A cellular condition called oxidative stress can kill cancer cells. The finding that skin cancer cells evade such destruction using lipids acquired while passing through lymphatic vessels reveals a mechanism that boosts cancer spread.

The spread of cancer to distant parts of the body, such as to a compartment of the lymphatic system called a lymph node, indicates a poor prognosis for many types of the disease. However, for certain tumours, such as the skin cancer melanoma, lymph-node removal to prevent this spread does not increase survival time1,2. This finding might be explained by observations suggesting that the lymphatic system (which helps to maintain fluid balance and provides immune cells with a route for their movement) supplies vessels that offer an entry point through which spreading cancer cells can reach blood vessels3,4 on their way to distant organs. Once they have travelled there, the cancer cells seed and form secondary tumours called metastases. Thus, lymph-node infiltration is not necessarily an endpoint, but rather a stopover on the cells’ journey elsewhere. Yet the advantage of this detour has been unclear. Writing in Nature, Ubellacker et al.5 reveal the boost that cancer cells receive in transit through the lymphatic system.

Cancer spread, or metastasis, is an inefficient process6,7, and many cancer cells die in the bloodstream. A major contributory factor is oxidative stress in tumour cells. Studies have found that antioxidant treatment to block such stress causes an increase in the number of tumour cells in the bloodstream, and a rise in cancer spread to distant sites8,9. Oxidative stress can induce several types of cell death, but Ubellacker and colleagues show in mice that human or mouse melanoma cells in the bloodstream are killed by ferroptosis (Fig. 1), a cell-death mechanism that depends on lipid oxidation10.

The authors report that pretreating melanoma cells with the ferroptosis-inhibitor molecule liproxstatin-1 resulted in more metastases when the cells were injected into the animals’ bloodstream than when cells were not pretreated. By contrast, melanoma cells that disseminated through the lymphatic system produced the same degree of metastasis irrespective of liproxstatin-1 treatment, suggesting that such cells did not undergo ferroptosis. This finding indicates that, while in the lymphatic system, cancer cells acquire the ability to thwart a cell-death mechanism that usually impedes their progress if they move directly into the bloodstream. Moreover, Ubellacker et al. found that the number of melanoma cells in the animals’ lymph fluid was higher than the number in the bloodstream, and that cells that disseminated through the lymphatic system were more likely to form metastases than were those that did not. This finding is remarkable, because it shows that only particular environments induce ferroptosis, and it suggests that melanoma cells that move through the lymph system and then exit into the bloodstream are more likely to survive than are cells that do not pass through the lymph.
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Journal of Phlebology and Lymphology
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