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