by ecancer reporter Janet Fricker

Stopping a treatment believed to block metastasis of breast cancer to other organs leads to the ‘paradoxical’ effect of accelerating the growth of lung metastases, caution Swiss researchers in Nature.

Expression of C-C chemokine ligand 2 (CCL2) by breast tumours has been demonstrated to recruit CCR2 expressing inflammatory monocytes to primary tumours and metastatic sites.

Furthermore, studies have shown that CCL2 neutralisation in mice inhibits metastasis by retaining monocytes in the bone marrow, and that high expression of CCL2 correlates with decreased survival of breast cancer patients.

In the current study, Mohamed Benitres-Alj and colleagues, from Friedrich Miescher Institute for Biomedical Research, Basel, assessed the effect of CCL2 neutralisation on tumour growth and metastasis in mouse models.

Although anti-CCL2 treatment had no effect on primary tumour growth, the team demonstrated that it reduced the number of lung metastases and circulating tumour cells.

Intravital imaging additionally showed that anti-CCL2 treatment reduced cancer cell motility and blood vessel leakiness in the tumour, correlating with fewer circulating tumour cells.

Next, the team examined the persistence of the anti-metastatic effect after treatment discontinuation, finding that antibodies were cleared within 10 days, leading to a rebound of CCL2 levels in the lungs.

They observed dramatic increases in lung and liver metastases, increases in circulating tumour cells, and increased expression of IL-6 in serum and metastatic lung tissue.

IL-6 induced expression of pro angiogenic VEGF-A in monocytes ex vivo.

“Together these data support the idea that the complex tumour microenvironment is critical for effective anti-tumour strategies. Anti-CCL2 treatment decreased breast cancer metastases in mice, but interruption of anti-CCL2 treatment precipitated an unexpected influx of monocytes in to the metastatic site and overshooting IL-6 levels within the metastatic microenvironment,” write the authors, adding this led to local enhancement of angiogenesis, metastatic disease and a fatal outcome.

“Therefore our results prompt extreme caution when considering anti-CCL2 treatment of metastatic breast cancer and other neoplasias and suggest that therapeutic interference with the tumour microenvironment might lead to tissue remodelling not only locally but also at remote sites such as the bone marrow, with unexpected far-reaching consequences including a worsened prognosis for cancer patients.”

Reference

L Bonapace, M Coissieux, J Wyckoff, et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature.