of the animals.

Taken together, these results suggest that interruption of anti-CCL2 treatment induces an influx of macrophages into metastatic sites, leading to increased IL-6 levels, angiogenesis and accelerated metastasis.

In a News and Views in the same issue of Nature², Ioanna Keklikoglou and Michele de Palma of the Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland comment that these results underline both the potential and the drawbacks of anti-macrophage therapy for cancer.

They suggest that such treatments would be most effective with careful timing and when combined with other therapies that target the complex tumour micro-environment.

References

1. Bonapace, L., Coissieux, M-M., Wyckoff, J., Mertz, K.D., Varga, Z., Junt, T. and Bentires-Alj, M. (2014). Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130-133.

2. Keklikoglou, I. and de Palma, M. (2014). Metastasis risk after anti-macrophage therapy. Nature 515, 46-47.