Comprehensive Characterization of Tumor Purity and Its Clinical Implications in Gastric Cancer

Solid tumour tissues are composed of tumour and non-tumour cells, such as stromal cells and immune cells. These non-tumour cells constitute an essential part of the tumour microenvironment (TME), which decrease the tumour purity and play an important role in carcinogenesis, malignancy progression, treatment resistance and prognostic assessment. However, the implications of various purity levels in gastric cancer (GC) remain largely unknown. In the present study, we used an in-silico approach to infer the tumour purity of 2,259 GC samples obtained from our hospital and 12 public datasets based on the transcriptomic data. We systematically evaluated the association of tumour purity with clinical outcomes, biological features, TME characteristics and treatment response in GC. We found that tumour purity might be a patient-specific intrinsic characteristic of GC. Low tumour purity was independently correlated with shorter survival time and faster recurrence and significantly associated with mesenchymal, invasive and metastatic phenotypes. Integrating GC purity into a clinical prognostic nomogram significantly improved predictive validity and reliability. In addition, low tumour purity was strongly associated with immune and stromal cell functions. Fibroblasts, endothelial cells and monocytes were markedly enriched in low-purity tumours, serving as robust indicators of a poor prognosis. Moreover, patients with low GC purity may not benefit more from adjuvant chemotherapy. Our findings highlight that tumour purity confers important clinical, biological, microenvironmental and treatment implications for patients with GC. Therefore, a comprehensive evaluation of tumour purity in individual tumours can provide more insights into the molecular mechanisms of GC, facilitate precise classification and clinical prediction and help to develop more effective individualised treatment strategies.

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ApoE-TREM2 axis induces pathogenic senescent-like myeloid cells in prostate cancer

10.21203/rs.3.rs-500924/v1 ◽

2021 ◽

Author(s):

Arianna Calcinotto ◽

Nicolò Bancaro ◽

Martina Troiani ◽

Rydell Arzola ◽

Angela Rita Elia ◽

...

Keyword(s):

Prostate Cancer ◽

Histone Deacetylase Inhibitors ◽

Tumour Progression ◽

Myeloid Cells ◽

Suppressor Cells ◽

Treatment Resistance ◽

Tumour Microenvironment ◽

Tumour Cells ◽

Mrna Levels ◽

Immature Myeloid Cells

Abstract Tumour cells promote the expansion and intra-tumoural recruitment of Myeloid-derived suppressor cells (MDSCs), a subset of immature myeloid cells, that support tumour cell proliferation and confer treatment resistance. While immature myeloid cells have a very short lifespan, whether pathogenic MDSCs can persist in the tumour microenvironment remains unknown. Here, we report the identification of a subset of long-lasting MDSCs that upregulate markers of cellular senescence and the TREM2 receptor. Senescent-like MDSCs possess higher pro-inflammatory capabilities compared to canonical MDSCs. Genetic and pharmacological elimination of senescent-like MDSCs decreases tumour progression in different mouse models of prostate cancer. Mechanistically, we find that Apolipoprotein E (ApoE) secreted by prostate tumour cells binds TREM2 in senescent-like MDSCs, thereby regulating the survival of these cells. ApoE and TREM2 mRNA levels are upregulated in prostate cancers and correlate with poor patients’ prognosis. Taken together, these results reveal a novel mechanism by which the tumour microenvironment shapes the intra-tumoural immune response. Pathogenic senescent-like MDSCs persist longer in the tumour microenvironment and can be eliminated by histone deacetylase inhibitors enhancing the efficacy of standard therapy in prostate cancer.

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LncRNA PVT1 Mediates Antiapoptosis and 5-Fluorouracil Resistance via Increasing Bcl2 Expression in Gastric Cancer

Journal of Oncology ◽

10.1155/2019/9325407 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 13

Author(s):

Peizhun Du ◽

Cheng’en Hu ◽

Yunyun Qin ◽

Jing Zhao ◽

Rajan Patel ◽

...

Keyword(s):

Gastric Cancer ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Treatment Resistance ◽

Cell Viability Assay ◽

Western Blot Assay ◽

Viability Assay ◽

Kaplan Meier ◽

Relative Gene ◽

Variant Translocation

Purpose. Plasmacytoma variant translocation 1 (PVT1) is a long noncoding RNA encoded by the human PVT1 gene, which has been verified to mediate tumorigenesis in gastric cancer. However, the underlying molecular mechanisms of PVT1 in gastric cancer (GC) remain largely unknown. Methods. The tumorigenic ability of PVT1 was verified by subcutaneous and orthotopic mouse models. Flow cytometry assay and TdT-mediated dUTP Nick-End Labeling staining were conducted to explore the effects of PVT1 on gastric cancer cell apoptosis. We investigated the relative gene and protein that are involved in apoptosis in real-time PCR and western blot assay. The resistance to 5- Fluorouracil (5-Fu) caused by PVT1 was evaluated using cell viability assay. Then, to confirm the effects of PVT1 on 5-Fu resistance, we conducted the Kaplan-Meier analysis based on three public databases. Results. We confirmed that PVT1 can promote the progression of gastric cancer. PVT1 inhibited the apoptosis of GC cells, which may account for its promotion on GC. We confirmed that PVT1 can regulate the expression of Bcl2 and enhance drug-resistance of gastric cancer to 5-Fu. Kaplan-Meier analysis showed that patients with high PVT1 expression do not experience survival related benefits from 5-Fu based chemotherapy; instead, therapy containing no 5-Fu chemotherapy can improve the first progression survival and overall survival of high PVT1 expression GC patients significantly. Conclusion. Our results showed that PVT1 can inhibit the apoptosis and enhance the 5-Fu resistance of gastric cancer through the activation of Bcl2. PVT1 has the potential to serve as an indicator to predict 5-Fu treatment resistance.

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The Advancing Roles of Exosomes in Breast Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.731062 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xi Wang ◽

Chunxiao Sun ◽

Xiang Huang ◽

Jun Li ◽

Ziyi Fu ◽

...

Keyword(s):

Breast Cancer ◽

Breast Tissue ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Treatment Resistance ◽

Bioactive Molecules ◽

Advanced Treatment ◽

Target Cells ◽

Tumor Treatment ◽

Multiple Interactions

Breast cancer (BC) develops from breast tissue and is the most common aggressive malignant tumor in women worldwide. Although advanced treatment strategies have been applied and reduced current mortality rates, BC control remains unsatisfactory. It is essential to elucidate the underlying molecular mechanisms to assist clinical options. Exosomes are a type of extracellular vesicles and mediate cellular communications by delivering various biomolecules (oncogenes, oncomiRs, proteins, and even pharmacological compounds). These bioactive molecules can be transferred to change the transcriptome of target cells and influence tumor-related signaling pathways. Extensive studies have implicated exosomes in BC biology, including therapeutic resistance and the surrounding microenvironment. This review focuses on discussing the functions of exosomes in tumor treatment resistance, invasion and metastasis of BC. Moreover, we will also summarize multiple interactions between exosomes and the BC tumor microenvironment. Finally, we propose promising clinical applications of exosomes in BC.

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Potential of Bioactive Food Components against Gastric Cancer: Insights into Molecular Mechanism and Therapeutic Targets

Cancers ◽

10.3390/cancers13184502 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4502

Author(s):

Seog Young Kang ◽

Dongwon Hwang ◽

Soyoung Shin ◽

Jinju Park ◽

Myoungchan Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Molecular Mechanisms ◽

Experimental Studies ◽

Treatment Strategies ◽

Food Products ◽

Therapeutic Effects ◽

Cancer Management ◽

Food Components ◽

Prevention And Treatment ◽

Bioactive Food Components

Gastric cancer, also known as stomach cancer, is a cancer that develops from the lining of the stomach. Accumulated evidence and epidemiological studies have indicated that bioactive food components from natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action has not yet been elucidated. Particularly, experimental studies have shown that natural bioactive food products display a protective effect against gastric cancer via numerous molecular mechanisms, such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy, as well as immunotherapy, and its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. However, administration of naturally occurring bioactive phytochemical food components could increase the efficacy of gastric chemotherapy and other chemotherapeutic resistance. Additionally, several studies have suggested that bioactive food components with structural stability, potential bioavailability, and powerful bioactivity are important to develop novel treatment strategies for gastric cancer management, which may minimize the adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural bioactive food products on the prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.

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High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas

Cancers ◽

10.3390/cancers13133198 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3198

Author(s):

Edith Willscher ◽

Lydia Hopp ◽

Markus Kreuz ◽

Maria Schmidt ◽

Siras Hakobyan ◽

...

Keyword(s):

Molecular Mechanisms ◽

Tumor Development ◽

Treatment Resistance ◽

Lower Grade ◽

Cell Functions ◽

Gene Level ◽

Level Information ◽

Diffuse Gliomas ◽

Grade Ii ◽

Immunogenic Properties

Molecular mechanisms of lower-grade (II–III) diffuse gliomas (LGG) are still poorly understood, mainly because of their heterogeneity. They split into astrocytoma- (IDH-A) and oligodendroglioma-like (IDH-O) tumors both carrying mutations(s) at the isocitrate dehydrogenase (IDH) gene and into IDH wild type (IDH-wt) gliomas of glioblastoma resemblance. We generated detailed maps of the transcriptomes and DNA methylomes, revealing that cell functions divided into three major archetypic hallmarks: (i) increased proliferation in IDH-wt and, to a lesser degree, IDH-O; (ii) increased inflammation in IDH-A and IDH-wt; and (iii) the loss of synaptic transmission in all subtypes. Immunogenic properties of IDH-A are diverse, partly resembling signatures observed in grade IV mesenchymal glioblastomas or in grade I pilocytic astrocytomas. We analyzed details of coregulation between gene expression and DNA methylation and of the immunogenic micro-environment presumably driving tumor development and treatment resistance. Our transcriptome and methylome maps support personalized, case-by-case views to decipher the heterogeneity of glioma states in terms of data portraits. Thereby, molecular cartography provides a graphical coordinate system that links gene-level information with glioma subtypes, their phenotypes, and clinical context.

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Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression

Cells ◽

10.3390/cells10010056 ◽

2021 ◽

Vol 10 (1) ◽

pp. 56

Author(s):

Jesse D. Armitage ◽

Hannah V. Newnes ◽

Alison McDonnell ◽

Anthony Bosco ◽

Jason Waithman

Keyword(s):

Extracellular Matrix ◽

Immune System ◽

Treatment Strategies ◽

Tumour Response ◽

Tumour Microenvironment ◽

Tumour Cells ◽

Fine Tuning ◽

Malignant Tissue ◽

New Treatment ◽

Complex Architecture

Immunotherapy has revolutionised the treatment of cancers by harnessing the power of the immune system to eradicate malignant tissue. However, it is well recognised that some cancers are highly resistant to these therapies, which is in part attributed to the immunosuppressive landscape of the tumour microenvironment (TME). The contexture of the TME is highly heterogeneous and contains a complex architecture of immune, stromal, vascular and tumour cells in addition to acellular components such as the extracellular matrix. While understanding the dynamics of the TME has been instrumental in predicting durable responses to immunotherapy and developing new treatment strategies, recent evidence challenges the fundamental paradigms of how tumours can effectively subvert immunosurveillance. Here, we discuss the various immunosuppressive features of the TME and how fine-tuning these mechanisms, rather than ablating them completely, may result in a more comprehensive and balanced anti-tumour response.

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α-Tomatine Inhibits Proliferation, Metastasis, Drug Resistance and Immune Infiltration Through the PI3K-AKT-MAPK Axis in Gastric Cancer

10.21203/rs.3.rs-53224/v1 ◽

2020 ◽

Author(s):

Di Zhang ◽

Hao Yuan ◽

Si-Si Mo ◽

Xian-Wei Mo ◽

Wei-Zhong Tang ◽

...

Keyword(s):

Gastric Cancer ◽

Molecular Mechanisms ◽

Immune Cell ◽

Inhibitory Effect ◽

Mapk Signaling ◽

Immune Infiltration ◽

Cell Functions ◽

Proliferation And Metastasis ◽

Steroidal Glycoalkaloid ◽

Mapk Signaling Pathways

Abstract Background: α-Tomatine, a naturally existing steroidal glycoalkaloid in immature green tomatoes, had anticarcinogenic performances in various types of cancer cells. Within this study, we aimed to investigate the efficacy and potential molecular mechanism of α-tomatine in gastric cancer (GC) and the association with immune infiltration and prognosis.Methods: We used human GC cells MGC803, BGC823, SGC7901 and SGC7901/DDP to evaluate the cell functions of α-tomatine, and the molecular mechanisms of α-tomatine were investigated by qRT-PCR and western blotting analysis. Timer database was used to analyzed the correlation of targets repressed by α-tomatine, immune infiltration and prognosis. Results: Results showed that α-tomatine strongly inhibited PI3K-AKT and MAPK signaling pathways, thereby repressing the proliferation and metastasis of GC cells with different differentiations and cisplatin resistance. The inhibitory effect of α-tomatine on TWIST, Slug and PARP in SGC7901/DDP cells also suggested α-tomatine provided a feasible approach for confronting metastasis of clinical cisplatin resistant cases. Immunologically, α-tomatine could partially modulate the process and consequences of immune infiltration based on the correlation between 65 genes corresponding to interacting proteins and immune cell infiltration. α-Tomatine could improve prognosis of GC patients by inhibiting AKT3, VIM, FN1 and SNAI2, and at least partially counteract immune dysfunction triggered by macrophage infiltration. Conclusion: Strategies for treating GC should not be restricted to single, repetitive drug use, they should be predisposed to emerging, multi-target drugs. GC was highly susceptible to α-tomatine suggesting that α-tomatine could be used as an emerging and promising approach to confront GC.

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Molecular Evolutionary Process of Advanced Gastric Cancer During Sequential Chemotherapy Detected by Circulating Tumor DNA

10.21203/rs.3.rs-823245/v1 ◽

2021 ◽

Author(s):

Wenqi Xi ◽

Chenfei Zhou ◽

Shouwei Zhang ◽

Yi Zhao ◽

Yawei Chen ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Copy Number ◽

Treatment Strategies ◽

Evolutionary Process ◽

Treatment Resistance ◽

Circulating Tumor Dna ◽

Copy Number Variations ◽

Current Data ◽

Sequential Chemotherapy

Abstract Background: Chemotherapy is the major strategy for advanced gastric cancer (AGC) patients, whereits efficacy has largely plateaued. Tumor evolutionary theory provides a promising strategy to optimize paradigm of cancer treatment, while current data of molecular changes during sequential chemotherapy is too insufficient to understandevolutionary process in tumors. Methods: Here, we performed NGS analysison 100 circulatingtumor DNA (ctDNA) samples collected from 27 AGC patients during treatment of sequentialchemotherapy. We observed dynamic changes of copy number instability (CNI) and gene-level copy number variations (CNVs) during the treatment.Results: Gene-levelCNV profiles were similar between baseline and end oftreatment. Subsequent regimens did not significantly change the CNV profiles driven by first-line regimens. Based on changes of copy number values of genes during treatment, resistance related genes of all four regimens were identified, respectively. These genes could be enriched into several common oncologic pathways, while exhibited a high inter-patient heterogeneity. Genes with different copy number values between baseline and end of treatment could be the targets of by molecular matched therapy. Conclusions: Our study provides important information to understand molecular evolutionary process of AGS patients during sequential chemotherapy first and can help to optimize future treatment strategies.

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