Cancer is one of the leading causes of human death, despite enormous efforts to explore cancer biology and develop anticancer therapies. The main challenges in cancer research are establishing an efficient tumor microenvironment in vitro and exploring efficient means for screening anticancer drugs to reveal the nature of cancer and develop treatments. The tumor microenvironment possesses human-specific biophysical and biochemical factors that are difficult to recapitulate in conventional in vitro planar cell models and in vivo animal models. Therefore, model limitations have hindered the translation of basic research findings to clinical applications. In this review, we introduce the recent progress in tumor-on-a-chip devices for cancer biology research, medicine assessment, and biomedical applications in detail. The emerging tumor-on-a-chip platforms integrating 3D cell culture, microfluidic technology, and tissue engineering have successfully mimicked the pivotal structural and functional characteristics of the in vivo tumor microenvironment. The recent advances in tumor-on-a-chip platforms for cancer biology studies and biomedical applications are detailed and analyzed in this review. This review should be valuable for further understanding the mechanisms of the tumor evolution process, screening anticancer drugs, and developing cancer therapies, and it addresses the challenges and potential opportunities in predicting drug screening and cancer treatment.
Background: Hepatocellular carcinoma (HCC) often presents with multiple nodules within the liver, with limited effective interventions. The high genetic heterogeneity of HCC might be the major cause of treatment failure. We aimed to characterize genomic heterogeneity, infer clonal evolution, investigate RNA expression pattern and explore tumour immune microenvironment profile of multifocal HCC.Patients and methods: Whole-exome sequencing and RNA sequencing were carried out in 34 tumours and 6 adjacent normal liver tissue samples from 6 multifocal HCC patients. Protein expression of Ki67, AFP, P53, Survivin and CD8 was detected by immunohistochemistry. Fluorescence in situ hybridization was carried out to validate the amplification status of sorafenibtargeted genes.Results: We deciphered genomic and transcriptional heterogeneity among tumours in each multifocal HCC patient including mutational profiles, copy number alterations, tumour evolutionary trajectory and tumour immune microenvironment profiles. Of note, sorafenib-targeted alterations were identified in the trunk of phylogenetic tree in only one out of the six patients, which may explain the relative low treatment response rate to sorafenib in clinical practice. Moreover, we demonstrated RNA expression patterns and tumour immune microenvironment profiles of all nodules. We found that RNA expression pattern was associated with Edmondson-Steiner grading. Based on the differential expression of 66 reported immune markers, unsupervised hierarchical clustering analysis of 34 nodules identified immune subsets: one low expression cluster with seven nodules and one high expression cluster with 11 nodules. CD8þ T cells were more enriched in nodules of the high expression cluster.Conclusions: Our study provided a detailed view of genomic and transcriptional heterogeneity, clonal evolution and immune infiltration of multifocal HCC. The heterogeneity of druggable targets and immune landscape might help interpret the clinical responsiveness to targeted drugs and immunotherapy for multifocal HCC patients.
BaCKgRoUND aND aIMS:The dynamic N6methyladenosine (m 6 A) mRNA modification is essential for acute stress response and cancer progression. Sublethal heat stress from insufficient radiofrequency ablation (IRFA) has been confirmed to promote HCC progression; however, whether m 6 A machinery is involved in IRFA-induced HCC recurrence remains open for study. appRoaCH aND ReSUltS: Using an IRFA HCC orthotopic mouse model, we detected a higher level of m 6 A reader YTH N6-methyladenosine RNA binding protein 1-3 (YTHDF1) in the sublethal-heat-exposed transitional zone close to the ablation center than that in the farther area. In addition, we validated the increased m 6 A modification and elevated YTHDF1 protein level in sublethal-heat-treated HCC cell lines, HCC patient-derived xenograft (PDX) mouse model, and patients' HCC tissues. Functionally, gain-of-function/lossof-function assays showed that YTHDF1 promotes HCC cell viability and metastasis. Knockdown of YTHDF1 drastically restrains the tumor metastasis evoked by sublethal heat treatment in tail vein injection lung metastasis and orthotopic HCC mouse models. Mechanistically, we found that sublethal heat treatment increases epidermal factor growth receptor (EGFR) m 6 A modification in the vicinity of the 5′ untranslated region and promotes its binding with YTHDF1, which enhances the translation of EGFR mRNA. The sublethalheat-induced up-regulation of EGFR level was further confirmed in the IRFA HCC PDX mouse model and patients' tissues. Combination of YTHDF1 silencing and EGFR inhibition suppressed the malignancies of HCC cells synergically. CoNClUSIoNS:The m 6 A-YTHDF1-EGFR axis promotes HCC progression after IRFA, supporting the rationale for targeting m 6 A machinery combined with EGFR inhibitors to suppress HCC metastasis after RFA. (Hepatology 2021;74:1339-1356). R adiofrequency ablation (RFA) is now recommended as one of the curative therapies for early-stage HCC by guidelines of the American Association for the Study of Liver
This study aimed to develop and validate a risk score for early prediction of venous thromboembolism (VTE) in patients with lung cancer. A total of 827 patients with lung cancer from February 2013 to February 2018 in our hospital were retrospectively analyzed. Demographic and clinicopathological variables independently correlated to VTE were applied to develop the risk score in the development group while examined in the validation group. The regression coefficients of multivariable logistic regression test were applied to assign a risk score system. The incidence of VTE was 12.3%, 12.7%, and 11.8% in all patients, in the development and validation groups, respectively. The 496 patients in the development group were classified into 3 groups: low risk (scores ≤3), moderate risk (scores 4-5), and high risk (scores ≥6). The risk of VTE was significantly and positively related to the risk scores in both development and validation groups. The risk score system aided proper stratification of patients with either high or low risk of VTE in the development and validation groups ( c statistic = 0.819 and 0.827, respectively). This risk score system based on the factors with most significant correlation showed good predictive ability and is potentially useful for predicting VTE in patients with lung cancer. However, it was developed and validated by a retrospective analysis and has significant limitations, and a prospective validation with all the classic variables assessing the thrombotic risk is needed for a solid conclusion.
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