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 miniendoscopic 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 colitisassociated neoplasms.

Crucial involvement of the CCL3‐CCR5 axis‐mediated fibroblast accumulation in colitis‐associated carcinogenesis in mice

“…12 CAF-derived epiregulin is proposed to be crucially involved in AOM/DSS-induced neoplasms by activating mitogen-activated protein kinase (MAPK) pathway. 13 However, we failed to observe a sustained elevation of epiregulin and the effects of CCL3 or CCR5 deficiency on its expression in colon. On the contrary, HB-EGF expression was markedly attenuated in CCL3-or CCR5-deficient mice, implying that the CCL3-CCR5 axis can regulate HB-EGF expression by fibroblasts in colon.…”

“…11 In the AOM/DSS-induced CAC model, the contribution of CAF-derived growth factors has been documented. 12,13 However, the mechanism regulating CAF trafficking in AOM/DSS-induced CAC remains unclear. We observed that AOM/DSS treatment enhanced the intracolonic expression of another chemokine, CCL3, which can exhibit biological effects on leukocytes and non-leukocyte cells, particularly fibroblasts.…”

Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

“…Because Areg and Ereg are both ADAM17 substrates (53), it has been postulated that ADAM17-mediated ErbB ligand shedding to produce soluble ligands plays critical role in activating ErbB signaling in IECs (21). Although the cellular source of these ErbB ligands was not clearly defined in this study, other studies have highlighted the contribution of ErbB ligand/EGFR signaling axis from nonepithelial mucosal cell types, including myeloid/ immune cells and pericryptal myofibroblasts found in the lamina propria (54,55).…”

Cosmc is an X-linked inflammatory bowel disease risk gene that spatially regulates gut microbiota and contributes to sex-specific risk

“…Epithelia were purified (35) and immunoblots performed (36) with antibodies against Cosmc (C4; Santa Cruz) and actin (H-10; Santa Cruz).…”

“…Intestinal epithelia were purified (35) and total RNA isolated by RNeasy (Qiagen) with RNA quality and purity assessed by Agilent BioAnalyzer and nanodrop, respectively. University of California, Los Angeles (UCLA) genomics core performed RNA amplification and hybridization on Illumina mouse ref 8 v2.0 expression chips.…”