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Ihh suppresses expression of ErbB family members in fibroblasts a Quantitative RT-PCR analysis for Betacellulin (BTC), Epiregulin (EREG), and Neuregulin (NRG1) in colons from Apc+/+Ihh+/+ (n = 9), Apc−/−Ihh+/+ (n = 9) and Apc−/−Ihh−/− (n = 9) mice. b In situ hybridization (RNAscope) for BTC, EREG, and NRG1 mRNA in colons of each group. Representative image of n = 9 mice per group is shown. c In situ hybridization (RNAscope) for BTC, EREG, and NRG1 mRNA in combination with immunofluorescent stainings for fibroblast-marker gp38, epithelial cell marker E-cadherin and proliferation marker BrdU in colons of the double mutant mice. Single dots represent expression of a single mRNA copy. Representative image of n = 9 mice is shown. Scale bar: 25 μm. Bars represent mean. *P < 0.05, **P < 0.01. Statistical analyses performed using one-way ANOVA.
Source publication
Indian Hedgehog (Ihh) is a morphogen expressed by epithelial cells in the small intestine and colon that signals in a paracrine manner to gp38+ stromal cells. The loss of Ihh signaling results in increased epithelial proliferation, lengthening and multiplication of intestinal crypts and the activation of a stromal cell immune response. How Ihh cont...
Citations
... Neufert et al. [91] found that CAFs were the main producer of EREG in the tumor microenvironment of colitis-associated cancers and that EREG deficiency impaired colitis-associated tumor growth in mice, thereby indicating the tumor-promoting role of CAF-derived EREG. In a murine model of colonic adenoma, EREG was upregulated in colonic fibroblasts and recombinant EREG promoted the proliferation of colonic organoids [92]. Given that EREG is produced from fibroblasts [36] and macrophages in the lungs [93], EREG that is derived from stromal cells, such as fibroblasts and macrophages in the tumor microenvironment, may contribute to lung tumorigenesis. ...
Simple Summary
Epiregulin (EREG) is a member of the ErbB family of ligands that plays multiple roles in cellular processes, including cell proliferation, invasion, and angiogenesis. Accumulating evidence has indicated that EREG is involved in lung tumorigenesis and therapeutic resistance. It is becoming evident that EREG contributes to the epithelial–mesenchymal transition, cancer stemness, immune evasion, and resistance to anticancer drugs in several human cancers, including non-small cell lung cancer. In this review, we summarized the current understanding of EREG as an oncogene and discussed its oncogenic role in lung tumorigenesis and therapeutic resistance.
Abstract
Epidermal growth factor (EGF) signaling regulates multiple cellular processes and plays an essential role in tumorigenesis. Epiregulin (EREG), a member of the EGF family, binds to the epidermal growth factor receptor (EGFR) and ErbB4, and it stimulates EGFR-related downstream pathways. Increasing evidence indicates that both the aberrant expression and oncogenic function of EREG play pivotal roles in tumor development in many human cancers, including non-small cell lung cancer (NSCLC). EREG overexpression is induced by activating mutations in the EGFR, KRAS, and BRAF and contributes to the aggressive phenotypes of NSCLC with oncogenic drivers. Recent studies have elucidated the roles of EREG in a tumor microenvironment, including the epithelial–mesenchymal transition, angiogenesis, immune evasion, and resistance to anticancer therapy. In this review, we summarized the current understanding of EREG as an oncogene and discussed its oncogenic role in lung tumorigenesis and therapeutic resistance.
... In addition, EREG knockout mice were more sensitive to dextran sodium sulphate-induced colonic inflammation, but EREG loss did not affect Apc mutation-induced tumorigenesis (Lee et al., 2004). Recently,stromal NRG1,EREG,and Betacellulin (BTC) were suggested to be regulated by colonic epithelium-derived Indian hedgehog signaling, and to be functionally involved in Apc mutation-induced tumorigenesis (Westendorp et al., 2021). Demonstrating the complexity of the EGF ligand signaling and location, expression of EREG has been shown to be induced during regeneration in the GI epithelium, and EREG as well as another EGF ligand Amphiregulin (AREG) have been proposed to function as effectors of the epithelial regenerative YAP signaling (Gregorieff et al., 2015;Zhang et al., 2009). ...
Growth factors secreted by stromal fibroblasts regulate the intestinal epithelium. Stroma-derived Epidermal growth factor (EGF) family ligands are implicated in epithelial regeneration and tumorigenesis, but their specific contributions and associated mechanisms remain unclear. Here, we use primary intestinal organoids modeling homeostatic, injured, and tumorigenic epithelium to assess how fibroblast-derived EGF family ligands Neuregulin-1 (NRG1) and Epiregulin (EREG) regulate the intestinal epithelium. NRG1 was expressed exclusively in the stroma, robustly increased crypt budding and protected intestinal epithelial organoids from radiation-induced damage. NRG1 also induced regenerative features in the epithelium including a fetal-like transcriptome, suppression of the Lgr5+ stem cell pool, and remodeling of the epithelial actin cytoskeleton. Intriguingly, unlike EGF and EREG, NRG1 failed to support the growth of pre-tumorigenic intestinal organoids lacking the tumor suppressor Apc, commonly mutated in human colorectal cancer (CRC). Interestingly, high expression of stromal NRG1 was associated with improved survival in CRC cohorts, suggesting a tumor suppressive function. Our results highlight the power of stromal NRG1 in transcriptional reprogramming and protection of the intestinal epithelium from radiation injury without promoting tumorigenesis.
... Among diverse EGFR ligands, EREG significantly reduces cellular sensitivity to tyrosine kinase inhibitors and is associated with decreased response to targeted agents, providing a basis for clinical decision making [10]. Further, increased expression of EREG in cancerassociated fibroblasts also deserves attention, as it correlates with higher tumor stage, enhanced invasiveness and shorter overall survival of cancer patients [11][12][13]. However, the mechanism underlying treatment-inducible expression of EREG in human stroma and its pathological implications remain poorly defined. ...
... Despite the complexity and variability of the microenvironment across organ and/or species types, however, we do speculate that EREG expression is not limited to the TME of a specific cancer type such as PCa or BCa, but may be universal across diverse malignancies, a feature that merits sufficient attention. Indeed, high EREG expression in the microenvironment is found to be correlated with advanced pathological stages, cancer cell invasion, distant metastasis, shorter OS and DFS of diverse cancer types including oral squamous cell carcinoma, gastric cancer, glioblastoma, colorectal and non-small cell lung cancer [11,12,[68][69][70][71], supporting EREG one of the competent targets for anticancer therapies. Although there still remains much to do before the strategy involving EREG-specific targeting in an in vivo system can be technically translated to clinical settings, our study provides a new modality that may be further improved to minimize drug resistance by targeting the treatment-damaged TME of cancer patients. ...
The tumor microenvironment (TME) represents a milieu enabling cancer cells to develop malignant properties, while concerted interactions between cancer and stromal cells frequently shape an “activated/reprogramed” niche to accelerate pathological progression. Here we report that a soluble factor epiregulin (EREG) is produced by senescent stromal cells, which non-cell-autonomously develop the senescence-associated secretory phenotype (SASP) upon DNA damage. Genotoxicity triggers EREG expression by engaging NF-κB and C/EBP, a process supported by elevated chromatin accessibility and increased histone acetylation. Stromal EREG reprograms the expression profile of recipient neoplastic cells in a paracrine manner, causing upregulation of MARCHF4, a membrane-bound E3 ubiquitin ligase involved in malignant progression, specifically drug resistance. A combinational strategy that empowers EREG-specific targeting in treatment-damaged TME significantly promotes cancer therapeutic efficacy in preclinical trials, achieving response indices superior to those of solely targeting cancer cells. In clinical oncology, EREG is expressed in tumor stroma and handily measurable in circulating blood of cancer patients post-chemotherapy. This study establishes EREG as both a targetable SASP factor and a new noninvasive biomarker of treatment-damaged TME, thus disclosing its substantial value in translational medicine.
... Table 1 summarizes the potential functions of EREG. EREG is usually overexpressed in various human cancers such as bladder cancer [51][52][53], brain cancer [54][55][56][57], breast cancer [38,39,[58][59][60][61][62][63], ovarian and cervical cancer [36,64], colorectal cancer [47,[65][66][67][68][69][70][71][72], head and neck cancer [11,37,[73][74][75][76], liver cancer [77,78], lung cancer [31,[79][80][81][82], pancreatic cancer [83], prostate cancer [84], gastric cancer (GC) [85,86], and thymic cancer [35]. IHC staining analysis revealed that EREG expression was observed in 237 (64.7%) of 366 biopsy tissues obtained from patients with NSCLC and was correlated with nodal metastasis and shorter survival [80]. ...
... This finding suggested that the tumor-promoting role of MUC1 is compensated by increased EREG production in the TME. Depletion of tumor suppressor gene-Indian hedgehog increased EREG/Adenoma Polyposis Coli (Apc) pathway-driven intestinal epithelial transformation in colonic stromal cells [72]. Collectively, the results indicate that autocrine and paracrine EREG may mainly activate EGFR downstream pathways in various cancer TMEs that contribute to tumorigenesis (Figure 4). ...
Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers.
