Fig 3 - available via license: Creative Commons Attribution 4.0 International
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Relationship between collagen fibers and elastin fibers. Panel (A) shows a scatter plot of the significant correlation between collagen and elastin. As the collagen increase, the variance of elastin also increases. Panel (B) shows a scatter plot classified by F stage. A circle indicates an F3 patient, whereas a triangle indicates an F4 patient. The solid line is the trend line for F3 patients, whereas the broken line is the trend line for F4 patients.
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Background & aims:
The fibrosis stage, which is evaluated by the distribution pattern of collagen fibers, is a major predictor for the development of hepatocellular carcinoma (HCC) for patients with hepatitis C. Meanwhile, the role of elastin fibers has not yet been elucidated. The present study was conducted to determine the significance of quant...
Citations
... 3 Moreover, the prevention and early detection of HCC due to chronic hepatitis B is an important clinical issue. 4 Liver fibrosis is the most important factor associated with HCC development in patients with chronic hepatitis, including hepatitis B. 5,6 Therefore, accurate assessment of liver fibrosis status is crucial in clinical practice. Although liver biopsy is the gold standard for assessing liver fibrosis, liver biopsy has several limitations including invasiveness, complications, and cost. ...
Background and Aim
Magnetic resonance elastography (MRE) is used for the evaluation of liver fibrosis; however, it remains unclear whether MRE‐based liver stiffness is associated with hepatocellular carcinoma (HCC) development, particularly in patients with chronic hepatitis B.
Methods
A total of 504 patients with chronic hepatitis B receiving MRE were enrolled. The primary endpoint was the association between MRE‐based liver stiffness and HCC.
Results
In a cross‐sectional analysis at the time of MRE measurement, the median (interquartile range) liver stiffness values in patients with presence or history of HCC and those without HCC were 3.68 (2.89–4.96) and 2.60 (2.22–3.45) kPa, respectively, and liver stiffness was significantly higher in patients with presence or history of HCC than in those without HCC ( P < 0.001). In a longitudinal analysis of patients without HCC, the 1‐, 3‐, and 5‐year cumulative incidence of HCC in patients with liver stiffness ≥3.6 kPa and those with liver stiffness <3.6 kPa were 3.8%, 7.0%, and 22.9%, and 0%, 0.9%, and 1.5%, respectively ( P < 0.001). In the multivariable analysis, MRE‐based liver stiffness (per 1 kPa) or liver stiffness ≥3.6 kPa was an independent factor for HCC development with an adjusted hazard ratio (aHR) of 1.61 (95% confidence interval [CI], 1.3–2.0) or aHR of 8.22 (95% CI, 2.1–31).
Conclusion
MRE‐based liver stiffness is associated with HCC risk in patients with chronic hepatitis B and may be used for the early prediction of HCC development and determination of indications for treatment.
... ELN encodes one of the two components of elastic fibers that form part of the extracellular matrix and confer elasticity to organs and tissues. Abnormal ELN levels have been observed in many fibrotic diseases, including kidney [68], lung [69], and liver fibrosis [70], and ELN accumulation is associated with the development of hepatocellular carcinoma [71]. ELN has also been shown to regulate tumor development and the tumor microenvironment (TME) in colorectal cancer [72]. ...
Background:
Gastric cancer (GC) is one of the most common causes of cancer-related fatalities worldwide, and its progression is associated with RNA modifications. Here, using RNA modification-related genes (RNAMRGs), we aimed to construct a prognostic model for patients with GC.
Methods:
Based on RNAMRGs, RNA modification scores (RNAMSs) were obtained for GC samples from The Cancer Genome Atlas and were divided into high- and low-RNAMS groups. Differential analysis and weighted correlation network analysis were performed for the differential expressed genes (DEGs) to obtain the key genes. Next, univariate Cox regression, least absolute shrinkage and selection operator, and multivariate Cox regression analyses were performed to obtain the model. According to the model risk score, samples were divided into high- and low-risk groups. Enrichment analysis and immunoassays were performed for the DEGs in these groups. Four external datasets from Gene Expression Omnibus data base were used to test the accuracy of the predictive model.
Results:
We identified SELP and CST2 as key DEGs, which were used to generate the predictive model. The high-risk group had a worse prognosis compared to the low-risk group (p < 0.05). Enrichment analysis and immunoassays revealed that 144 DEGs related to immune cell infiltration were associated with the Wnt signaling pathway and included hub genes such as ELN. Overall mutation levels, tumor mutation burden, and microsatellite instability were lower, but tumor immune dysfunction and exclusion scores were greater (p < 0.05) in the high-risk group than in the low-risk group. The validation results showed that the prediction model score can accurately predict the prognosis of GC patients. Finally, a nomogram was constructed using the risk score combined with the clinicopathological characteristics of patients with GC.
Conclusion:
This risk score from the prediction model related to the tumor microenvironment and immunotherapy could accurately predict the overall survival of GC patients.
... Lysyl-oxidases and transglutaminases produced by various types of cancer (associated) cells are able to create collagen-elastin crosslinks, producing more rigid fibers that promote migration [158,159]. Indeed, elastin was shown to be a critical component of the ECM that promotes the development of hepatocellular carcinoma [160], can increase proliferation, and promote epithelial-tomesenchymal transition in colorectal cancer [161]. ...
The dense cancer microenvironment is a significant barrier that limits the penetration of anticancer agents, thereby restraining the efficacy of molecular and nanoscale cancer therapeutics. Developing new strategies to enhance the permeability of cancer tissues is of major interest to overcome treatment resistance. Nonetheless, early strategies based on small molecule inhibitors or matrix-degrading enzymes have led to disappointing clinical outcomes by causing increased chemotherapy toxicity and promoting disease progression. In recent years, photodynamic therapy (PDT) has emerged as a novel approach to increase the permeability of cancer tissues. By producing excessive amounts of reactive oxygen species selectively in the cancer microenvironment, PDT increases the accumulation, penetration depth, and efficacy of chemotherapeutics. Importantly, the increased cancer permeability has not been associated to increased metastasis formation. In this review, we provide novel insights into the mechanisms by which this effect, called photodynamic priming, can increase cancer permeability without promoting cell migration and dissemination. This review demonstrates that PDT oxidizes and degrades extracellular matrix proteins, reduces the capacity of cancer cells to adhere to the altered matrix, and interferes with mechanotransduction pathways that promote cancer cell migration and differentiation. Significant knowledge gaps are identified regarding the involvement of critical signaling pathways, and to which extent these events are influenced by the complicated PDT dosimetry. Addressing these knowledge gaps will be vital to further develop PDT as an adjuvant approach to improve cancer permeability, demonstrate the safety and efficacy of this priming approach, and render more cancer patients eligible to receive life-extending treatments.
... 6,7 Liver fibrosis is the most important prognostic factor for liver-related morbidity and mortality in patients with NAFLD and accurate diagnosis of liver fibrosis is important in clinical practice. 8,9 Liver biopsy is the gold standard for the assessment of liver fibrosis. 10,11 However, liver biopsy has several limitations including sampling variability, and intra-and inter-observer reproducibility as well as its invasive nature and has potential risks including pain, infection, bleeding, perforation and rarely death. ...
Liver fibrosis is the most important prognostic factor in patients with nonalcoholic fatty liver disease (NAFLD). Several noninvasive markers for fibrosis, including blood-based markers and imaging based-markers have been developed. Indirect fibrosis markers (e.g. fibrosis-4 index and NAFLD fibrosis score) consist of standard laboratory data and clinical parameters. Given its availability and high negative predictive value for advanced fibrosis, these markers are suitable for screening at primary care. Blood-based fibrogenesis markers (enhanced liver fibrosis and N-terminal propeptide of type 3 collagen), ultrasound-based modalities (vibration-controlled transient elastography, point shear wave elastography [SWE], and two-dimensional SWE), and magnetic resonance elastography have high diagnostic accuracy for liver fibrosis and are suitable for diagnosing liver fibrosis at secondary care centers. Sequential use of these markers can increase diagnostic accuracy and reduce health care costs. Furthermore, combining noninvasive makers may assist in identifying candidates for pharmacological trials and reducing screening failure. Emerging data suggest that these noninvasive markers are associated with liver-related events (hepatocellular carcinoma and decompensation) and mortality. Furthermore, delta change in noninvasive markers over time is also associated with time-course change in fibrosis, liver-related event risk, and mortality risk. However, the association between liver fibrosis and cardiovascular disease (CVD) risk is still controversial. CVD risk may decrease in patients with decompensated liver disease and noninvasive markers may be useful for assessing CVD risk in these patients. Therefore, noninvasive markers may be utilized as measures of fibrosis as well as real-time prognostic tools, in place of liver biopsy. This article is protected by copyright. All rights reserved.
... Liver fibrosis is an important factor associated with liver-related complications and mortality in patients with chronic liver disease. [5][6][7] Liver biopsy, which is the gold standard for the assessment of liver fibrosis, has several limitations including invasiveness, sampling error, and intra-and inter-observer reproducibility. 8 Non-invasive methods to assess liver fibrosis are currently used in clinical practice to resolve these issues. ...
... Therefore, further studies are warranted to assess the role of liver stiffness measured with MRE as a risk marker for MACE and extrahepatic cancer.4.2 | In context with published literatureHCC and decompensation are major causes of mortality in patients with chronic liver disease. Histological stage of liver fibrosis is significantly associated with liver-related complications and mortality in patients with viral hepatitis, NAFLD and alcoholic liver disease as well as in those with other chronic liver diseases.[5][6][7] Several studies demonstrated that MRE-associated liver stiffness was significantly associated with HCC, decompensation and mortality in patients with chronic liver disease related to various aetiologies.[22][23][24][25] ...
Background
Magnetic resonance elastography (MRE) has the highest diagnostic accuracy for liver fibrosis; however, the association between MRE-associated liver stiffness and the development of hepatic and extrahepatic complications as well as mortality remains unclear.
Aim
In this study, we investigated the longitudinal association between MRE-associated liver stiffness and complications and mortality.
Methods
This retrospective study included 2373 consecutive patients with chronic liver disease. All patients received standard of care and the development of complications was assessed every 1-6 months.
Results
Newly diagnosed hepatocellular carcinoma (HCC), decompensation, major adverse cardiovascular events (MACE), extrahepatic cancer and death were observed in 99, 117, 73, 77 and 170 patients respectively. In multivariable analysis, the adjusted hazard ratios (aHR) (95% confidence interval [CI]) for HCC, decompensation, MACE, extrahepatic cancer and mortality were 1.28 (1.2-1.4), 1.34 (1.3-1.4), 0.96 (0.9-1.1), 1.00 (0.9-1.1) and 1.17 (1.1-1.2), respectively, with each 1-kPa increase in liver stiffness. Similarly, the aHR (95% CI) for HCC, decompensation, MACE, extrahepatic cancer and mortality were 4.20 (2.2-8.2), 67.5 (9.2-492), 0.83 (0.4-1.7), 0.90 (0.5-1.7) and 2.90 (1.6-5.4), respectively, in patients with cirrhosis (>4.7 kPa) compared to those with minimal fibrosis (<3 kPa).
Conclusions
Increased MRE-associated liver stiffness was associated with increased risk for HCC, decompensation and mortality in a dose-dependent fashion but not with MACE or extrahepatic cancer, implicating a significant role for MRE in liver-related events and mortality; however, further studies are warranted to explore its role in MACE and extrahepatic cancer.
... Liver stiffness that correlates fibrosis in the liver is associated with HCC risk. (32)(33)(34) Because liver stiffness changes over time, not only during DAA treatment but also after SVR, this indicates that HCC risk changes over time. (35)(36)(37) Therefore, HCC risk should be evaluated not only at the time of SVR but also at any point after SVR. ...
The identification of patients with advanced fibrosis who do not need any further hepatocellular carcinoma (HCC) surveillance after the eradication of hepatitis C is pivotal. In this study, we developed a simple serum‐based risk model that could identify patients with low‐risk HCC. This was a nationwide multicenter study involving 16 Hospitals in Japan. Patients with advanced fibrosis (1,325 in a derivation cohort and 508 in a validation cohort) who achieved sustained virological responses at 24 weeks after treatment (SVR24) were enrolled. The HCC risk model at any point after SVR24 and its change were evaluated, and subsequent HCC development was analyzed. Based on the multivariable analysis, patients fulfilling all of the factors (GAF4 criteria: gamma‐glutamyl transferase < 28 IU/L, alpha‐fetoprotein < 4.0 ng/mL, and Fibrosis‐4 Index < 4.28) were classified as low‐risk and others were classified as high‐risk. When patients were stratified at the SVR24, and 1 year, and 2 years after SVR24, subsequent HCC development was significantly lower in low‐risk patients (0.5‐1.1 per 100 person‐years in the derivation cohort and 0.9‐1.1 per 100 person‐years in the validation cohort) than in high‐risk patients at each point. HCC risk from 1 year after SVR24 decreased in patients whose risk improved from high‐risk to low‐risk (HCC incidence: 0.6 per 100 person‐years [hazard ratio (HR) = 0.163 in the derivation cohort] and 1.3 per 100 person‐years [HR = 0.239 in the validation cohort]) than in those with sustained high risk. Conclusion: The HCC risk model based on simple serum markers at any point after SVR and its change can identify patients with advanced fibrosis who are at low HCC risk, and these patients may be able to reduce HCC surveillance.
... It has been described that dedifferentiated components in DC tissues may include malignant fibrous histiocytoma (35), fibrosarcoma (36), osteosarcoma (37), rhabdomyoblastoma (38) and rhabdomyosarcoma (39). Our study discovered that the presence of a nonfibrous dedifferentiation element had significantly positive prognostic implications in DC, which was in line with previous reports (40). Prior data have suggested that cancer-related fibroblasts can promote cancer development and progression by modulating the integrin signaling pathway (41)(42)(43), which has also been linked with tumor progression and metastasis (44). ...
Background
Currently, the clinicopathological and prognostic characteristics of dedifferentiated chordoma (DC) and poorly differentiated chordoma (PDC) remain poorly understood. In this study, we sought to characterize clinicopathological parameters in a large PDC/DC cohort and determine their correlations with progression-free survival (PFS) and overall survival (OS) of patients. We also attempted to compare clinical features between PDC/DC and conventional chordoma (CC).
Methods
Literature searches (from inception to June 01, 2020) using Medline, Embase, Google Scholar and Wanfang databases were conducted to identify eligible studies according to predefined criteria. The local database at our center was also retrospectively reviewed to include CC patients for comparative analysis.
Results
Fifty-eight studies from the literature and 90 CC patients from our local institute were identified; in total, 54 PDC patients and 96 DC patients were analyzed. Overall, PDC or DC had distinct characteristics from CC, while PDC and DC shared similar clinical features. Adjuvant radiotherapy and chemotherapy were associated with both PFS and OS in PDC patients in the univariate and/or multivariate analyses. In the DC cohort, tumor resection type, adjuvant chemotherapy and tumor dedifferentiation components significantly affected PFS, whereas none of them were predictive of outcome in the multivariate analysis. By analyzing OS, we found that surgery, resection type and the time to dedifferentiation predicted the survival of DC patients; however, only surgery remained significant after adjusting for other covariables.
Conclusions
These data may offer useful information to better understand the clinical characteristics of PDC/DC and may be helpful in improving the outcome prediction of patients.
... Identification of subjects with liver fibrosis in chronic liver disease (CLD) is important because liver fibrosis strongly correlates with prognosis and mortality [1,2]. However, these subjects have no subjective symptoms, and early detection is difficult. ...
Chronic liver disease is generally widespread, and a test for screening fibrotic subjects in a large population is needed. The ability of Wisteria floribunda agglutinin-positive mac-2 binding protein (WFA+-M2BP) to detect significant fibrosis was investigated in health checkup subjects in this research. Of 2021 health checkup subjects enrolled in this prospective cross-sectional study, those with WFA+-M2BP ≥ 1.0 were defined as high risk. Liver fibrosis was evaluated using magnetic resonance elastography (MRE) in subjects with high risk. The primary outcome was the positive predictive value (PPV) of WFA+-M2BP for significant fibrosis (liver stiffness ≥ 2.97 kPa by MRE). This trial was registered with the UMIN clinical trial registry, UMIN000036175. WFA+-M2BP ≥ 1.0 was observed in 5.3% of the 2021 subjects. The PPV for significant fibrosis with the threshold of WFA+-M2BP at ≥1.0, ≥1.1, ≥1.2, ≥1.3, ≥1.4, and ≥1.5 was 29.2%, 36.4%, 43.5%, 42.9%, 62.5%, and 71.4%, respectively. A WFA+-M2BP of 1.2 was selected as the optimal threshold for significant fibrosis among high-risk subjects, and the PPV, negative predictive value, sensitivity, and specificity for significant fibrosis were 43.5%, 84.0%, 71.4%, and 61.8%, respectively. WFA+-M2BP ≥ 1.2 was significantly associated with significant fibrosis, with an odds ratio (OR) of 4.04 (95% confidence interval (CI): 1.1–16, p = 0.04), but not FIB-4 ≥ 2.67 (OR: 2.40, 95%CI: 0.7–8.6, p-value = 0.2). In conclusion, WFA+-M2BP is associated with significant fibrosis and could narrow down potential subjects with liver fibrosis. The strategy of narrowing down fibrosis subjects using WFA+-M2BP may be used to screen for fibrotic subjects in a large population.
... Salesse et al. (2018) also identified that ELN promotes human breast cancer cell invasiveness via increasing the activity of matrix metalloproteinases (MMPs), which is the main enzyme to cleave ECM products. Besides, Yasui et al. (2016) indicated that ELN could be served as a biomarker for the development of hepatocellular carcinoma. However, the role of ELN in BLCA has not been reported yet. ...
Background
Bladder cancer (BLCA) is the 11th most common malignancy worldwide. Although significant improvements have been made in screening, diagnosis, and precise management in recent years, the prognosis of BLCA remains bleak.
Objectives
This study aimed to investigate the prognostic significance of tumor-infiltrating immune cells and construct ceRNA networks in BLCA patients.
Methods
The expression data of BLCA patients were obtained from The Cancer Genome Atlas (TCGA) database. A competing endogenous RNA (ceRNA) network was constructed to identify the hub genes involved in the prognosis of BLCA. The CIBERSORT algorithm was utilized to investigate the infiltration levels of 22 subsets of immune cells. Ultimately, the nomogram was generated to visualize the survival probability of each patient, with the calibration curve being performed to assess its performance. Furthermore, the Pearson correlation test was used to explore the correlation between the identified hub genes in the ceRNA network and the prognostic-related immune cells.
Results
A total of eight elements in the ceRNA network were considered as key members and correlated with the prognosis of BLCA, including ELN, SREBF1, DSC2, TTLL7, DIP2C, SATB1, hsa-miR-20a-5p, and hsa-miR-29c-3p. T cells CD8, T cells follicular helper (Tfh), and neutrophils were identified as independent prognostic factors in BLCA. The co-expression analysis showed that there was a significant correlation between the identified hub genes and immune cells.
Conclusion
Our results suggest that the mechanism of hsa-miR-29c-3p regulates the expression of ELN and DSC2, and the infiltration of Tfh and neutrophils might play pivotal roles in the progression of BLCA.
... Collagens, laminins and fibronectins, in particular, directly and indirectly, interact with tumor cells and are able to change the function and phenotype due to external stimuli, such as therapy 8,9 . Elastin, another component of the ECM has recently been identified as an independent predictor of HCC development 10 . The VX2 rabbit model for liver cancer is a well-studied model for testing and evaluation of preclinical interventional 11,12 and systemic therapies 13 on an HCC surrogate tumor. ...
... Few studies aimed to prove the linkage between the elastic ECM and peritumoral matrix, tumorigenesis and tumor progression. Yasui et al. 10 confirmed the predictive role of increased elastin fiber accumulation within the hepatic ECM for the development of HCC in patients. Maehara et al. 29 examined histopathological specimens of explanted human HCC and observed increased elastin and elastin-collagen components within the tumors. ...
To investigate the imaging performance of an elastin-specific molecular magnetic resonance imaging (MRI) probe with respect to the extracellular matrix (ECM) in an experimental hepatic cancer model. Twelve rabbits with hepatic VX2 tumors were examined using 3 T MRI 14, 21, and 28 days after tumor implantation for two subsequent days (gadobutrol, day 1; elastin-specific probe, day 2). The relative enhancement (RE) of segmented tumor regions (central and margin) and the peritumoral matrix was calculated using pre-contrast and delayed-phase T1w sequences. MRI measurements were correlated to histopathology and element-specific and spatially resolved mass spectrometry (MS). Mixed-model analysis was performed to assess the performance of the elastin-specific probe. In comparison to gadobutrol, the elastin probe showed significantly stronger RE, which was pronounced in the tumor margin (day 14–28: P ≤ 0.007). In addition, the elastin probe was superior in discriminating between tumor regions (χ²(4) = 65.87; P < 0.001). MRI-based measurements of the elastin probe significantly correlated with the ex vivo elastinstain (R = .84; P <0 .001) and absolute gadolinium concentrations (ICP-MS: R = .73, P <0 .01). LA-ICP-MS imaging confirmed the colocalization of the elastin-specific probe with elastic fibers. Elastin-specific molecular MRI is superior to non-specific gadolinium-based contrast agents in imaging the ECM of hepatic tumors and the peritumoral tissue.
