Tumor fibroblast–derived epiregulin promotes growth of colitis-associated neoplasms through ERK
Clemens Neufert, … , Ugur Sahin, Markus F. Neurath
Clemens Neufert, … , Ugur Sahin, Markus F. Neurath
Published March 15, 2013
Citation Information: J Clin Invest. 2013;123(4):1428-1443. https://doi.org/10.1172/JCI63748.
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Research Article Oncology

Tumor fibroblast–derived epiregulin promotes growth of colitis-associated neoplasms through ERK

Abstract

Molecular mechanisms specific to colitis-associated cancers have been poorly characterized. Using comparative whole-genome expression profiling, we observed differential expression of epiregulin (EREG) in mouse models of colitis-associated, but not sporadic, colorectal cancer. Similarly, EREG expression was significantly upregulated in cohorts of patients with colitis-associated cancer. Furthermore, tumor-associated fibroblasts were identified as a major source of EREG in colitis-associated neoplasms. Functional studies showed that Ereg-deficient mice, although more prone to colitis, were strongly protected from colitis-associated tumors. Serial endoscopic studies revealed that EREG promoted tumor growth rather than initiation. Additionally, we demonstrated that fibroblast-derived EREG requires ERK activation to induce proliferation of intestinal epithelial cells (IEC) and tumor development in vivo. To demonstrate the functional relevance of EREG-producing tumor-associated fibroblasts, we developed a novel system for adoptive transfer of these cells via mini-endoscopic local injection. It was found that transfer of EREG-producing, but not Ereg-deficient, fibroblasts from tumors significantly augmented growth of colitis-associated neoplasms in vivo. In conclusion, our data indicate that EREG and tumor-associated fibroblasts play a crucial role in controlling tumor growth in colitis-associated neoplasms.

Authors

Clemens Neufert, Christoph Becker, Özlem Türeci, Maximilian J. Waldner, Ingo Backert, Katharina Floh, Imke Atreya, Moritz Leppkes, Andre Jefremow, Michael Vieth, Regine Schneider-Stock, Patricia Klinger, Florian R. Greten, David W. Threadgill, Ugur Sahin, Markus F. Neurath

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Figure 7

EREG directly increases proliferation in IECs and promotes colon tumor growth.

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EREG directly increases proliferation in IECs and promotes colon tumor g...
(A) Full-thickness rectosigmoidal pieces were incubated with PBS or EREG (500 ng/ml) and analyzed by immunohistochemistry for Ki67. Representative images out of 3 experiments are shown. Scale bars: 100 μm. (B) Staining was quantified by counting of positive cells per crypt. *P < 0.05. (C) IEC were grown in 12-well plates with varying concentrations of EREG. Cell numbers were determined after 24 and 48 hours. The experiment was performed in duplicate and repeated 3 times with similar results. *P < 0.05; **P < 0.01. (D–F) Rectosigmoidal tumors were induced in WT animals by AOM and 1 cycle of DSS. Starting at day 30, repeated injections of PBS (n = 5), recombinant EREG (n = 5), EGF (n = 3), or AREG (n = 3) were performed in the base of small tumors 4 times in 10 days. The change in tumor load was assessed by endoscopy at day 45. Data from 1 out of 2 experiments are shown and represent mean values ± SD. *P < 0.05.