IEO model: A novel concept describing the complete metastatic process in the liver microenvironment.
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ABSTRACT:
SUBMITTER: Wang L
PROVIDER: S-EPMC7204638 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
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Project description:Although mobile technologies such as smartphone apps are promising means for motivating people to adopt a healthier lifestyle (mHealth apps), previous studies have shown low adoption and continued use rates. Developing the means to address this issue requires further understanding of mHealth app nonusers and adoption processes. This study utilized a stage model approach based on the Precaution Adoption Process Model (PAPM), which proposes that people pass through qualitatively different motivational stages when adopting a behavior.To establish a better understanding of between-stage transitions during app adoption, this study aimed to investigate the adoption process of nutrition and fitness app usage, and the sociodemographic and behavioral characteristics and decision-making style preferences of people at different adoption stages.Participants (N=1236) were recruited onsite within the cohort study Konstanz Life Study. Use of mobile devices and nutrition and fitness apps, 5 behavior adoption stages of using nutrition and fitness apps, preference for intuition and deliberation in eating decision-making (E-PID), healthy eating style, sociodemographic variables, and body mass index (BMI) were assessed.Analysis of the 5 behavior adoption stages showed that stage 1 ("unengaged") was the most prevalent motivational stage for both nutrition and fitness app use, with half of the participants stating that they had never thought about using a nutrition app (52.41%, 533/1017), whereas less than one-third stated they had never thought about using a fitness app (29.25%, 301/1029). "Unengaged" nonusers (stage 1) showed a higher preference for an intuitive decision-making style when making eating decisions, whereas those who were already "acting" (stage 4) showed a greater preference for a deliberative decision-making style (F4,1012=21.83, P<.001). Furthermore, participants differed widely in their readiness to adopt nutrition and fitness apps, ranging from having "decided to" but not yet begun to act (stage 2; nutrition: 6.88%, 70/1017; fitness: 9.23%, 95/1029) to being "disengaged" following previous adoption (stage 5; nutrition: 13.77%, 140/1017; fitness: 15.06%, 155/1029).Using a behavior stage model approach to describe the process of adopting nutrition and fitness apps revealed motivational stage differences between nonusers (being "unengaged," having "decided not to act," having "decided to act," and being "disengaged"), which might contribute to a better understanding of the process of adopting mHealth apps and thus inform the future development of digital interventions. This study highlights that new user groups might be better reached by apps designed to address a more intuitive decision-making style.
| S-EPMC5871740 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the most common form of liver cancer. This study aims to develop a new method to generate an HCC mouse model with a human tumor, and imitates the tumor microenvironment (TME) of clinical patients. Here, we have generated functional, three-dimensional sheet-like human HCC organoids in vitro, using luciferase-expressing Huh7 cells, human iPSC-derived endothelial cells (iPSC-EC), and human iPSC-derived mesenchymal cells (iPSC-MC). The HCC organoid, capped by ultra-purified alginate gel, was implanted into the disrupted liver using an ultrasonic homogenizer in the immune-deficient mouse, which improved the survival and engraftment rate. We successfully introduced different types of controllable TME into the model and studied the roles of TME in HCC tumor growth. The results showed the role of the iPSC-EC and iPSC-MC combination, especially the iPSC-MC, in promoting HCC growth. We also demonstrated that liver fibrosis could promote HCC tumor growth. However, it is not affected by non-alcoholic fatty liver disease. Furthermore, the implantation of HCC organoids to humanized mice demonstrated that the immune response is important in slowing down tumor growth at an early stage. In conclusion, we have created an HCC model that is useful for studying HCC development and developing new treatment options in the future.
| S-EPMC8394300 | biostudies-literature
Project description:The liver is the most common site for colorectal cancer (CRC) metastasis and there is an urgent need for new tissue culture models to study colorectal cancer liver metastasis (CRLM) as current models do not mimic the biological, biochemical, and structural characteristics of the metastatic microenvironment. Decellularization provides a novel approach for the study of the cancer extracellular matrix (ECM) as decellularized scaffolds retain tissue-specific features and biological properties. In the present study, we created a 3D model of CRC and matched CRLM using patient-derived decellularized ECM scaffolds seeded with the HT-29 CRC cell line. Here, we show an increased HT-29 cell proliferation and migration capability when cultured in cancer-derived scaffolds compared to same-patient healthy colon and liver tissues. HT-29 cells cultured in CRLM scaffolds also displayed an indication of epithelial-mesenchymal transition (EMT), with a loss of E-cadherin and increased Vimentin expression. EMT was confirmed by gene expression profiling, with the most represented biological processes in CRLM-seeded scaffolds involving demethylation, deacetylation, a cellular response to stress metabolic processes, and a response to the oxygen level and starvation. HT-29 cells cultured in cancer-specific 3D microenvironments showed a reduced response to treatment with 5-fluorouracil and 5-fluorouracil combined with Irinotecan when used at a standard IC50 (as determined in the 2D culture). Our 3D culture system with patient-derived tissue-specific decellularized ECM better recapitulates the metastatic microenvironment compared to conventional 2D culture conditions and represents a relevant approach for the study of CRLM progression and assessing the response to chemotherapy agents.
| S-EPMC7072130 | biostudies-literature
Project description:Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment. Fatty liver upregulated Rab27a expression, which facilitated EV production from hepatocytes. In the liver, these EVs transferred YAP signaling-regulating microRNAs to cancer cells to augment YAP activity by suppressing LATS2. Increased YAP activity in CRC liver metastasis with fatty liver promoted cancer cell growth and an immunosuppressive microenvironment by M2 macrophage infiltration through CYR61 production. Patients with CRC liver metastasis and fatty liver had elevated nuclear YAP expression, CYR61 expression, and M2 macrophage infiltration. Our data indicate that fatty liver-induced EV-microRNAs, YAP signaling, and an immunosuppressive microenvironment promote the growth of CRC liver metastasis.
| S-EPMC10524732 | biostudies-literature
Project description:Preclinical murine models in which primary tumors spontaneously metastasize to distant organs are valuable tools to study metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line, NT2.5-lung metastasis (-LM), that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. Within one week of orthotopic implantation of NT2.5-LM in NeuN mice, distant metastases can be observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. Metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. We demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT) and enrichment in EMT-regulating pathways, suggestive of their enhanced metastatic potential. The new NT2.5-LM model provides more rapid and spontaneous development of widespread metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses targeting distant visceral metastases.
| S-EPMC10862766 | biostudies-literature
Project description:ObjectiveMotor evoked potentials (MEPs) play a pivotal role in transcranial magnetic stimulation (TMS), e.g., for determining the motor threshold and probing cortical excitability. Sampled across the range of stimulation strengths, MEPs outline an input-output (IO) curve, which is often used to characterize the corticospinal tract. More detailed understanding of the signal generation and variability of MEPs would provide insight into the underlying physiology and aid correct statistical treatment of MEP data.MethodsA novel regression model is tested using measured IO data of twelve subjects. The model splits MEP variability into two independent contributions, acting on both sides of a strong sigmoidal nonlinearity that represents neural recruitment. Traditional sigmoidal regression with a single variability source after the nonlinearity is used for comparison.ResultsThe distribution of MEP amplitudes varied across different stimulation strengths, violating statistical assumptions in traditional regression models. In contrast to the conventional regression model, the dual variability source model better described the IO characteristics including phenomena such as changing distribution spread and skewness along the IO curve.ConclusionsMEP variability is best described by two sources that most likely separate variability in the initial excitation process from effects occurring later on. The new model enables more accurate and sensitive estimation of the IO curve characteristics, enhancing its power as a detection tool, and may apply to other brain stimulation modalities. Furthermore, it extracts new information from the IO data concerning the neural variability-information that has previously been treated as noise.
| S-EPMC4108579 | biostudies-literature
Project description:BACKGROUND:Peritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to treat clinically due to widespread tumor dissemination in the peritoneal cavity. METHODS:We developed a clinically relevant, genetically induced, peritoneal carcinomatosis model that recapitulates the histological morphology and immunosuppressive state of the tumor microenvironment of metastatic peritoneal HGSCs by intraperitoneally injecting shp53, AKT, c-Myc, luciferase and sleeping beauty transposase, followed by electroporation (EP) in the peritoneal cavity of immunocompetent mice (intraperitoneal (IP)/EP mice). RESULTS:Similar to the spread of human ovarian cancers, IP/EP mice displayed multiple tumor nodules attached to the surface of the abdomen. Histopathological analysis indicated that these tumors were epithelial in origin. These IP/EP mice also displayed a loss of CD3+ T cell infiltration in tumors, highly expressed inhibitory checkpoint molecules in tumor-infiltrating and global CD4+ and CD8+ T cells, and increased levels of transforming growth factor-? in the ascites, all of which contribute to the promotion of tumor growth. CONCLUSIONS:Overall, our tumor model recapitulates clinical peritoneal HGSC metastasis, which makes it ideal for preclinical drug screening, testing of immunotherapy-based therapeutics and studying of the tumor biology of peritoneal carcinomatosis.
| S-EPMC7057437 | biostudies-literature
Project description:BackgroundThe resection and partial liver segment II/III transplantation with delayed total hepatectomy (RAPID) concept is a novel transplantation technique for removal of non-resectable liver tumours. The aim of this study was to establish a simulated RAPID model to explore the mechanism involved in the liver regeneration.MethodsA RAPID model was created in rats involving cold ischaemia and reperfusion of the selected future liver remnant (FLR), portal vein ligation, followed by resection of the deportalized lobes in a second step. Histology, liver regeneration and inflammatory markers in RAPID-treated rats were compared with those in controls that underwent 70 per cent hepatectomy with the same FLR size. The effects of interleukin (IL) 6 and macrophage polarization on hepatocyte viability were evaluated in an in vitro co-culture system of macrophages and BRL hepatocytes.ResultsThe survival rate in RAPID and control hepatectomy groups was 100 per cent. The regeneration rate was higher in the RAPID-treated rats, with higher levels of IL-6 and M1 macrophage polarization (P < 0·050). BRL hepatocytes co-cultured with M1 macrophages showed a higher proliferation rate through activation of the IL-6/signal transducer and activator of transcription 3/extracellular signal-regulated kinase pathway. This enhancement of proliferation was inhibited by tocilizumab or gadolinium trichloride (P < 0·050).ConclusionThe surgical model provides a simulation of RAPID that can be used to study the liver regeneration profile. Surgical Relevance The mechanisms sustaining liver regeneration are a relevant field of research to reduce the 'small for size' liver syndrome when the future liver remnant is not adequate. Several surgical strategies have been introduced both for liver resection and transplant surgery, mostly related to this issue and to the scarcity of grafts, among these the RAPID concept involving the use of an auxiliary segment II/III donor liver that expands to a sufficient size until a safe second-stage hepatectomy can be performed. Understanding the mechanisms and pitfalls of the liver regeneration profile may help in tailoring surgical strategies and in selecting patients. In this experimental model the authors investigated liver histology, regeneration and inflammatory markers in RAPID-treated rats.
| S-EPMC7528512 | biostudies-literature
Project description:BackgroundChemotherapeutic agents are used to control tumor proliferation. However, their influence in the pre-metastatic niche of target organs has not been well studied. Oxaliplatin (OXA) is a drug applied in standard treatments of colorectal cancer (CRC), while the direct effect of which on the pre-metastatic microenvironment of the liver remains unclear.MethodsModels of liver metastases were established with luciferase expressing CT26 cells in BALB/c and BALB/c-nude mice. Single-cell RNA Sequencing was performed to examine the immune microenvironment in the liver elicited by OXA. Immunofluorescence and flowcytometry were utilized to confirm the changes in the number of immune cells. LDH, CellTrace CFSE Cell Proliferation and apoptosis assays were conducted to explore the impact of OXA on T cells ex vivo. The correlation between chemotherapy-related lymphopenia and metastases was assessed by meta-analysis.ResultsHerein we discovered that administration of OXA prior to the occurrence of liver metastasis actually accelerated tumor development and colonization in the liver. Single-cell RNA sequencing revealed that the landscape of the liver immune microenvironment had been changed to immunosuppressive phenotype. Macrophages after the treatment of OXA exhibited a high ability to inhibit the activation of T cells. Further investigation revealed a significant decrease in the number of T cells in the liver, particularly CD8+ T cells with reduced capacity of proliferation, activation, and killing. When mice were treated with T cell supplementation, the OXA-induced metastasis was notably abolished, indicating that the OXA-primed liver microenvironment could be reversed by the infusion of T cells. Consistent with our findings in mice, a meta-analysis was performed to verify that chemotherapy-related lymphopenia was associated with an inferior prognosis related with high incidence of metastasis, suggesting the pivotal role of chemotherapy in pre-metastatic niche formation. Furthermore, a notable reduction in the count of both macrophages and T cells was observed in the liver of colorectal cancer (CRC) patient undergoing OXA-based chemotherapy.ConclusionsOur findings proposed that immunosuppressive microenvironment in liver induced by OXA enhanced liver metastasis of colorectal cancer, which highlighted a new consideration to balance the pro metastases and anti-cancer possibility of OXA treatment.
| S-EPMC10494354 | biostudies-literature
Project description:Colorectal cancer (CRC) patients with liver metastases usually obtain less benefit from immunotherapy, and the underlying mechanisms remain understudied. Here, we identify that fibrinogen-like protein 1 (FGL1), secreted from cancer cells and hepatocytes, facilitates the progression of CRC in an intraportal injection model by reducing the infiltration of T cells. Mechanistically, tumor-associated macrophages (TAMs) activate NF-ĸB by secreting TNFα/IL-1β in the liver microenvironment and transcriptionally upregulate OTU deubiquitinase 1 (OTUD1) expression, which enhances FGL1 stability via deubiquitination. Disrupting the TAM-OTUD1-FGL1 axis inhibits metastatic tumor progression and synergizes with immune checkpoint blockade (ICB) therapy. Clinically, high plasma FGL1 levels predict poor outcomes and reduced ICB therapy benefits. Benzethonium chloride, an FDA-approved antiseptics, curbs FGL1 secretion, thereby inhibiting liver metastatic tumor growth. Overall, this study uncovers the critical roles and posttranslational regulatory mechanism of FGL1 in promoting metastatic tumor progression, highlighting the TAM-OTUD1-FGL1 axis as a potential target for cancer immunotherapy.
| S-EPMC10593839 | biostudies-literature