Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 15 January 2013
Vol. 6, Issue 258, p. ec12
[DOI: 10.1126/scisignal.2003959]


Cancer Chemotherapeutics Inflame Tumor Growth

Leslie K. Ferrarelli

Science Signaling, AAAS, Washington, DC 20005, USA

Whereas acute inflammation induced by chemotherapeutics aids in the antitumor response, chronic inflammation is protumorigenic. Gemcitabine (Gem) and 5-fluorouracil (5-FU) disrupt DNA replication to inhibit rapidly dividing cells, which can disrupt tumor growth and also enhance the activation of tumor-specific CD8+ T cells by selectively depleting myeloid-derived suppressor cells (MDSCs), but these drugs do not prevent tumor relapse. Bruchard et al. showed that Gem and 5-FU stimulated the release of protumorigenic interleukins from MDSCs before their depletion and that this was a mechanism that limited their antitumor efficacy. In MSC-2 cells, established cultures of MDSCs, Gem, or 5-FU activated the NOD-like receptor family pyrin domain–containing-3 protein (NLRP3)–dependent "inflammasome" complex—which activates caspase-1 to stimulate interleukin-1β (IL-1β) secretion—by inducing a cytosolic influx of cathepsin B, which is normally contained in lysosomes. Addition of a cathepsin B inhibitor or bafilomycin A, a lysosomal acidification inhibitor, to MSC-2 cells reduced 5-FU- or Gem-induced caspase-1 activation. In tumor-bearing mice and colon cancer patients treated with either Gem or 5-FU, NLRP3 activation and IL-1β secretion occurred exclusively with MDSCs. Genetic inactivation of either NLRP3 or caspase-1 to prevent IL-1β secretion restricted tumor growth and prolonged survival of 5-FU–treated mice bearing EL4 (lymphoblast), 4T1 (mammary), B16F10 (melanoma), or LLC (Lewis lung) carcinomas. Similarly, genetic inactivation of the IL-1 receptor (IL-1R) or treatment with an IL-1R antagonist (IL-1Ra) also enhanced the antiproliferative effect of 5-FU on EL4 tumor cells but did not affect tumor cell viability, indicating that the effects of IL-1β were on mouse host, not the xenografted tumor cells. MDSC-secreted IL-1β enhanced the secretion of a second cytokine, IL-17, from proinflammatory CD4+ T cells, the population of which increased in the tumor-draining lymph nodes of mice treated with 5-FU or Gem. IL-17 is implicated in angiogenesis, a critical process for tumor progression. The expression of proangiogenic genes (Eng and Pecam1) and T helper 17 cell–related genes (Il17a and Rorc), which are all regulated by IL-17, in the tissue surrounding the tumor was increased in vivo. IL-1Ra treatment combined with 5-FU blocked the induction of IL-17–regulated genes. Similar to Nlrp3–/– or Il-1R–/– cells, 5-FU was more effective at restricting tumor growth in Il17a–/– than in wild-type mice. MDSC depletion was critical to the antitumor effect of 5-FU, but depletion with 5-FU alone was not achievable without caspase-1 activation. The findings indicate that an improved chemotherapeutic strategy may be to combine IL-1 inhibition and 5-FU treatment.

M. Bruchard, G. Mignot, V. Derangère, F. Chalmin, A. Chevriaux, F. Végran, W. Boireau, B. Simon, B. Ryffel, J. L. Connat, J. Kanellopoulos, F. Martin, C. Rébé, L. Apetoh, F. Ghiringhelli, Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19, 57–64 (2013). [PubMed]

Citation: L. K. Ferrarelli, Chemotherapeutics Inflame Tumor Growth. Sci. Signal. 6, ec12 (2013).

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882