Major finding: Platinum-activated MSCs release distinct fatty acids that mediate resistance to chemotherapy.
Impact: COX-1 or TXAS inhibitors may prevent MSC-induced chemoresistance.
Clinical relevance: Fish oil and algae extracts rich in these fatty acids neutralize the effect of cisplatin.
Platinum-based chemotherapy is the major treatment for many types of cancer, but development of resistance is a major obstacle to effective treatment. Roodhart and colleagues show that mouse tumors recruit mesenchymal stem cells (MSC) that are specifically activated by platinum chemotherapy and induce resistance to a broad range of chemotherapeutic agents by activating a cytoprotective response in the host tissue. A systematic metabolomic analysis of medium harvested from platinum-treated MSCs identified two distinct platinum-induced fatty acids (PIFA), KHT and 16:4(n-3), that could individually induce complete resistance to cisplatin at picomolar concentrations. Increased MSC levels were identified in patients with metastatic disease and a specific increase in PIFAs was identified in patients treated with platinum-based chemotherapy, validating these findings in human cancers. Because KHT is a by-product of thromboxane A2 synthesis, which requires both thromboxane-A synthase (TXAS) and upstream processing by cyclooxygenase (COX) of fatty acids released from cell membranes, the authors preincubated MSCs with inhibitors targeting individual steps of this metabolic pathway. They observed that administration of indomethacin (a COX-1 inhibitor) or ozagrel (a TXAS inhibitor) prior to platinum treatment abrogated MSC-induced resistance and enhanced the antitumor efficacy of platinum compounds in mouse tumor models, suggesting potentially druggable targets to prevent chemoresistance. Importantly, 16:4(n-3) is abundant in frequently used supplements such as fish oil and algae extract, indicating that rather than having beneficial effects on health in cancer patients, these natural supplements may promote resistance to chemotherapy. Indeed, a single oral dose of either fish oil or algae extract in mice neutralized the effect of cisplatin on tumors, further demonstrating the clinical relevance of fatty acids in chemoresistance.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details.
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