scholarly journals Emergence of an adaptive epigenetic cell state in human bladder urothelial carcinoma evolution

2021 ◽  
Author(s):  
Yu Xiao ◽  
Wan Jin ◽  
Kaiyu Qian ◽  
Kai Wu ◽  
Gang Wang ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Poor Prognosis ◽  
Therapy Resistance ◽  
Cellular Mechanism ◽  
Intratumor Heterogeneity ◽  
Advanced Stage ◽  
Human Bladder ◽  
Clinical Prognosis ◽  
Bladder Urothelial Carcinoma ◽  
Transcriptional Plasticity

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) facilitates therapy resistance and immune evasion to affect clinical prognosis directly. However, the molecular and cellular mechanism generating ITH in BLCA remains elusive. Here we show that a TM4SF1-positive cancer subpopulation (TPCS) drives ITH diversification in BLCA. By extensive profiling of the epigenome and transcriptome of BLCA from 79 donors across all stages, we elucidated the evolution trajectories of luminal and basal BLCA. TPCS emerges from the basal trajectory and shows extensive transcriptional plasticity with a distinct epigenomic landscape. Clinically, TPCS were enriched in advanced stage patients and associated with poor prognosis. Our results showed how cancer adapts to its environment by adopting a stem cell-like epigenomic landscape.

scholarly journals Upregulation of Versican Associated with Tumor Progression, Metastasis, and Poor Prognosis in Bladder Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Qi Zhang ◽  
Junxiu Wu ◽  
Xinpeng Chen ◽  
Ming Zhao ◽  
Dahong Zhang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Poor Prognosis ◽  
Molecular Subtype ◽  
Histological Grade ◽  
Mrna Level ◽  
Human Bladder ◽  
Clinical Prognosis ◽  
Ecm Remodeling ◽  
Kaplan Meier

Objective. This work analyzes the role of versican (VCAN) on bladder cancer (BLCA). Versican (VCAN) is a chondroitin sulfate proteoglycan which is important for tumorigenesis and the development of cancer. However, the expression of VCAN on human bladder cancer (BLCA) has been rarely reported. Methods. The clinical significance of VCAN in BLCA has been determined by our bioinformatics tools. Then, we performed immunohistochemical staining (IHC) and analyzed the correlation between VCAN expression and clinicopathological features. Results. The bioinformatics results reveal that a high VCAN mRNA level was significantly associated with stage, histological subtype, molecular subtype, and metastasis in BLCA. Furthermore, IHC reveals that expression of VCAN was significantly correlated with the number of tumors, invasion depth, lymph node metastasis, distant metastasis, and histological grade. Kaplan-Meier survival analysis reveals that patients with a high expression of VCAN have poor prognosis than those patients with a low expression of VCAN. According to our result from the bioinformatics database, the mechanism of VCAN in BLCA revealed that VCAN was related to FBN1 and genes of the ECM remodeling pathway (MMP1, MMP2). Conclusion. VCAN expression might be included in the process of carcinogenesis and prognosis. Hence, VCAN could be a reliable biomarker of the clinical prognosis on BLCA.

scholarly journals Gas6/Axl Signaling Pathway in the Tumor Immune Microenvironment

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1850 ◽  
Author(s):  
Mai Tanaka ◽  
Dietmar W. Siemann
Keyword(s):  
Tumor Microenvironment ◽  
Signaling Pathway ◽  
Immune Evasion ◽  
Tyrosine Kinases ◽  
Immune Cell ◽  
Expression Patterns ◽  
Therapy Resistance ◽  
Host Cells ◽  
Clinical Prognosis

Receptor tyrosine kinases have been shown to dysregulate a number of pathways associated with tumor development, progression, and metastasis. Axl is a receptor tyrosine kinase expressed in many cancer types and has been associated with therapy resistance and poor clinical prognosis and outcomes. In addition, Axl and its ligand growth arrest specific 6 (Gas6) protein are expressed by a number of host cells. The Gas6/Axl signaling pathway has been implicated in the promotion of tumor cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. As a result, Axl is an attractive, novel therapeutic target to impair multiple stages of tumor progression from both neoplastic and host cell axes. This review focuses on the role of the Gas6/Axl signaling pathway in promoting the immunosuppressive tumor microenvironment, as immune evasion is considered one of the hallmarks of cancer. The review discusses the structure and activation of the Gas6/Axl signaling pathway, GAS6 and AXL expression patterns in the tumor microenvironment, mechanisms of Axl-mediated tumor immune response, and the role of Gas6/Axl signaling in immune cell recruitment.

scholarly journals The Effect of Heterogenous Subregions in Glioblastomas on Survival Stratification: A Radiomics Analysis Using the Multimodality MRI

2021 ◽  
Vol 20 ◽  
pp. 153303382110330
Author(s):  
Lulu Yin ◽  
Yan Liu ◽  
Xi Zhang ◽  
Hongbing Lu ◽  
Yang Liu
Keyword(s):  
Poor Prognosis ◽  
Intratumor Heterogeneity ◽  
Short Term ◽  
Prognostic Information ◽  
Manual Delineation ◽  
Flair Sequence ◽  
The Poor ◽  
Contrast Enhanced ◽  
Mri Sequences

Intratumor heterogeneity is partly responsible for the poor prognosis of glioblastoma (GBM) patients. In this study, we aimed to assess the effect of different heterogeneous subregions of GBM on overall survival (OS) stratification. A total of 105 GBM patients were retrospectively enrolled and divided into long-term and short-term OS groups. Four MRI sequences, including contrast-enhanced T1-weighted imaging (T1C), T1, T2, and FLAIR, were collected for each patient. Then, 4 heterogeneous subregions, i.e. the region of entire abnormality (rEA), the regions of contrast-enhanced tumor (rCET), necrosis (rNec) and edema/non-contrast-enhanced tumor (rE/nCET), were manually drawn from the 4 MRI sequences. For each subregion, 50 radiomics features were extracted. The stratification performance of 4 heterogeneous subregions, as well as the performances of 4 MRI sequences, was evaluated both alone and in combination. Our results showed that rEA was superior in stratifying long-and short-term OS. For the 4 MRI sequences used in this study, the FLAIR sequence demonstrated the best performance of survival stratification based on the manual delineation of heterogeneous subregions. Our results suggest that heterogeneous subregions of GBMs contain different prognostic information, which should be considered when investigating survival stratification in patients with GBM.

scholarly journals Discovery of Spatial Peptide Signatures for Neuroblastoma Risk Assessment by MALDI Mass Spectrometry Imaging

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3184
Author(s):  
Zhiyang Wu ◽  
Patrick Hundsdoerfer ◽  
Johannes H. Schulte ◽  
Kathy Astrahantseff ◽  
Senguel Boral ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Risk Assessment ◽  
Mass Spectrometry Imaging ◽  
Principal Component ◽  
Therapy Resistance ◽  
Risk Classification ◽  
Intratumor Heterogeneity ◽  
Ionization Mass ◽  
Characteristic Analysis ◽  
Analytical Strategy

Risk classification plays a crucial role in clinical management and therapy decisions in children with neuroblastoma. Risk assessment is currently based on patient criteria and molecular factors in single tumor biopsies at diagnosis. Growing evidence of extensive neuroblastoma intratumor heterogeneity drives the need for novel diagnostics to assess molecular profiles more comprehensively in spatial resolution to better predict risk for tumor progression and therapy resistance. We present a pilot study investigating the feasibility and potential of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to identify spatial peptide heterogeneity in neuroblastoma tissues of divergent current risk classification: high versus low/intermediate risk. Univariate (receiver operating characteristic analysis) and multivariate (segmentation, principal component analysis) statistical strategies identified spatially discriminative risk-associated MALDI-based peptide signatures. The AHNAK nucleoprotein and collapsin response mediator protein 1 (CRMP1) were identified as proteins associated with these peptide signatures, and their differential expression in the neuroblastomas of divergent risk was immunohistochemically validated. This proof-of-concept study demonstrates that MALDI-MSI combined with univariate and multivariate analysis strategies can identify spatially discriminative risk-associated peptide signatures in neuroblastoma tissues. These results suggest a promising new analytical strategy improving risk classification and providing new biological insights into neuroblastoma intratumor heterogeneity.

scholarly journals Recent Advancements in the Mechanisms Underlying Resistance to PD-1/PD-L1 Blockade Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 663
Author(s):  
Yu Yuan ◽  
Abdalla Adam ◽  
Chen Zhao ◽  
Honglei Chen
Keyword(s):  
Immune Evasion ◽  
Immune Checkpoint ◽  
Poor Prognosis ◽  
Target Therapy ◽  
Acquired Resistance ◽  
Immune Checkpoint Blockade ◽  
Therapeutic Strategies ◽  
Present Evidence ◽  
Immunosuppressive Factor

Release of immunoreactive negative regulatory factors such as immune checkpoint limits antitumor responses. PD-L1 as a significant immunosuppressive factor has been involved in resistance to therapies such as chemotherapy and target therapy in various cancers. Via interacting with PD-1, PD-L1 can regulate other factors or lead to immune evasion of cancer cells. Besides, immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in the different tumors, but a significant percentage of patients cannot benefit from this therapy due to primary and acquired resistance during treatment. In this review, we described the utility of PD-L1 expression levels for predicting poor prognosis in some tumors and present evidence for a role of PD-L1 in resistance to therapies through PD-1/PD-L1 pathway and other correlating signaling pathways. Afterwards, we elaborate the key mechanisms underlying resistance to PD-1/PD-L1 blockade in cancer immunotherapy. Furthermore, promising combination of therapeutic strategies for patients resistant to PD-1/PD-L1 blockade therapy or other therapies associated with PD-L1 expression was also summarized.

scholarly journals A Systems Approach to Brain Tumor Treatment

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3152
Author(s):  
James H. Park ◽  
Adrian Lopez Garcia de Lomana ◽  
Diego M. Marzese ◽  
Tiffany Juarez ◽  
Abdullah Feroze ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Rational Design ◽  
Clinical Medicine ◽  
Systems Approach ◽  
Therapy Resistance ◽  
High Rate ◽  
Intratumor Heterogeneity ◽  
Primary Therapy ◽  
Molecular Features

Brain tumors are among the most lethal tumors. Glioblastoma, the most frequent primary brain tumor in adults, has a median survival time of approximately 15 months after diagnosis or a five-year survival rate of 10%; the recurrence rate is nearly 90%. Unfortunately, this prognosis has not improved for several decades. The lack of progress in the treatment of brain tumors has been attributed to their high rate of primary therapy resistance. Challenges such as pronounced inter-patient variability, intratumoral heterogeneity, and drug delivery across the blood–brain barrier hinder progress. A comprehensive, multiscale understanding of the disease, from the molecular to the whole tumor level, is needed to address the intratumor heterogeneity resulting from the coexistence of a diversity of neoplastic and non-neoplastic cell types in the tumor tissue. By contrast, inter-patient variability must be addressed by subtyping brain tumors to stratify patients and identify the best-matched drug(s) and therapies for a particular patient or cohort of patients. Accomplishing these diverse tasks will require a new framework, one involving a systems perspective in assessing the immense complexity of brain tumors. This would in turn entail a shift in how clinical medicine interfaces with the rapidly advancing high-throughput (HTP) technologies that have enabled the omics-scale profiling of molecular features of brain tumors from the single-cell to the tissue level. However, several gaps must be closed before such a framework can fulfill the promise of precision and personalized medicine for brain tumors. Ultimately, the goal is to integrate seamlessly multiscale systems analyses of patient tumors and clinical medicine. Accomplishing this goal would facilitate the rational design of therapeutic strategies matched to the characteristics of patients and their tumors. Here, we discuss some of the technologies, methodologies, and computational tools that will facilitate the realization of this vision to practice.

scholarly journals The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 439 ◽  
Author(s):  
Vanessa Delcroix ◽  
Olivier Mauduit ◽  
Nolwenn Tessier ◽  
Anaïs Montillaud ◽  
Tom Lesluyes ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Therapy Resistance ◽  
High Grade ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Well Differentiated

By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated with a better outcome for patients. Moreover, KL is downregulated in dedifferentiated liposarcomas (DDLPS) compared to well-differentiated tumors and adipose tissue. Because DDLPS are high-grade tumors associated with poor prognosis, we examined the potential of KL as a tool for overcoming therapy resistance. First, we confirmed the attenuation of IGF-1-induced calcium (Ca2+)-response and Extracellular signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation in KL-overexpressing human DDLPS cells. KL overexpression also reduced cell proliferation, clonogenicity, and increased apoptosis induced by gemcitabine, thapsigargin, and ABT-737, all of which are counteracted by IGF-1R-dependent signaling and activate Ca2+-dependent endoplasmic reticulum (ER) stress. Then, we monitored cell death and cytosolic Ca2+-responses and demonstrated that KL increases the reticular Ca2+-leakage by maintaining TRPC6 at the ER and opening the translocon. Only the latter is necessary for sensitizing DDLPS cells to reticular stressors. This was associated with ERK1/2 inhibition and could be mimicked with IGF-1R or MEK inhibitors. These observations provide a new therapeutic strategy in the management of DDLPS.

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