Editors' ChoiceCancer

Fibroblasts in Colon Cancer: Turned Traitor by Chemotherapy

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Science Translational Medicine  01 Jan 2014:
Vol. 6, Issue 217, pp. 217ec3
DOI: 10.1126/scitranslmed.3008240

Solid tumors are not just made up of tumor cells; the malignant cells exist in the context of nonmalignant stromal cells, such as fibroblasts, epithelial cells, and blood vessels. As such, no matter how aggressive, malignant cells also need to learn how to play nice—a tumor’s ability to coexist with nontransformed elements within its microenvironment may be equally important to its growth. Now, Lotti et al. show that resident fibroblasts secretly aid and abet the enemy by directly promoting tumor survival through a paracrine mechanism involving interleukin-17 (IL-17). The surprising twist is that this rogue fibroblast behavior that promotes cancer is potently activated by chemotherapy.

By using a coculture system, the authors incubated fibroblasts with human cancer-inducing cells (CICs) in vitro. Isolated fibroblasts had a minimal effect on adenosine triphosphate (ATP) activity by CICs; however, fibroblasts pretreated with 5-fluorouracil, oxaliplatin, and leucovorin, a typical chemotherapy regimen for colon cancer, led to a robust increase in CIC activity. Because this effect was also seen while using conditioned media, cell contact does not appear to be required. Next, the authors performed a series of elegant in vivo experiments with tumor cells coimplanted with fibroblasts into immunocompromised mice. Chemotherapy pretreatment of fibroblasts led to markedly increased tumor volumes and greater cell cycling of isolated tumor cells compared with untreated fibroblasts. Lastly, to identify the mechanism whereby fibroblasts support tumorogenesis, the authors used a 120-cytokine array to identify three candidate cytokines up-regulated by chemotherapy and ultimately showed through both gain- and loss-of-function experiments in vitro that the IL17/IL-17 receptor system was required and sufficient for fibroblast-induced CIC chemoresistence.

This paper illustrates the complex interplay among members of the tumor microenvironment and uncovers an unexpected potential off-target effect of 5-fluorouracil/oxaliplatin–based chemotherapy treatment for colorectal cancer. This work provides a proof of principle to study the addition of anti–IL-17 immunomodulation to standard chemotherapy regimens for colorectal cancer. The larger message is that even therapies with established mechanisms and proven efficacy may have unintended consequences. Thus, the best path to new therapies is often derived from drilling down to fully understand in greater detail both on- and off-target mechanisms of standard treatments.

F. Lotti et al., Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J. Exp. Med. 13, 2851–2872 (2013). [Abstract]

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