Most metastatic solid tumours will be treated with chemotherapy. This is generally effective in the short term but its long term efficacy is compromised by the development of resistance. Several mechanisms for the development of tumour resistance have been proposed, some arising from the tumour micro-environment and others from the tumour cells themselves. This micro-environment includes inflammatory and bone marrow derived cells recruited into the stroma by the developing tumour. A group of bone marrow derived cells that can differentiate into other cell types, the mesenchymal stem cells (MSCs) are known to promote tumour growth, angiogenesis, and metastasis.

A team of researchers led by Emile Voest at the University Medical Center Utrecht, Utrecht, The Netherlands has now investigated the possibility that these cells might also promote resistance to chemotherapy. They first established a mouse model in which MSCs were harvested from the mouse bone marrow and injected into tumour-bearing mice, either as first isolated or after repeated culturing to establish their purity. These cells were observed to accumulate in the tumour but not in other, neighbouring tissues.

They then treated the mice with the commonly used platinum-based chemotherapy agent cisplatin, and found that tumours that had been injected with MSCs were almost completely resistant to the drug. This effect was observed in two different cancer models, one of lung and the other of colon carcinoma, and regardless of whether the MSCs had been cultured before they were injected. Resistance was induced just as effectively when the stem cells were injected subcutaneously rather than directly at the site of the tumour, suggesting that this was a systemic effect and probably due to the release of a chemical factor. The fact that cultured medium harvested from MSCs cultured with cisplatin had the same resistance-inducing effect as the cells themselves provided further evidence for this theory. This cultured medium was able to confer resistance to drugs other than platinum-containing ones, but culturing the MSCs with the same drugs (which included doxorubicin) did not induce resistance.

Taken together, these results suggested that platinum-containing drugs stimulate MSCs to secrete a factor that can confer resistance to chemotherapy through some general mechanism. The researchers then used a metabolomics approach to identify the nature of this factor. Systematic fractionation of the cultured medium revealed it to include two distinct polyunsaturated fatty acids, 12-oxo-5,8,10-heptadecatrienoic acid (also known as KHT) and hexadeca-4,7,10,13-tetraenoic acid. These are both synthesised within the cyclo-oxygenase (COX)-1 / thromboxane synthase (TXAS) pathway, the former being a by-product of the synthesis of thromboxane A2. Voest and her co-workers pre-incubated cultured MSCs with compounds that are known to inhibit the various steps within this pathway before incubating them with cisplatin. Interestingly, inhibitors of the enzymes phospholipase A2, cyclo-oxygenase 1 and thromboxane synthase prevented the induction of resistance, whereas inhibitors of other enzymes in the pathway had no effect. A mechanism could be derived for the release of the two fatty acids that involved these three enzymes alone.

Voest and her co-workers went on to investigate the clinical relevance of these potentially important findings. They first tested the whole peripheral blood of cancer patients and found that the blood of patients with metastatic disease contained significantly more MSCs than that of patients with no residual disease after surgery. Furthermore, the concentrations of the two fatty acids involved were found to be elevated after chemotherapy with platinum-containing but not other agents. Inhibiting the enzymes that produce fatty acids from MSCs may become an important strategy in preventing resistance to chemotherapy. Of more immediate importance, however, is the fact that some food products, including fish oils often taken as supplements by cancer patients, contain small quantities of the fatty acids. Patients taking platinum-based drugs in particular should be advised to avoid taking these supplements.

Reference

Roodhart, J.M.L., Daenen,, L.G.M., Stigter, E.C.A. and 17 others (2011), Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids, Cancer Cell 20, 370–383. doi: 10.1016/j.ccr.2011.08.010