ArticleOncogene2014
Heparin-binding epidermal growth factor-like growth factor eliminates constraints on activated Kras to promote rapid onset of pancreatic neoplasia.
Article in Oncogene, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- Loss of HNF6 expression correlates with human pancreatic cancer progression.Laboratory investigation; a journal of technical methods and pathology · 2014Pooled it
- Mechanistic Foundations of KRAS-Driven Tumor Ecosystems: Integrating Crosstalk among Immune, Metabolic, Microbial, and Stromal Microenvironment.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Precision immune regulation in KRAS-mutated cancers: the final piece of the puzzle?Journal of experimental & clinical cancer research : CR · 2025Review
- Interaction of the tumor suppressor SMAD4 and WNT signaling in progression to oral squamous cell carcinoma.The Journal of pathology · 2024Article
- Trapping all ERBB ligands decreases pancreatic lesions in a murine model of pancreatic ductal adenocarcinoma.Molecular oncology · 2023Article
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- Article
- Proteolytic pan-RAS Cleavage Leads to Tumor Regression in Patient-derived Pancreatic Cancer Xenografts.Molecular cancer therapeutics · 2022Article
- Innate immunity in pancreatic cancer: Lineage tracing and function.Frontiers in immunology · 2022Review
- Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis.Frontiers in cell and developmental biology · 2022Article
- Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Therapeutic Opportunities and Clinical Challenges.Cancers · 2021Review
- Colon epithelial cell TGFβ signaling modulates the expression of tight junction proteins and barrier function in mice.American journal of physiology. Gastrointestinal and liver physiology · 2021Article
- Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice.Molecular oncology · 2020Article
- Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer.Cancer cell · 2020Article
- Hiding in plain sight.Science (New York, N.Y.) · 2019Article
- The Gene Expression Biomarkers for Chronic Obstructive Pulmonary Disease and Interstitial Lung Disease.Frontiers in genetics · 2019Article
- Myeloid Cell-Derived HB-EGF Drives Tissue Recovery After Pancreatitis.Cellular and molecular gastroenterology and hepatology · 2019Article
- Oncogenic KRAS and the EGFR loop in pancreatic carcinogenesis-A connection to licensing nodes.Small GTPases · 2018Review
- Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer.Cellular and molecular gastroenterology and hepatology · 2018Article
- Epithelial-Myeloid cell crosstalk regulates acinar cell plasticity and pancreatic remodeling in mice.eLife · 2017Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
Pancreatic cancer remains as one of the most deadly cancers with few treatment options at late stages and little information about how it develops through earlier stages. Activating mutation of the Kras gene has been implicated in, but is not sufficient for, tumorigenesis. In mouse models of pancreatic cancer, loss of tumor suppressor genes in conjunction with Kras mutation leads to gradual stochastic acquisition of neoplastic precursors and carcinomas, whereas many cells remain phenotypically unaltered in younger mice. Here, we demonstrate that two oncogenic events, mutation of Kras and production of the growth factor heparin-binding epidermal growth factor-like growth factor (HB-EGF), are sufficient for rapid and complete neoplastic transformation of the exocrine pancreas. We found that macrophages are the major source of HB-EGF production in pancreatic cancer tissue samples, and that macrophages are present in high density and in close association with human pancreatic cancer lesions. In a mouse model, high macrophage density was observed at the earliest stages of neoplastic transformation. The consequence of elevated HB-EGF signaling was investigated without the confounding effects of other macrophage-produced factors via transgenic overexpression of the active form of HB-EGF. In this model, HB-EGF was sufficient to promote Kras-initiated tumorigenesis, inducing rapid and complete neoplastic transformation of the entire exocrine pancreas shortly after birth. HB-EGF overexpression and Kras(G12D) together, but neither alone, increased proliferation with increased cyclinD1 and decreased Cdkn2a/2d (p16/p19(Ink4A/Arf)). These findings establish the importance of oncogenic synergy in cancer initiation and promotion, and establish a molecular link between inflammation and the earliest stages of tumor induction.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.