Using lymph node swelling as a potential biomarker for successful vaccination.
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ABSTRACT:
SUBMITTER: Brewer KD
PROVIDER: S-EPMC5094952 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Colorectal cancer (CRC)-associated mortality is primarily caused by lymph node (LN) and distant metastasis, highlighting the need for biomarkers that predict LN metastasis and facilitate better therapeutic strategies. We used an Isobaric Tags for Relative and Absolute Quantification (iTRAQ)-based comparative proteomics approach to identify novel biomarkers for predicting LN metastasis in CRC patients. We analyzed five paired samples of CRC with or without LN metastasis, adjacent normal mucosa, and normal colon mucosa, and differentially expressed proteins were identified and subsequently validated at the protein and/or mRNA levels by immunohistochemistry and qRT-PCR, respectively. We identified 55 proteins specifically associated with LN metastasis, from which we selected ezrin for further analysis and functional assessment. Expression of ezrin at both the protein and mRNA levels was significantly higher in CRC tissues than in adjacent normal colonic mucosa. In univariate analysis, high ezrin expression was significantly associated with tumor progression and poor prognosis, which was consistent with our in vitro findings that ezrin promotes the metastatic capacity of CRC cells by enabling cell invasion and migration. In multivariate analysis, high levels of ezrin protein and mRNA in CRC samples were independent predictors of LN metastasis. Our data thus identify ezrin as a novel protein and mRNA biomarker for predicting LN metastasis in CRC patients.
| S-EPMC5739786 | biostudies-literature
Project description:Lymph nodes (LNs) comprise two main structural elements: fibroblastic reticular cells that form dedicated niches for immune cell interaction and capsular fibroblasts that build a shell around the organ. Immunological challenge causes LNs to increase more than tenfold in size within a few days. Here, we characterized the biomechanics of LN swelling on the cellular and organ scale. We identified lymphocyte trapping by influx and proliferation as drivers of an outward pressure force, causing fibroblastic reticular cells of the T-zone (TRCs) and their associated conduits to stretch. After an initial phase of relaxation, TRCs sensed the resulting strain through cell matrix adhesions, which coordinated local growth and remodeling of the stromal network. While the expanded TRC network readopted its typical configuration, a massive fibrotic reaction of the organ capsule set in and countered further organ expansion. Thus, different fibroblast populations mechanically control LN swelling in a multitier fashion.
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Project description:Background: To investigate the relationship between CXCR4-related circular RNAs (circRNAs) in exosomes and lymph node metastasis of lung adenocarcinoma. Methods: Totally 41 lung adenocarcinoma tissues (21 with lymph node metastasis and 20 without) were collected. Expression of CXCR4 protein was detected by western blotting analysis. A stable PC9/CXCR4-shRNA and PC14/CXCR4-shRNA knockdown lung adenocarcinoma cell lines were established and subjected to functional assays (cell proliferation, colony formation, migration and invasion) for phenotype changes. Exo-hsa-circRNAs (has-circRNAs in exosomes) were detected in vivo and in vitro. The diagnostic value of differentially expressed exo-has-circRNAs was evaluated. Results: Expression levels of CXCR4 were higher in patients with lymph node metastasis than in those without (P = 0.001). Silencing CXCR4 expression in PC9 and PC14 cell lines with short hairpin RNA could effectively abolish colony formation frequency, proliferation rate, migration rate, and the number of invasive cells (all P < 0.001). Exo_circRNA_0056616 was detected in both PC-9/CXCR4-shRNA cells and lung adenocarcinoma plasma at significantly higher levels than in the corresponding control (P < 0.001). When a receiver operating characteristic (ROC) curve for plasma exo-hsa_circRNA_0056616 levels and diagnosis of lymph node metastasis of lung adenocarcinoma was generated, a cutoff value of 0.394 was identified with an area under the curve of 0.812 (95% confidence interval 0.720-0.903), a sensitivity of 0.792, and specificity of 0.810. Conclusions: Taken together, our findings suggested that CXCR4 was higher in the lung adenocarcinoma tissues with lymph node metastasis. Higher plasma levels of exo-hsa_circRNA_0056616 in these patients also suggest that this circRNA represents a potential biomarker for lymph node metastasis predictor in lung adenocarcinoma.
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Project description:Lymph node metastasis is a major factor that affects prognosis in patients with lung adenocarcinoma (LUAD). In some cases, lymph node metastasis has already occurred when the primary tumors are still small (i.e., early T stages), however, relevant studies on early lymph node metastasis are limited, and effective biomarkers remain lacking. This study aimed to explore new molecular biomarker for early lymph node metastasis in LUAD using transcriptome sequencing and experimental validation. Here, we performed transcriptome sequencing on tissues from 16 matched patients with Stage-T1 LUAD (eight cases of lymph node metastasis and eight cases of non-metastasis), and verified the transcriptome profiles in TCGA, GSE68465, and GSE43580 cohorts. With the bioinformatics analysis, we identified a higher abundance of M0 macrophages in the metastatic group using the CIBERSORT algorithm and immunohistochemistry (IHC) analysis and the enrichment of the epithelial-mesenchymal transition (EMT) pathway was identified in patients with higher M0 infiltration levels. Subsequently, the EMT hallmark gene SPP1, encoding secreted phosphoprotein 1 (SPP1), was identified to be significantly correlated with macrophage infiltration and M2 polarization, and was determined to be a key risk indicator for early lymph node metastasis. Notably, SPP1 in the blood, as detected by enzyme-linked immunosorbent assay (ELISA) showed a superior predictive capability for early lymph node metastasis [area under the curve (AUC) = 0.74]. Furthermore, a long non-coding RNA (lncRNA, AC037441), negatively correlated with SPP1 and macrophage infiltration, had also been identified and validated to be involved in the regulation of early lymph node metastasis. In conclusion, we revealed the potential role of macrophages in lymph node metastasis and identified the macrophage-related gene SPP1 as a potential biomarker for early lymph node metastasis in LUAD.
| S-EPMC8502925 | biostudies-literature
Project description:BackgroundThis study aimed to assess the correlation of katanin P60 expression with clinical characteristics and survival profiles of surgical non-small cell lung cancer (NSCLC) patients.MethodsTwo hundred and sixty-five primary NSCLC patients treated by surgical resection were retrospectively viewed. The expression of katanin P60 in the tumor specimen was detected by the immunohistochemical (IHC) staining assay. Preoperative clinical data were collected from patients' medical records, and survival data were extracted from follow-up records.ResultsThere were 127 (47.9%) and 138 (52.1%) patients with katanin P60-low expression and -high expression, respectively; in addition, patients presenting katanin P60-high+, -high++, and -high+++ expression were 62 (23.4%), 63 (23.8%), and 13 (4.9%), respectively. Katanin P60 expression was correlated with lymph node (LYN) metastasis and advanced TNM stage but not pathological grade, tumor size, carcinoembryonic antigen (CEA) level or other non-tumor features in NSCLC patients. Regarding survival profiles, disease-free survival (DFS) and overall survival (OS) were both the lowest in katanin P60-high+++ expression patients, followed with katanin P60-high++ patients, katanin P60-high+ patients, and the highest in katanin P60-low expression patients. Further analysis illustrated that katanin P60-high expression was an independent predictive factor for unfavorable DFS and OS in NSCLC patients.ConclusionsKatanin P60 presents potential as a biomarker for lymph node metastasis and prognosis in NSCLC patients.
| S-EPMC7339556 | biostudies-literature
Project description:Whether the expression status of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2) receptor and Ki-67 show concordance between the primary tumors and the synchronous axillary lymph node (ALN) metastases has been discussed in numerous studies. However, to date, the results of these studies remain controversial. Therefore, the present study aimed to investigate whether the expression of ER, PR, HER-2 and Ki-67 was in concordance between the primary tumors and synchronous ALN metastases in patients with operable breast cancer (BC). A total of 60 tissue samples were collected from patients with primary operable BC diagnosed with primary tumors and synchronous ALN metastases. The expression levels of the four biomarkers, ER, PR, HER-2 and Ki-67, were assessed in primary lesions and synchronous ALN metastases samples using immunohistochemistry. The cut-off values were set to 10% for ER and PR, while the labeling index of Ki-67 was set to 14%. The immunostaining intensity of ER and PR was scored as negative (?), 1+, 2+ and 3+. The criteria for HER-2 testing in BC were implemented according to the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines. The concordance rates for ER, PR and HER-2 were 96.7 (58/60), 96.7 (58/60) and 90% (54/60), respectively. In addition, the kappa values of consistency in the primary lesions and the synchronous ALN metastases were 0.773 for ER, 0.654 for PR and 0.785 for HER-2. Furthermore, the P-values of ER, PR and Ki-67 numerical variables between the two groups were 0.393, 0.400 and 0.331, respectively, as demonstrated using a non-parametric Wilcoxon signed rank test. The findings of the present study demonstrated a high degree of concordance between the expression of ER, PR, HER-2 and Ki-67 in the primary tumors and that in the synchronous ALN metastases, suggesting that the BC primary tumor biomarkers may be used for the prognosis of synchronous ALN metastases in patients with operable BC.
| S-EPMC7520755 | biostudies-literature
Project description:Dendritic cells (DCs) capture pathogens and foreign antigen (Ag) in peripheral tissues and migrate to secondary lymphoid tissues, such as lymph nodes (LNs), where they present processed Ag as MHC-bound peptide (pMHC) to naïve T cells. Interactions between DCs and T cells result, over periods of hours, in activation, clonal expansion and differentiation of antigen-specific T cells, leading to primed cells that can now participate in immune responses. Two-photon microscopy (2PM) has been widely adopted to analyze lymphocyte dynamics and can serve as a powerful in vivo assay for cell trafficking and activation over short length and time scales. Linking biological phenomena between vastly different spatiotemporal scales can be achieved using a systems biology approach. We developed a 3D agent-based cellular model of a LN that allows for the simultaneous in silico simulation of T cell trafficking, activation and production of effector cells under different antigen (Ag) conditions. The model anatomy is based on in situ analysis of LN sections (from primates and mice) and cell dynamics based on quantitative measurements from 2PM imaging of mice. Our simulations make three important predictions. First, T cell encounters by DCs and T cell receptor (TCR) repertoire scanning are more efficient in a 3D model compared with 2D, suggesting that a 3D model is needed to analyze LN function. Second, LNs are able to produce primed CD4+T cells at the same efficiency over broad ranges of cognate frequencies (from 10(-5) to 10(-2)). Third, reducing the time that naïve T cells are required to bind DCs before becoming activated will increase the rate at which effector cells are produced. This 3D model provides a robust platform to study how T cell trafficking and activation dynamics relate to the efficiency of T cell priming and clonal expansion. We envision that this systems biology approach will provide novel insights for guiding vaccine development and understanding immune responses to infection.
| S-EPMC3783027 | biostudies-literature
Project description:Lymph nodes are important peripheral immune organs in which numerous important immune responses occur. During the process of lymphatic metastasis, lymph nodes are also sites through which tumor cells must pass. Therefore, it is essential to develop a drug delivery system that can specifically transfer immunostimulatory medicine into lymph nodes to block lymphatic metastasis. Here, we developed a nucleic acid drug delivery system containing cationic agarose (C-agarose) and CpG oligodeoxynucleotides. C-agarose has a high affinity for Siglec-1 on the surface of lymph node sinus macrophages, which have a high specificity for targeting lymph nodes. Subcutaneous implantation of C-agarose+CpG gel caused the accumulation of CpG in the lymph node sinus macrophages and generated antitumor immune responses in the lymph node. C-agarose+CpG gel treatment decreased the metastasis size in the tumor-draining lymph node (TDLN) and lung metastatic nodules and suppressed tumor growth in both a mouse 4T1 breast cancer model and a B16F10 melanoma model. On this basis, this study proposes a nonsurgical invasive lymph node targeting immunotherapy concept that may provide a new approach for antitumor metastasis.
| S-EPMC6529739 | biostudies-literature
Project description:BACKGROUND AND AIMS:Curative surgery saves ≈50% of all patients with colorectal cancer (CRC) while remaining patients have synchronous or will develop metachronous metastases. Presently, the single most important prognostic factor is histopathological detection of disseminated tumor cells in regional lymph nodes. However, the routine method has several limitations. The aim was to identify biomarker mRNAs that could be combined in a formula that would allow better prediction of patients' survival after surgery. METHODS:Screening for biomarker mRNAs overexpressed in CRC was performed by genome-wide hybridization bead array, with verification by qRT-PCR. Specific qRT-PCR assays with copy standards were developed for 5 selected genes and mRNA expression levels determined in lymph nodes from 174 CRC patients (517 nodes) and 24 control patients (118 nodes). Prognostic value of biomarker mRNAs was estimated. A cut-off was set using univariate Cox regression analysis and used for calculation of differences between patient groups in disease-free survival 12 years after surgery (Kaplan-Meier survival model) and risk for recurrent disease (Cox's regression analysis). A formula was constructed for evaluation of the prognostic value of the biomarkers in combination. RESULTS:Two new biomarkers, SLC35D3 and POSTN with prognostic value were identified. SLC35D3 was expressed in the epithelium derived tumor cells and POSTN in fibroblasts. Combined with CEACAM5, KLK6 and MUC2 they could be used to identify risk groups. A formula was constructed using CEACAM5 as denominator for KLK6, SLC35D3 and MUC2 and 18S rRNA as denominator for POSTN. The formula yielded 5 categories (-1, 0, 1, 2, 3). Categories (-1 and 0) had good prognosis, categories (1 and 2) relatively poor prognosis and category (3) very poor prognosis. CONCLUSION:Lymph node analysis using 5 selected biomarker mRNAs and 18S rRNA in combination allowed allocation of CRC patients to different risk categories with respect to recurrent disease.
| S-EPMC7015415 | biostudies-literature
Project description:ObjectivesThe diagnosis of cervical lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) patients constitutes an essential requirement for clinical staging and treatment selection. However, clinical assessment by physical examination and different imaging modalities, as well as by histological examination of routine lymph node cryosections can miss micrometastases, while false positives may lead to unnecessary elective lymph node neck resections. Here, we explored the feasibility of developing a sensitive assay system for desmoglein 3 (DSG3) as a predictive biomarker for lymph node metastasis in HNSCC.Materials and methodsDSG3 expression was determined in multiple general cancer- and HNSCC-tissue microarrays (TMAs), in negative and positive HNSCC metastatic cervical lymph nodes, and in a variety of HNSCC and control cell lines. A nanostructured immunoarray system was developed for the ultrasensitive detection of DSG3 in lymph node tissue lysates.ResultsWe demonstrate that DSG3 is highly expressed in all HNSCC lesions and their metastatic cervical lymph nodes, but absent in non-invaded lymph nodes. We show that DSG3 can be rapidly detected with high sensitivity using a simple microfluidic immunoarray platform, even in human tissue sections including very few HNSCC invading cells, hence distinguishing between positive and negative lymph nodes.ConclusionWe provide a proof of principle supporting that ultrasensitive nanostructured assay systems for DSG3 can be exploited to detect micrometastatic HNSCC lesions in lymph nodes, which can improve the diagnosis and guide in the selection of appropriate therapeutic intervention modalities for HNSCC patients.
| S-EPMC3546158 | biostudies-literature