Editors' ChoiceCancer

Waking a Sleeping Giant…on Purpose?

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Science Translational Medicine  27 Nov 2013:
Vol. 5, Issue 213, pp. 213ec196
DOI: 10.1126/scitranslmed.3008069

After treatment, some cancers such as breast cancer, prostate cancer, and melanoma can remain at bay for many years in a hibernation-like state called tumor dormancy. What causes tumors to remain dormant for long periods, and what factors trigger their awakening and regrowth? Can recurrences be predicted and treated before they fully emerge? The mechanisms behind the phenomenon of tumor dormancy and reemergence are still poorly understood. In preclinical mouse models of cancer, a variety of therapies promote apparent cures, only for relapse to occur after long periods without detectable disease. Now, Kottke et al. uncover early biomarkers of tumor recurrence and demonstrate a critical role for the innate immune system in sculpting the transition from minimal disease to overt tumors.

Taking advantage of multiple mouse models of tumor dormancy, Kottke and colleagues show that levels of proinflammatory cytokine interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) transiently spiked at sites of residual tumor and early tumor recurrences, mimicking the body’s natural response to infection. Spikes of IL-6 and VEGF were also detected in the blood of mice that ultimately developed recurrences. On the basis of these findings, the authors designed a clever reporter system fusing luciferase to a VEGF promoter in order to prospectively identify mice that would develop frank tumors. Early interventions of second-line treatments, including interferons and natural killer cells, were effective in animals that were predicted to relapse. Coaxing the tumors to awaken prematurely with VEGF treatment caused the rapid emergence of tumors that were sensitive to their original therapy, whereas tumors allowed to recur naturally were resistant to frontline therapy. This suggests that dormant tumors when denied the time to evolve and evade the innate immune system remain sensitive to initial therapy.

The authors suggest that purposefully waking dormant tumors before they have opportunity to evade the innate immune system may result in therapeutically sensitive tumors and, with treatment, prolong patient survival. These studies were performed in mice, and the role of the innate immune system in human tumor dormancy is still controversial. However, these findings argue that biomarkers for recurrence may exist and provide impetus to survey patients at high risk for relapse. Such surveys may determine whether IL-6 and VEGF spikes portend relapse and thereby provide an early treatment opportunity. Maybe dormant tumors, much like sleepy humans, are especially vulnerable to attack.

T. Kottke et al., Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence. Nat. Med., published online 17 November 2013 (10.1038/nm.3397). [ Abstract]

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