Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice

Dubé, Philip E.; Liu, Cambrian Y.; Girish, Nandini; Washington, Mary Kay; Polk, D. Brent

doi:10.1038/s41598-018-27353-w

Cited by 20 publications

(14 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DSS treatment was as previously described (52,53). Briefly, mice were trained to drink from water bottles, then exposed to water bottles containing 0.5-3% wt/vol DSS (36-50 kDa molar mass; MP Biomedicals) in distilled water, which served as their only source of drinking water for 6 days.…”

Section: Dss Colitismentioning

confidence: 99%

See 1 more Smart Citation

Persistence of Lgr5+ colonic epithelial stem cells in mouse models of inflammatory bowel disease

Girish

Liu

Gadeock

et al. 2021

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

Intestinal mucosal healing is the primary therapeutic goal of medical treatments for inflammatory bowel disease (IBD). Epithelial stem cells are key players in the healing process. Lgr5+ stem cells maintain cellular turnover during homeostasis in the colonic crypt. However, they are lost and dispensable for repair in a wide variety of injury models, including dextran sulfate sodium (DSS) colitis, radiation, helminth infection, and T-cell activation. The direct loss of Lgr5+ cells activates a plasticity response in the epithelium in which other cell types can serve as stem cells. Whether this paradigm applies to mouse models of IBD remains unknown. In contrast to previously tested models, IBD models involve an inflammatory response rooted in the loss of immunologic tolerance to intestinal luminal contents including the microbiome. Here we show the persistence of Lgr5+ cells in oxazolone, TNBS, and Il10-/- and Il10-/- Tnfr1-/- IBD models. This contrasts with results obtained from DSS-induced injury. Through high-throughput expression profiling, we find that these colitis models were associated with distinct patterns of cytokine expression. Direct exposure of colonic epithelial organoids to DSS, oxazolone, or TNBS resulted in increased apoptosis and loss of Lgr5+ cells. Targeted ablation of Lgr5+ cells resulted in severe exacerbation of chronic, antibody-induced IL-10-deficient colitis, but had only modest effects in TNBS-induced colitis. These results show that distinct mouse models of IBD-like colitis induce different patterns of Lgr5+ stem cell retention and function.

show abstract

Section: Dss Colitismentioning

confidence: 99%

“…Immunohistochemical labeling on formalin-fixed paraffin-embedded sections was performed according to standard procedures and as previously described (37,52). Staining signal was revealed using the Immpress HRP reagent kits (Vector Labs) in conjunction with DAB reagents (Vector Labs).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Persistence of Lgr5+ colonic epithelial stem cells in mouse models of inflammatory bowel disease

Girish

Liu

Gadeock

et al. 2021

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several growth factors and signaling cascades promote IEC proliferation [25–27]. Among these, the epidermal growth factor receptor (EGFR) and the downstream mitogen-activated protein kinase (MAPK) pathways are implicated in epithelial proliferation during DSS colitis and wound healing [28, 29]. Therefore, we determined ERK1/2 activation after fluid supplementation in whole colon lysates.…”

Section: Resultsmentioning

confidence: 99%

Fluid supplementation accelerates epithelial repair during chemical colitis

et al. 2019

View full text Add to dashboard Cite

The dextran sulfate sodium (DSS) model of colitis is a common animal model of inflammatory bowel disease that causes pain and distress. In this study, we aimed to determine whether fluid supplementation can be used as a welfare-based intervention to minimize animal suffering. C57Bl/6 females undergoing acute colitis by administration of 3% DSS in drinking water were supplemented with 1 mL intraperitoneal injections of NaCl and compared to non-supplemented control mice. Mouse behavior and locomotive activity were assessed on days 5–6 after DSS initiation by means of tail suspension, novel object recognition and open field activity tests. Mice were euthanized after either the acute (day 7) or the recovery phase (day 12) of colitis and inflammation, epithelial proliferation, and differentiation were assessed by means of histology, immunohistochemistry, quantitative PCR, and western blot. We found that fluid-supplemented mice had reduced signs of colitis with no alterations in behavior or locomotive activity. Furthermore, we observed an accelerated epithelial repair response after fluid hydration during the acute phase of colitis, characterized by increased crypt proliferation, activation of ERK1/2, and modulation of TGF-β1 expression. Consistent with these findings, fluid-supplemented mice had increased numbers of goblet cells, upregulated expression of differentiation markers for absorptive enterocytes, and reduced inflammation during the recovery phase. Our results show that fluid hydration does not reduce stress in DSS-treated mice but alters colitis evolution by reducing clinical signs and accelerating epithelial repair. These results argue against the routine use of fluid supplementation in DSS-treated mice.

show abstract

“…Animal studies have shown that early administration of gefitinib, an EGFR kinase inhibitor, can increase the tumour size, whereas its late administration can reduce the tumour size. EGFR plays an important role in the pathological development of IBD, especially CAC [ 39 , 40 ]. The mechanism of EGFR in IBD treatment is unclear, yet most studies show that EGFR is closely related to cytokines and mitochondrial autophagy [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Active Ingredients and Potential Mechanisms of the Gan Jiang-Huang Qin-Huang Lian-Ren Shen Decoction against Ulcerative Colitis: A Network Pharmacology and Molecular Docking-Based Study

Zhou

Zhang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

Background. Ulcerative colitis (UC), a chronic and nonspecific inflammatory bowel disease, seriously affects the quality of patients’ life. Han Re Bing Yong Fa (treating diseases with both cool- and warm-natured herbs) is a classical therapeutic principle of traditional Chinese medicine (TCM), which is often used to treat chronic diseases, including UC. The Gan Jiang-Huang Qin-Huang Lian-Ren Shen decoction (GJHQHLRSD), a representative of Han Re Bing Yong Fa, is effective in alleviating inflammatory symptoms in UC. However, the pharmacological mechanism underlying its anti-inflammatory effect remains unclear. Methods. A network pharmacology strategy, including the construction and analysis of the drug–disease network, was used to explore the complex mechanism of GJHQHLRSD treatment of UC. In addition, molecular docking technology was used to preliminarily examine the binding ability of the potential active components and core therapeutic targets of GJHQHLRSD. Results. The network pharmacology results revealed 140 targets of GJHQHLRSD which are involved in UC. The PPI network analysis identified seven target genes: BCL2L1, NR3C1, ALOX5, S1PR5, NR1I2, CYP2D6, and LPAR6. The molecular docking results revealed that the following displayed strongest combined effects: EGFR with kaempferol, ERK1 with worenine, STAT3 with Palmidin A, BCL2L1 with diop and VEGFA with ginsenoside Rg3. The KEGG and gene ontology enrichment analyses results indicated that GJHQHLRSD functions by regulating the EGFR signaling pathway in UC treatment. Other effective biological processes involved in UC treatment included cancer-related as well as inflammation and viral infection signaling pathways, such as the “MicroRNAs in cancer,” “TNF signaling pathway,” and “JAK-STAT signaling pathway.” Conclusions. This study reflects the multicomponent, multitarget, and multipathway characteristics of the action mechanism of GJHQHLRSD in treating UC. Furthermore, it helps better understand the TCM therapeutic principle of Han Re Bing Yong Fa and explore novel candidate drug targets for UC treatment.

show abstract

Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice

Cited by 20 publications

References 85 publications

Persistence of Lgr5+ colonic epithelial stem cells in mouse models of inflammatory bowel disease

Persistence of Lgr5+ colonic epithelial stem cells in mouse models of inflammatory bowel disease

Fluid supplementation accelerates epithelial repair during chemical colitis

Active Ingredients and Potential Mechanisms of the Gan Jiang-Huang Qin-Huang Lian-Ren Shen Decoction against Ulcerative Colitis: A Network Pharmacology and Molecular Docking-Based Study

Contact Info

Product

Resources

About