scholarly journals LGR5 marks targetable tumor-initiating cells in mouse liver cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Wanlu Cao ◽  
Meng Li ◽  
Jiaye Liu ◽  
Shaoshi Zhang ◽  
Lisanne Noordam ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Mouse Liver ◽  
Liver Tumors ◽  
Treatment Resistance ◽  
Therapeutic Benefit ◽  
Stem Cell Marker ◽  
Rare Cancer ◽  
Tumor Initiating Cells ◽  
Cancer Types

AbstractCancer stem cells (CSCs) or tumor-initiating cells (TICs) are thought to be the main drivers for disease progression and treatment resistance across various cancer types. Identifying and targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the enrichment of LGR5 expressing cells, a well-recognized stem cell marker, in mouse liver tumors, and the upregulation of LGR5 expression in human hepatocellular carcinoma. Isolated LGR5 expressing cells from mouse liver tumors are superior in initiating organoids and forming tumors upon engraftment, featuring candidate TICs. These cells are resistant to conventional treatment including sorafenib and 5-FU. Importantly, LGR5 lineage ablation significantly inhibits organoid initiation and tumor growth. The combination of LGR5 ablation with 5-FU, but not sorafenib, further augments the therapeutic efficacy in vivo. Thus, we have identified the LGR5+ compartment as an important TIC population, representing a viable therapeutic target for combating liver cancer.

scholarly journals Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression

2020 ◽  
pp. jbc.RA120.015335
Author(s):  
Yuan Deng ◽  
Ming Li ◽  
Minghui Zhuo ◽  
Peng Guo ◽  
Qiang Chen ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Cancer Progression ◽  
Liver Tumors ◽  
The Self ◽  
High Rate ◽  
Sox9 Expression ◽  
Self Renewal ◽  
Lysine Demethylase

Cancer stem-like cells (CSCs) contribute to the high rate of tumor heterogeneity, metastasis, therapeutic resistance, and recurrence. Histone lysine demethylase 4D (KDM4D or JMJD2D) is highly expressed in colon and liver tumors, where it promotes cancer progression; however, the role of JMJD2D in CSCs remains unclear. Here, we show that JMJD2D expression was increased in liver cancer stem-like cells (LCSCs); downregulation of JMJD2D inhibited the self-renewal of LCSCs in vitro and in vivo and inhibited the lung metastasis of LCSCs by reducing the survival and the early lung seeding of circulating LCSCs. Mechanistically, JMJD2D promoted LCSC self-renewal by enhancing the expression of CSC markers EpCAM and Sox9; JMJD2D reduced H3K9me3 levels on the promoters of EpCAM and Sox9 to enhance their transcription via interaction with β-catenin/TCF4 and Notch1 intracellular domain, respectively. Restoration of EpCAM and Sox9 expression in JMJD2D-knockdown liver cancer cells rescued the self-renewal of LCSCs. Pharmacological inhibition of JMJD2D using 5-c-8HQ reduced the self-renewal of LCSCs and liver cancer progression. Collectively, our findings suggest that JMJD2D promotes LCSC self-renewal by enhancing EpCAM and Sox9 expression via Wnt/β-catenin and Notch signaling pathways and is a potential therapeutic target for liver cancer.

Development of radiotherapeutic rhenium-188 liposomes in alginate microspheres (Rhe-LAMs) for treatment of liver tumors and technetium-99m liposomes in alginate microspheres (Tech-LAMs) for image-guided treatment planning.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15599-e15599
Author(s):  
Ryan D. Bitar ◽  
Jorge Lopera ◽  
Ande Bao ◽  
Jaclyn Merlo ◽  
Francisco Cigarroa ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Treatment Planning ◽  
Liver Tumors ◽  
Effective Means ◽  
Nuclear Imaging ◽  
Technetium 99M ◽  
Image Guided ◽  
Imaging Results ◽  
Radioactivity Retention

e15599 Background: Radio-embolic agents such as beta-emitting yttrium-90 spheres have been widely adopted as a modality for liver cancer therapy; however, their production can be timely and costly, shunting to the lungs may occur, and post-procedural visualization is limited. Alginate, a polysaccharide which can easily be formed into microspheres, has already been investigated for drug delivery applications; however, we propose utilizing alginate to manufacture radioembolic microspheres for intra-arterial delivery to liver tumors: Rhenium-188/186-labeled liposomes in alginate microspheres (Rhe-LAMS) as a radioembolic agent for the treatment of liver tumors and technetium-99m labeled liposomes in alginate microspheres (Tech-LAMs) as an agent for nuclear image-guided pre-treatment planning for liver cancer patients. Methods: Liposomes were manufactured and labeled with either Re-188/186 or Tc-99m. The liposomes were then mixed with alginate solution and then cross-linked with CaCl2 to form microspheres. Microsphere diameter was evaluated via light microscopy, and retention of radioactivity was measured over time via dosimeter. Microspheres containing free Re-186/Tc-99m (i.e. no liposomes) were also constructed for control comparison. To test in vivo stability, Tech-LAMs were intra-arterially injected into the liver of rabbits for nuclear imaging. Results: 2 ml batches of Rhe-LAMS/Tech-LAMS of 20-80 microns could be manufactured in 3 hours. Radiolabeling efficiency of the liposomes reached 85% and retention of radioactivity in microspheres reached 75%. After overnight incubation, 90% activity was retained. Control microspheres showed a retention of < 5%. In vivo imaging revealed absent activity in the lungs and high embolic activity in the liver. Conclusions: Our novel method demonstrated success regarding radioactivity retention and embolization capabilities. We envision this method to be a quickly-producible, cost-efficient, and effective means for radioembolization of liver tumors that could be adopted by any radiopharmacy.

scholarly journals The M1 aminopeptidase NPEPPS is a novel regulator of cisplatin sensitivity

2021 ◽  
Author(s):  
Robert T. Jones ◽  
Andrew Goodspeed ◽  
Maryam C. Akbarzadeh ◽  
Mathijs Scholtes ◽  
Hedvig Vekony ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cisplatin Resistance ◽  
Treatment Resistance ◽  
Anion Channel ◽  
List Type ◽  
Cancer Models ◽  
Cisplatin Sensitivity ◽  
Cancer Types

ABSTRACTDespite routine use of platinum-based chemotherapeutics across diverse cancer types, there remains a need to improve efficacy and patient selection for treatment. A multi-omic assessment of five human bladder cancer cell lines and their chemotherapy resistant derivatives, coupled with whole-genome CRISPR screens were used to identify puromycin- sensitive aminopeptidase, NPEPPS, as a novel functional driver of treatment resistance to cisplatin. Depletion of NPEPPS resulted in enhanced cellular cisplatin import, sensitization of resistant cancer cells to cisplatin in vitro and in vivo. Pharmacologic inhibition of NPEPPS with tosedostat in cells and in chemoresistant, patient-derived tumor organoids improved response to cisplatin. Depletion of LRRC8A and LRRC8D, two subunits of the volume regulated anion channel (VRAC), a known importer of intracellular cisplatin, enhanced resistance to cisplatin. Linking NPEPPS function to VRAC cisplatin import supports NPEPPS as a driver of cisplatin resistance and by virtue of clinically available inhibitors, the potential for rapid clinical translation.HIGHLIGHTS∙CRISPR screens with multi-omics identify NPEPPS as a driver of cisplatin resistance∙NPEPPS depletion in multiple bladder cancer models enhances cisplatin sensitivity∙LRRC8A and LRRC8D loss increase resistance to cisplatin in CRISPR screens∙Unique resource of functional and multi-omic data is provided to the community

Simultaneous Drug and Gene Delivery from the Biodegradable Poly(ε-caprolactone) Nanofibers for the Treatment of Liver Cancer

2015 ◽  
Vol 15 (10) ◽  
pp. 7971-7975 ◽  
Author(s):  
Hui-Lian Che ◽  
Hwa Jeong Lee ◽  
Koichiro Uto ◽  
Mitsuhiro Ebara ◽  
Won Jong Kim ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Liver Cancer ◽  
Sustained Release ◽  
Liver Tumors ◽  
Cancer Drug ◽  
Therapeutic Gene ◽  
Anti Cancer ◽  
Drug And Gene Delivery

In this study, we present anti-cancer drug containing nanofiber-mediated gene delivery to treat liver cancer. Electro-spun nanofibers have big potential for local delivery and sustained release of therapeutic gene and drugs. We reported a temperature-responsive nanofibers mainly compounded by branched poly(ε-caprolactone) (PCL) macro-monomers and anti-cancer drug paclitaxel. The nanofiber could be administrated into liver tumors to dramatically hinder their growth and prevent their metastasis. As a result, paclitaxel encapsulated PCL (PTX/PCL) nanofibers with diameters of around several tens nanometers to 10 nm were successfully obtained by electro-spinning andobserved in scanning electron microscopy (SEM). Nanoparticles composed of disulfide cross-linked branched PEI (ssPEI) and anti-cancer therapeutic gene miRNA-145 were complexed based on the electrostatic interaction and coated over the paclitaxel-loaded nanofiber. MicroRNA 145/ssPEI nanoparticles (MSNs) immobilized on the PTX/PCL nanofiber showed time-dependent sustained release of the microRNA for enhanced uptake in neighboring liver cancer cells without any noticeable cytotoxicity. From this study we are expecting a synergistic effect on the cancer cell suppression since we have combined the drug and gene delivery. This approach uses the nanofibers and nanoparticles together for the treatment of cancer and the detailed investigation in vitro and in vivo must be conducted for the practicality of this study. The polymer is biodegradable and the toxicity issues must be cleared by our approach.

scholarly journals Transformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jingyu Chen ◽  
Anketse Debebe ◽  
Ni Zeng ◽  
Janel Kopp ◽  
Lina He ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Cancer ◽  
Liver Tumors ◽  
Liver Parenchyma ◽  
Tumor Formation ◽  
Lineage Tracing ◽  
Liver Carcinogenesis ◽  
Tumor Initiating Cells ◽  
Chronic Injury ◽  
Pten Loss

AbstractSOX9 (Sex-determining region Y Box 9) is a well-characterized transcription factor that is a marker for progenitor cells in various tissues. In the liver, cells delineated by SOX9 are responsible for regenerating liver parenchyma when cell proliferation is impaired following chronic injury. However, whether these SOX9+ cells play a role in liver carcinogenesis has not been fully understood, although high SOX9 expression has been linked to poor survival outcome in liver cancer patients. To address this question, we developed a liver cancer mouse model (PtenloxP/loxP; Sox9-CreERT+; R26RYFP) where tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome ten) is deleted in SOX9+ cells following tamoxifen injection. In this paper, we employ lineage-tracing to demonstrate the tumorigenicity potential of the Pten-, SOX9+ cells. We show that these cells are capable of giving rise to mixed-lineage tumors that manifest features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA). Our results suggest that PTEN loss induces the transformation of SOX9+ cells. We further show that to activate these transformed SOX9+ cells, the presence of liver injury is crucial. Liver injury, induced by hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or high-fat diet (HFD), substantially increases tumor incidence and accelerates liver carcinogenesis from SOX9+ cells in Pten null mice but not in control mice. We further examine the mechanisms underlying tumor formation in this model to show that concurrent with the induction of niche signal (i.e., Wnt signaling), liver injury significantly stimulates the expansion of tumor-initiating cells (TICs). Together, these data show that (1) SOX9+ cells have the potential to become TICs following the primary transformation (i.e. Pten deletion) and that (2) liver injury is necessary for promoting the activation and proliferation of transformed SOX9+ cells, resulting in the genesis of mixed-lineage liver tumors.

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.

Relationship of the p75 neurotrophin receptor (p75NTR) and hypoxic response and treatment resistance in malignant gliomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13026-e13026
Author(s):  
Rajappa Kenchappa ◽  
Peter A. J. Forsyth
Keyword(s):  
Radiation Treatment ◽  
Expression Profiles ◽  
Malignant Gliomas ◽  
Gene Expression Profiles ◽  
Treatment Resistance ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Tumor Initiating Cells

e13026 Background: Malignant gliomas (MGs) are resistant to Radiotherapy (RT). The molecular pathways that produce resistance to therapy and ability to tolerate hypoxia are poorly understood. We previously found that the p75NTR causes invasion & proliferation of MGs/Brain Tumor Initiating Cells (BTICs). We think MGs use the neurotrophin-rich brain environment as a survival advantage to resist treatment by expressing the p75NTR. We hypothesize that hypoxia cause p75NTR proteolysis which produces HIF-1α stabilization and activation of hypoxic responses. This repertoire of hypoxic responses leads to resistance to both hypoxia & radiotherapy (RT) and account for MG recurrence. Methods: We used glioma cells and BTICs they express very low or and high levels of p75NTR and manipulated the expression of p75NTR by shRNAs and activation by mutant receptors and pharmacological inhibitors. We exposed these cells to hypoxia and radiation treatment and performed biochemical and functional assays. We have also used paired pre and post-RT frozen patient specimens. Gene expression profiles were analyzed for patients using microarray expression data for 516 primary GBM patients from the TCGA and 239 patients from Moffitt’s Total Cancer Care (TCC) project. Results: We found that inhibiting p75NTR pharmacologically significantly reduced invasion/proliferation of MGs/BTICs in vitro & in vivo. We have also found that p75NTR is required for HIF-1α stabilization and VEGF expression in MGs/BTICs in vitro & in vivo, that p75NTR expressing MGs/BTICs are very resistant to hypoxia & RT in vitro, and these effects are reversed with inhibition of p75NTR signaling. In addition, p75NTR expression and its cleavage are associated with treatment resistance in patient specimens. We also found using TCGA and Moffitt patient specimen data that the p75NTR/Siah2/PHD axis is expressed in MG patients and associated with RT resistance/poor prognosis. Conclusions: These results suggest that p75NTR expression/cleavage are required for HIF-1α pathway activation and hence the phenotype of MGs/BTICs and their treatment resistance. Targeting the p75NTR signaling axis therefore will provide novel therapeutic approaches.

scholarly journals Pooled AAV-CRISPR Screen with Targeted Amplicon Sequencing

2017 ◽  
Author(s):  
Guangchuan Wang ◽  
Ryan D. Chow ◽  
Lupeng Ye ◽  
Christopher D. Guzman ◽  
Xiaoyun Dai ◽  
...  
Keyword(s):  
Liver Tumors ◽  
Amplicon Sequencing ◽  
Genetic Studies ◽  
Cancer Driver ◽  
Gene Sets ◽  
Crispr Screen ◽  
Cancer Types ◽  
Lower Complexity ◽  
Molecular Inversion Probe

AbstractHigh-resolution, high-throughput direct in vivo screening of functional genetic factors in native tissues has long been challenging. Adeno-associated viruses (AAV) are powerful carriers of transgenes and have been shown to mediate efficient genome editing in various organs in mice. Here, we developed a new technological approach, Pooled AAV-CRISPR Screen with Targeted Amplicon Sequencing (PASTAS), and demonstrated its application for directly mapping functional cancer driver variants in the mouse liver in an autochthonous manner. Intravenous delivery of an AAV-CRISPR library targeting a set of the most frequently mutated tumor suppressor genes into fully immunocompetent conditional Cas9 knock-in mice consistently generated highly complex autochthonous liver tumors. The molecular landscapes of these genetically diverse tumors were mapped out by deep direct readout of Cas9-generated variants at predicted sgRNA cut sites using molecular inversion probe sequencing. Co-occurrence and correlation analyses as well as validation with lower complexity minipools further confirmed the potency of various co-mutated drivers. The PASTAS method can be applied to virtually any gene sets, any cancer types, or any type of in vivo genetic studies other than cancer.

Modeling liver cancer and therapy responsiveness using organoids derived from primary mouse liver tumors

2018 ◽  
Vol 40 (1) ◽  
pp. 145-154 ◽  
Author(s):  
Wanlu Cao ◽  
Jiaye Liu ◽  
Ling Wang ◽  
Meng Li ◽  
Monique M A Verstegen ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Mouse Liver ◽  
Liver Tumors ◽  
Primary Mouse

Mannose Conjugated Starch Nanoparticles for Preferential Targeting of Liver Cancer

2020 ◽  
Vol 17 ◽  
Author(s):  
Akhlesh Kumar Jain ◽  
Hitesh Sahu ◽  
Keerti Mishra ◽  
Suresh Thareja
Keyword(s):  
Side Effects ◽  
Liver Cancer ◽  
Entrapment Efficiency ◽  
Xrd Analysis ◽  
In Vitro Cytotoxicity ◽  
Physical Interaction ◽  
Scanning Calorimetry ◽  
Starch Nanoparticles

Aim: To design D-Mannose conjugated 5-Fluorouracil (5-FU) loaded Jackfruit seed starch nanoparticles (JFSSNPs) for site specific delivery. Background: Liver cancer is the third leading cause of death in world and fifth most often diagnosed cancer is the major global threat to public health. Treatment of liver cancer with conventional method bears several side effects, thus to undertake these side effects as a formulation challenge, it is necessary to develop novel target specific drug delivery system for the effective and better localization of drug into the proximity of target with restricting the movement of drug in normal tissues. Objective: To optimize and characterize the developed D-Mannose conjugated 5-Fluorouracil (5-FU) loaded Jackfruit seed starch nanoparticles (JFSSNPs) for effective treatment of liver cancer. Materials and methods: 5-FU loaded JFSSNPs were prepared and optimized formulation had higher encapsulation efficiency were conjugated with D-Mannose. These formulations were characterized for size, morphology, zeta potential, X-Ray Diffraction, and Differential Scanning Calorimetry. Potential of NPs were studied using in vitro cytotoxicity assay, in vivo kinetic studies and bio-distribution studies. Result and discussion: 5-Fluorouracil loaded NPs had particle size between 336 to 802nm with drug entrapment efficiency was between 64.2 to 82.3%. In XRD analysis, 5-FU peak was diminished in the diffractogram, which could be attributed to the successful incorporation of drug in amorphous form. DSC study suggests there was no physical interaction between 5- FU and Polymer. NPs showed sustained in vitro 5-FU release up to 2 hours. In vivo, mannose conjugated NPs prolonged the plasma level of 5-FU and assist selective accumulation of 5-FU in the liver (vs other organs spleen, kidney, lungs and heart) compared to unconjugated one and plain drug. Conclusion: In vivo, bio-distribution and plasma profile studies resulted in significantly higher concentration of 5- Fluorouracil liver suggesting that these carriers are efficient, viable, and targeted carrier of 5-FU treatment of liver cancer.

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