Hepatocellular carcinoma (HCC) is a frequent cancer with limited treatment options and poor prognosis. Tumorigenesis has been linked with macrophage-mediated chronic inflammation and diverse signaling pathways including the Epidermal Growth Factor Receptor (EGFR) pathway. The precise role of EGFR in HCC is unknown, and EGFR-inhibitors have shown disappointing clinical results. Here we discover that EGFR is expressed in liver macrophages in both human HCC and in a mouse HCC model. Mice lacking EGFR in macrophages show impaired hepatocarcinogenesis, whereas mice lacking EGFR in hepatocytes unexpectedly develop more HCC due to increased hepatocyte damage and compensatory proliferation. Mechanistically, following IL-1 stimulation, EGFR is required in liver macrophages to transcriptionally induce IL-6, which triggers hepatocyte proliferation and HCC. Importantly, the presence of EGFR-positive liver macrophages in HCC-patients is associated with poor survival. This study demonstrates a tumor-promoting mechanism for EGFR in non-tumor cells, which could lead to more effective precision medicine strategies.

The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR signaling axis has been shown to play a key role during liver regeneration following acute and chronic liver damage, as well as in cirrhosis and hepatocellular carcinoma (HCC) highlighting the importance of the EGFR in the development of liver diseases. Despite the frequent overexpression of EGFR in human HCC, clinical studies with EGFR inhibitors have so far shown only modest results. Interestingly, a recent study has shown that in human HCC and in mouse HCC models the EGFR is upregulated in liver macrophages where it plays a tumor-promoting function. Thus, the role of EGFR in liver diseases appears to be more complex than what anticipated. Further studies are needed to improve the molecular understanding of the cell-specific signaling pathways that control disease development and progression to be able to develop better therapies targeting major components of the EGFR signaling network in selected cell types. In this review, we compiled the current knowledge of EGFR signaling in different models of liver damage and diseases, mainly derived from the analysis of HCC cell lines and genetically engineered mouse models (GEMMs).

The epidermal growth factor receptor (EGFR) regulates cellular expression levels of breast cancer resistance protein (humans: ABCG2, rodents: Abcg2) via its downstream signaling pathways. Drugs that inhibit EGFR signaling (e.g., tyrosine kinase inhibitors, antibodies) may lead to ABCG2-mediated drug-drug interactions (DDIs) by changing the disposition of concomitantly administered ABCG2 substrate drugs. In this study, we used positron emission tomography and magnetic resonance imaging to compare disposition of the model Abcg2 substrate [C]erlotinib in a mouse model of hepatocyte-specific deletion of EGFR (EGFR mice, = 5) with EGFR control mice ( = 6), which have normal EGFR expression levels in all tissues. Integration plot analysis was used to estimate the rate constants for transfer of radioactivity from the liver into bile () and from the kidney into urine (). EGFR mice showed significantly lower radioactivity concentrations in the intestine (1.6-fold) and higher radioactivity concentrations in the urinary bladder (3.2-fold) compared with EGFR mice. was significantly decreased (3.0-fold) in EGFR mice, whereas k was by 2.2-fold increased. Western blot analysis of liver tissue confirmed deletion of EGFR and showed significant decreases in Abcg2 and increases in P-glycoprotein (Abcb1a/b) expression levels in EGFR versus EGFR mice. Our data show that EGFR deletion in hepatocytes leads to a reduction in Abcg2-mediated hepatobiliary clearance of a probe substrate accompanied by a shift to renal excretion of the drug, which raises the possibility that EGFR-inhibiting drugs may cause ABCG2-mediated DDIs.

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Aim: To demonstrate the clinical capability of ultra-fast whole body PET acquisition enabled by digital photon counting PET (dPET) and to assess and compare its diagnostic and quantitative characteristics to current clinical PET acquisition. Methods: Twenty-five patients scheduled for FDG whole body PET/ CT were imaged using three separate acquisitions as part of intraindividual comparison study with a pre-commercial release dPET/CT (Vereos) and cPET/CT (Gemini, Philips, Cleveland). Standard cPET imaging was performed at~75 min p.i. of~450 MBq FDG with investigational dPET imaged at~55 min p.i. The first dPET acquisition was performed using 90s/bed position, immediately followed by a 9s/bed position. Acquisition which lead to average table times of~15 and~2 min. These were compared with standard-of-care 90s/bed position cPET. The 9s/bed dPET listmode data were reconstructed using a previously optimized methodology. All other aspects of image acquisition were kept identical. Three blinded reviewers evaluated the data sets regarding visual characteristics, diagnostic confidence and semiquantitative readouts. Results: Visual assessment scores were significantly higher for 90s/bed dPET whole body (p<0.01) with no difference between 9s/bed dPET and 90s/bed cPET. Quantitatively, the 9s/bed dPET images presented slightly increased background noise, however there was no significant impact on diagnostic confidence or SUV measures of FDG-avid lesions. Conclusion: Next generation digital photon counting PET detector technology enables a new capability of Ultra-Fast (~2min) wholebody acquisition with comparable diagnostic confidence and quantitative precision to current generation cPET acquisitions taking 10 times longer. This allows for new PET workflow concepts, improved patient comfort, minimized patient motion and whole-body pseudo-dynamic imaging of tracer uptake. Aim: Detection of the extent of local recurrence and of metastases in biochemical recurrence (BCR) of prostate cancer facilitates selection of appropriate treatment. The FALCON trial (NCT02578940) assessed the impact of 18F-fluciclovine PET/CT on the clinical management of men with BCR of prostate cancer following initial radical therapy. Methods: Men being considered for curative-intent salvage therapy following first BCR were recruited at 6 UK sites. Management plans were documented prior to and following 18F-fluciclovine PET/CT imaging. Post-scan changes to treatment modality such as salvage radiotherapy [RT] to systemic therapy were classed as 'major' , while changes within a modality (e.g. modified RT fields) were classed as 'other'. A pre-planned interim analysis of the first 85 patients was conducted; recruitment was to be stopped for efficacy if the number of treatment changes was > 45 (52.9%; 97.5% CI: 40.3-62.3%), or for futility if ≤ 8 (9.4%, 97.5% CI: 3.6-18.9%). Results: The 85 enrolled patients were a mean 4.8 y post-initial diagnosis, with a median age of 67 y and median PSA of 0.63ng/mL. Twelve (14.1%) had a Gleason score ≤ 6, 60 (70.6%) had ...