scholarly journals Deleting in vivo β-catenin degradation domain in mouse hepatocytes drives hepatocellular carcinoma or hepatoblastoma-like tumors

2021 ◽  
Author(s):  
Robin Loesch ◽  
Stefano Caruso ◽  
Valerie Paradis ◽  
Cecile Godard ◽  
Angelique Gougelet ◽  
...  
Keyword(s):  
Mouse Models ◽  
Liver Tumors ◽  
Integrative Analysis ◽  
Hepatic Tumors ◽  
Normal Tissues ◽  
Mouse Tumors ◽  
Rnaseq Data ◽  
Well Differentiated ◽  
Low Prevalence

Background and aims: One-third of hepatocellular carcinomas (HCCs) have mutations that activate the β-catenin pathway with mostly CTNNB1 mutations. Mouse models using Adenomatous polyposis coli (Apc) loss-of-functions (LOF) are widely used to mimic β-catenin-dependent tumorigenesis. Considering the low prevalence of APC mutations in human HCCs we aimed to generate hepatic tumors through CTNNB1 exon 3 deletion (βcatΔex3) and to compare them to hepatic tumors with Apc LOF engineered through a frameshift in exon 15 (Apcfs-ex15). Methods: We used hepatic-specific and inducible Cre-lox mouse models as well as a hepatic-specific in vivo CRISPR/Cas9 approach using AAV vectors, to generate Apcfs-ex15 and βcatΔex3 hepatic tumors harboring activation of the β-catenin pathway. Tumors generated by the Cre-lox models were analyzed phenotypically using immunohistochemistry and were selected for transcriptomic analysis using RNA-sequencing. Mouse RNAseq data were compared to human RNAseq data (normal tissues (8), HCCs (48) and hepatoblastomas (9)) in an integrative analysis. Tumors generated via CRISPR were analyzed using DNA sequencing and immunohistochemistry. Results: Mice with βcatΔex3 alteration in hepatocytes developed liver tumors. Generated tumors were indistinguishable from those arising in Apcfs-ex15 mice. Both Apcfs-ex15 and βcatΔex3 mouse models induced two phenotypically distinct tumors (differentiated or undifferentiated). Integrative analysis of human and mouse tumors showed that mouse differentiated tumors are close to human well differentiated CTNNB1-mutated tumors, while undifferentiated ones are closer to human mesenchymal hepatoblastomas, and are activated for YAP signaling. Conclusion: Apcfs-ex15 and βcatΔex3 mouse models similarly induce tumors transcriptionally close to either well differentiated β-Catenin activated human HCCs or mesenchymal hepatoblastomas.

scholarly journals Genetically Engineered Mouse Models of Liver Tumorigenesis Reveal a Wide Histological Spectrum of Neoplastic and Non-Neoplastic Liver Lesions

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2265
Author(s):  
Katja Steiger ◽  
Nina Gross ◽  
Sebastian A. Widholz ◽  
Roland Rad ◽  
Wilko Weichert ◽  
...  
Keyword(s):  
Mouse Models ◽  
Liver Tumors ◽  
Genetically Engineered ◽  
Liver Lesions ◽  
Genetically Engineered Mouse Models ◽  
Chemically Induced ◽  
Wide Range ◽  
Correct Application ◽  
Huge Variety

Genetically engineered mouse models (GEMM) are an elegant tool to study liver carcinogenesis in vivo. Newly designed mouse models need detailed (histopathological) phenotyping when described for the first time to avoid misinterpretation and misconclusions. Many chemically induced models for hepatocarcinogenesis comprise a huge variety of histologically benign and malignant neoplastic, as well as non-neoplastic, lesions. Such comprehensive categorization data for GEMM are still missing. In this study, 874 microscopically categorized liver lesions from 369 macroscopically detected liver “tumors” from five different GEMM for liver tumorigenesis were included. The histologic spectrum of diagnosis included a wide range of both benign and malignant neoplastic (approx. 82%) and non-neoplastic (approx. 18%) lesions including hyperplasia, reactive bile duct changes or oval cell proliferations with huge variations among the various models and genetic backgrounds. Our study therefore critically demonstrates that models of liver tumorigenesis can harbor a huge variety of histopathologically distinct diagnosis and, depending on the genotype, notable variations are expectable. These findings are extremely important to warrant the correct application of GEMM in liver cancer research and clearly emphasize the role of basic histopathology as still being a crucial tool in modern biomedical research.

scholarly journals NIR-II emissive AIEgen photosensitizers enable ultrasensitive imaging-guided surgery and phototherapy to fully inhibit orthotopic hepatic tumors

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ruizhen Jia ◽  
Han Xu ◽  
Chenlu Wang ◽  
Lichao Su ◽  
Jinpeng Jing ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Near Infrared ◽  
Liver Tumors ◽  
Early Stage ◽  
Oxygen Species ◽  
Hepatic Tumors ◽  
Primary Liver Tumors ◽  
Guided Surgery

AbstractAccurate diagnosis and effective treatment of primary liver tumors are of great significance, and optical imaging has been widely employed in clinical imaging-guided surgery for liver tumors. The second near-infrared window (NIR-II) emissive AIEgen photosensitizers have attracted a lot of attention with higher-resolution bioimaging and deeper penetration. NIR-II aggregation-induced emission-based luminogen (AIEgen) photosensitizers have better phototherapeutic effects and accuracy of the image-guided surgery/phototherapy. Herein, an NIR-II AIEgen phototheranostic dot was proposed for NIR-II imaging-guided resection surgery and phototherapy for orthotopic hepatic tumors. Compared with indocyanine green (ICG), the AIEgen dots showed bright and sharp NIR-II emission at 1250 nm, which extended to 1600 nm with high photostability. Moreover, the AIEgen dots efficiently generated reactive oxygen species (ROS) for photodynamic therapy. Investigations of orthotopic liver tumors in vitro and in vivo demonstrated that AIEgen dots could be employed both for imaging-guided tumor surgery of early-stage tumors and for ‘downstaging’ intention to reduce the size. Moreover, the therapeutic strategy induced complete inhibition of orthotopic tumors without recurrence and with few side effects. Graphical Abstract

Imaging of angiogenesis in metastatic breast cancer by positron emission tomography (PET) using [18F]AH11585, an [18F]- labeled alphaVbeta3 (αvβ3) peptide

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14067-14067
Author(s):  
L. M. Kenny ◽  
E. Aboagye ◽  
P. S. Cohen ◽  
M. Miller ◽  
F. Turkheimer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
In Vivo Imaging ◽  
Liver Tumors ◽  
Metastatic Breast ◽  
Liver Lesions ◽  
High Background ◽  
Normal Tissues ◽  
Positron Emission

14067 Background: In vivo imaging of avβ3 expression in tumors and tumor endothelial cells may be a useful biomarker of angiogenesis. [18F]AH11585 is a novel peptide containing an Arginine-Glycine-Aspartic Acid (RGD) motif that binds to avβ3 with high affinity designed for use in PET studies. Methods: 7 patients with metastatic breast cancer (aged 37–68 years) received intravenous injections of [18F]AH11585 and were scanned dynamically by PET over 61.5 mins. Radioactivity concentrations, derived from regions of interest placed on tumour and normal tissues, were analysed mathematically to determine the net irreversible uptake (Ki), fractional retention (FRT) and standardized uptake at 56.5min (SUV) of the radiotracer. Computed tomography (CT) was performed within 4 weeks of the scan. Results: Tumor lesions were clearly visible on PET images in 6/7 patients. In one patient with a palpable supraclavicular lymph node not visible on CT, we were unsure if a hyperintense region visible by PET was tumor. In total 18/19 tumor lesions were identified on both PET and corresponding CT images. Tumors in areas of low background were hyperintense (lung, bone, breast) whereas those in areas of high background were hypointense regions (liver). Tumors with central necrosis showed high uptake of [18F]AH11585 around the periphery only. Mathematical analysis demonstrated irreversible retention of [18F]AH11585 in tumors. [18F]AH11585-PET discriminated between non-liver lesions (n=10) and normal tissues: Ki (p=0.002), FRT (p=0.0039), SUV (p=0.002). Corresponding comparisons for liver lesions (n=8) were significant for FRT (p=0.0078) and SUV (p=0.0078) only. Conclusions: [18F]AH11585 PET is a promisng method for in vivo imaging of avβ3 integrin expression in metastatic breast cancer. No significant financial relationships to disclose.

scholarly journals Proliferative polyploid cells give rise to tumors via ploidy reduction

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tomonori Matsumoto ◽  
Leslie Wakefield ◽  
Alexander Peters ◽  
Myron Peto ◽  
Paul Spellman ◽  
...  
Keyword(s):  
Cancer Progression ◽  
High Frequency ◽  
Chromosomal Instability ◽  
Liver Tumors ◽  
Tumor Development ◽  
Lineage Tracing ◽  
Normal Tissues ◽  
Polyploid Cells ◽  
Regenerative Nodules

AbstractPolyploidy is a hallmark of cancer, and closely related to chromosomal instability involved in cancer progression. Importantly, polyploid cells also exist in some normal tissues. Polyploid hepatocytes proliferate and dynamically reduce their ploidy during liver regeneration. This raises the question whether proliferating polyploids are prone to cancer via chromosome missegregation during mitosis and/or ploidy reduction. Conversely polyploids could be resistant to tumor development due to their redundant genomes. Therefore, the tumor-initiation risk of physiologic polyploidy and ploidy reduction is still unclear. Using in vivo lineage tracing we here show that polyploid hepatocytes readily form liver tumors via frequent ploidy reduction. Polyploid hepatocytes give rise to regenerative nodules with chromosome aberrations, which are enhanced by ploidy reduction. Although polyploidy should theoretically prevent tumor suppressor loss, the high frequency of ploidy reduction negates this protection. Importantly, polyploid hepatocytes that undergo multiple rounds of cell division become predominantly mononucleated and are resistant to ploidy reduction. Our results suggest that ploidy reduction is an early step in the initiation of carcinogenesis from polyploid hepatocytes.

scholarly journals Development of Alpha-emitting radioembolization for Hepatocellular Carcinoma: Longitudinal Monitoring of Actinium-225’s Daughters Through SPECT Imaging

2020 ◽  
Author(s):  
Yong Du ◽  
Angel Cortez ◽  
Mohammadreza Zarisfi ◽  
Anders Josefsson ◽  
Rebecca Krimins ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Mouse Model ◽  
Normal Tissue ◽  
Liver Tumors ◽  
Primary Liver Cancer ◽  
Treatment Options ◽  
Spect Imaging ◽  
Hepatic Tumors

Abstract Hepatocellular carcinoma is the most common primary liver cancer and the fifth most frequently diagnosed cancer worldwide. Most patients with advanced disease are offered non-surgical palliative treatment options. This work explores the first α-emitting radioembolization for the treatment and monitoring of hepatic tumors. Furthermore, this works demonstrates the first in vivo simultaneous multiple-radionuclide SPECT images of the complex decay chain of an [225Ac]Ac-labeled agent using a clinical SPECT system to monitor the temporal distribution. Methods: A DOTA chelator was modified with a lipophilic moiety and radiolabeled with Actinium-225. The resulting agent, [225Ac]Ac-DOTA-TDA, was emulsified in Lipiodol® and evaluated in vivo in mouse model and the VX2 rabbit technical model of liver cancer. SPECT imaging was performed to monitor distribution of the TAT agent and the free daughters.Results: [225Ac]Ac-DOTA-TDA was shown to retain within the HEP2G tumors and VX2 tumor, with minimal uptake within normal tissue. In the mouse model, significant improvements in overall survival were observed. SPECT imaging was able to distinguish between the Actinium-225 agent (Francium-221) and the loss of the longer lived daughter, Bismuth-213. Conclusion: A TAT agent emulsified in Lipiodol® is capable of targeting liver tumors with minimal accumulation in normal tissue, providing a potential therapeutic agent for the treatment of HCC as well as a variety of hepatic tumors. In addition, SPECT imaging presented here provides a foundation for imaging methodology and protocols that can be rapidly translated into the clinic to monitor Actinium-225-labeled agents.

Clinical Evaluation of Radio-Labelled Bleomycin for Tumor Detection

1978 ◽  
Vol 17 (06) ◽  
pp. 238-248
Author(s):  
H. Beekhuis ◽  
M.A.P.C. van de Poll ◽  
A. Versluis ◽  
H. Jurjens ◽  
M.G. Woldring ◽  
...  
Keyword(s):  
Clinical Evaluation ◽  
Acidic Solution ◽  
Tumor Detection ◽  
Neutral Solution ◽  
Normal Tissues ◽  
Patients With Cancer ◽  
Tumor Bearing

Investigations with bleomycin labelled with radionuclides other than 57Co in patients with cancer and in tumor-bearing animals are described. In patients 57Co-bleo appears to be a better tumor-seeking radiopharmaceutical than 111In-bleo, 99mTc-bleo or 197Hg-bleo. This can be explained by a higher stability in vivo and a better tumor-seeking property of 57Co-bleo and less disturbing activity in the cardiac pool and in bone and other normal tissues when assessing the scintigram.Results with 111In-bleo labelled in acidic solution are not essentially different from those with 111In-bleo labelled in neutral solution.Results of 197Hg-bleo are almost identical with those of 197HgCl2 regarding the tumor-seeking effect as well as the distribution in normal tissues and organs. Probably the complex of 197Hg to bleomycin is not stable in vivo. The superiority of 57Co-bleo over 99mTc-bleo, 197Hg-bleo and also over 67Cu-bleo is confirmed by experiments on tumor bearing animals.We may conclude that the indication for use of bleomycin as a tumor-seeking pharmaceutical labelled with 111In, 99mTc, 197Hg or 67Cu seems to be very limited.

scholarly journals PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Dawei Chen ◽  
Zhenguo Zhao ◽  
Lu Chen ◽  
Qinghua Li ◽  
Jixue Zou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Alternative Splicing ◽  
Protein Function ◽  
Vital Role ◽  
Normal Tissues ◽  
Mechanistic Analysis ◽  
Highly Correlated ◽  
Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A663-A663
Author(s):  
Keegan Cooke ◽  
Juan Estrada ◽  
Jinghui Zhan ◽  
Jonathan Werner ◽  
Fei Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mouse Models ◽  
T Cell Activation ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Human T Cells

BackgroundNeuroendocrine tumors (NET), including small cell lung cancer (SCLC), have poor prognosis and limited therapeutic options. AMG 757 is an HLE BiTE® immune therapy designed to redirect T cell cytotoxicity to NET cells by binding to Delta-like ligand 3 (DLL3) expressed on the tumor cell surface and CD3 on T cells.MethodsWe evaluated activity of AMG 757 in NET cells in vitro and in mouse models of neuroendocrine cancer in vivo. In vitro, co-cultures of NET cells and human T cells were treated with AMG 757 in a concentration range and T cell activation, cytokine production, and tumor cell killing were assessed. In vivo, AMG 757 antitumor efficacy was evaluated in xenograft NET and in orthotopic models designed to mimic primary and metastatic SCLC lesions. NSG mice bearing established NET were administered human T cells and then treated once weekly with AMG 757 or control HLE BiTE molecule; tumor growth inhibition was assessed. Pharmacodynamic effects of AMG 757 in tumors were also evaluated in SCLC models following a single administration of human T cells and AMG 757 or control HLE BiTE molecule.ResultsAMG 757 induced T cell activation, cytokine production, and potent T cell redirected killing of DLL3-expressing SCLC, neuroendocrine prostate cancer, and other DLL3-expressing NET cell lines in vitro. AMG 757-mediated redirected lysis was specific for DLL3-expressing cells. In patient-derived xenograft and orthotopic models of SCLC, single-dose AMG 757 effectively engaged human T cells administered systemically, leading to a significant increase in the number of human CD4+ and CD8+ T cells in primary and metastatic tumor lesions. Weekly administration of AMG 757 induced significant tumor growth inhibition of SCLC (figure 1) and other NET, including complete regression of established tumors and clearance of metastatic lesions. These findings warranted evaluation of AMG 757 (NCT03319940); the phase 1 study includes dose exploration (monotherapy and in combination with pembrolizumab) and dose expansion (monotherapy) in patients with SCLC (figure 2). A study of AMG 757 in patients with neuroendocrine prostate cancer is under development based on emerging data from the ongoing phase 1 study.Abstract 627 Figure 1AMG 757 Significantly reduced tumor growth in orthotopic SCLC mouse modelsAbstract 627 Figure 2AMG 757 Phase 1 study designConclusionsAMG 757 engages and activates T cells to kill DLL3-expressing SCLC and other NET cells in vitro and induces significant antitumor activity against established xenograft tumors in mouse models. These preclinical data support evaluation of AMG 757 in clinical studies of patients with NET.Ethics ApprovalAll in vivo work was conducted under IACUC-approved protocol #2009-00046.

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