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Chemotherapy: PIFAs de resistance

Lipidomics Gateway (26 October 2011) [doi:10.1038/lipidmaps.2011.31]

Platinum-based chemotherapy induces mesenchymal stem cells to release two distinct fatty acids — 12-oxo-5,8,10-heptadecatrienoic acid and 4,7,10,13-tetraenoic acid — that can confer resistance to multiple types of chemotherapy.

Fish oil supplements confer resistance to chemotherapy.

For several types of cancer, platinum-based chemotherapy represents the mainstay of care, but such treatment often loses efficacy as resistance — both tumour-cell intrinsic and tumour-environment-mediated — arises. Coerced by tumour cells, mesenchymal stem cells (MSCs) are already known to stimulate tumour growth, increase angiogenesis and promote metastasis, but a report by Roodhart et al. now indicates a key role for these cells in inducing chemotherapy resistance by releasing platinum-induced fatty acids.

The authors first showed that mouse MSCs abrogated the antitumour effects of cisplatin when injected into various tumour models just before chemotherapy. Conditioned medium harvested from cultured MSCs briefly preincubated with cisplatin also induced resistance in tumour-bearing mice, indicating that the tumour-protective effect of MSCs was mediated in a systemic manner. The secreted factor(s) induced resistance to diverse types of chemotherapy, not just platinum analogues, but only when the MSCs had been activated beforehand by platinum-based chemotherapeutics.

Roodhart et al. then observed that the secreted chemoprotective factors caused an acute and reversible reduction in tumour cell apoptosis. However, this effect was not mediated directly by the secreted factor(s) but probably by an intermediate factor released into the plasma by the host tissue. To identify the MSC-secreted resistance-inducing factor, the authors systematically fractionated conditioned medium by size, liquid-liquid, solid-phase extraction and degree of saturation. The two resulting fractions contained 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)); each of these so-called PIFAs (platinum-induced polyunsaturated fatty acids), when purified and injected into tumour-bearing mice, conferred resistance to cisplatin.

KHT is a by-product of the synthesis of thromboxane A2 from arachidonic acid, and Roodhart et al. found that pretreating MSCs with inhibitors of several key components of this pathway — phospholipase A2, cyclooxygenase-1 or thromboxane synthase, or an intracellular calcium chelator — abrogated the platinum-induced tumour-protective effect. As blocking the cyclooxygenase–thromboxane synthase pathway was sufficient to prevent chemoresistance, 16:4(n-3) probably also functions downstream of this pathway.

These results highlight that targeting this pathway might provide an attractive means of preventing resistance to platinum-based chemotherapy, but how clinically relevant is this MSC/PIFA-mediated resistance? Roodhart et al. observed considerably more MSCs (comparable to the number able to confer chemoresistance in mouse models) in the peripheral blood of cancer patients with metastasis compared to those without evidence of disease. In addition, MSCs from healthy human patients or conditioned medium from cisplatin-preincubated MSCs induced resistance when injected into mice growing human breast cancer cells; mass spectrometry confirmed the presence of KHT and 16:4(n-3) in the conditioned medium. Furthermore, 16:4(n-3) levels were markedly higher in plasma samples taken from patients with cancer shortly after cisplatin treatment compared with those undergoing non-platinum-based chemotherapy.

So, platinum-based chemotherapy induces MSCs to secrete the PIFAs KHT and 16:4(n-3), which confer resistance to a broad range of chemotherapeutics by indirectly preventing apoptosis. However, although Roodhart et al. have identified that key enzymes involved in PIFA synthesis could be drugable targets, they also raise concerns regarding the consumption of certain fatty acids during chemotherapy. The health benefits of fish oils are widely extolled, but Roodhart et al. found that commercially available fish oil products administered orally at doses similar to the converted advised human daily dose abrogated the antitumour effects of cisplatin in tumour-bearing mice. Not only does this emphasize the clinical relevance of these PIFAs in the development of chemotherapy resistance, but it also indicates that these products might actually be doing more harm than good in cancer patients undergoing chemotherapy.

Katrin Legg

- Copyright © 2011 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission

References:

ORIGINAL RESEARCH PAPER

  1. Roodhart, J.M.L. et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids.

    Cancer Cell 20, 370-383 (2011). doi:10.1016/j.ccr.2011.08.010

FURTHER READING

  1. Meads, M.B., Gatenby, R.A. and Dalton, W.S. Environment-mediated drug resistance: a major contributor to minimal residual disease.

    Nat. Rev. Cancer 9, 665-674 (2009). doi:10.1038/nrc2714

  2. Wang, D. and Dubois, R.N. Eicosanoids and cancer.

    Nat. Rev. Cancer 10, 181-193 (2010). doi:10.1038/nrc2809

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