Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance

Ge, Rongbin; Wang, Zongwei; Cheng, Liang

doi:10.1038/s41698-022-00272-w

Cited by 67 publications

(47 citation statements)

References 139 publications

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“…During tumor progression, each cell type interacts dynamically with cancer cells to alter the surrounding environment into one that promotes tumor development. These alterations consist of the recruitment of fibroblasts, migration of immune cells, stroma remodeling, and progression of tumor-specific vasculature [ 61 ]. The prognosis of cancer is correlated with immune cell infiltration and activation, thus the TME, which is composed of diverse infiltrating immune and stromal cells, may greatly impact therapy response and clinical outcome, in addition to playing a crucial role in cancer etiology and progression [ 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

EZH2 as a Prognostic Factor and Its Immune Implication with Molecular Characterization in Prostate Cancer: An Integrated Multi-Omics in Silico Analysis

Liu

Zhang

et al. 2022

Biomolecules

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Prostate cancer (PCa) is a type of potentially fatal malignant tumor. Immunotherapy has shown a lot of potential for various types of solid tumors, but the benefits have been less impressive in PCa. Enhancer of zeste homolog 2 (EZH2) is one of the three core subunits of the polycomb repressive complex 2 that has histone methyltransferase activity, and the immune effects of EZH2 in PCa are still unclear. The purpose of this study was to explore the potential of EZH2 as a prognostic factor and an immune therapeutic biomarker for PCa, as well as the expression pattern and biological functions. All analyses in this study were based on publicly available databases, mainly containing Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), UCSCXenaShiny, and TISIDB. We performed differential expression analysis, developed a prognostic model, and explored potential associations between EZH2 and DNA methylation modifications, tumor microenvironment (TME), immune-related genes, tumor mutation burden (TMB), tumor neoantigen burden (TNB), and representative mismatch repair (MMR) genes. We also investigated the molecular and immunological characterizations of EZH2. Finally, we predicted immunotherapeutic responses based on EZH2 expression levels. We found that EZH2 was highly expressed in PCa, was associated with a poor prognosis, and may serve as an independent prognostic factor. EZH2 expression in PCa was associated with DNA methylation modifications, TME, immune-related genes, TMB, TNB, and MMR. By gene set enrichment analysis and gene set variation analysis, we found that multiple functions and pathways related to tumorigenesis, progression, and immune activation were enriched. Finally, we inferred that immunotherapy may be more effective for PCa patients with low EZH2 expression. In conclusion, our study showed that EZH2 could be a potentially efficient predictor of prognosis and immune response in PCa patients.

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Section: Discussionmentioning

confidence: 99%

EZH2 as a Prognostic Factor and Its Immune Implication with Molecular Characterization in Prostate Cancer: An Integrated Multi-Omics in Silico Analysis

Liu

Zhang

et al. 2022

Biomolecules

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“…The differential metabolic demands among TME cells result in metabolic competition and symbiosis to support tumor-specific metabolic reprogramming. This causes the release of immunosuppressive metabolites, facilitates tumor progression, and mediates mechanisms of therapeutic resistance [ 312 , 314 , 315 , 316 , 317 , 318 ]. Exosomes from prostate CAFs are capable of shifting metabolism in recipient tumor cells by suppressing OXPHOS, thereby increasing glycolysis and enhancing glutamine metabolism as a source of intermediate metabolites [ 319 ].…”

Section: Tumor Microenvironment (Tme)mentioning

confidence: 99%

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

et al. 2022

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There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.

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“…It is undebatable that PCa patients in clinical studies are the gold standard of research in this area. The species differences in metabolic landscape and tumor microenvironment between rodents and humans can pose a discrepancy in outcome [ 112 ]. While it is recognizable that humans should not be involved in research on PCa, or as a matter a fact for any disease, until the safety and efficacy of the compounds have been established with reasonable confidence, the pharmacokinetics, DDI, and other drug deposition-related studies face lesser regulatory stringency than during drug development stage.…”

Section: Clinical Research Models Of Pcamentioning

confidence: 99%

Preclinical and Clinical Research Models of Prostate Cancer: A Brief Overview

Gregori

Johora

Deb

2022

Life

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The incidence and mortality from prostate cancer (PCa) are on the rise which poses a major public health concern worldwide. In this narrative review, we have summarized the characteristics of major in vitro and in vivo PCa models including their utility in developing treatment strategies. Androgens, particularly, testosterone and dihydrotestosterone (DHT) activate the androgen receptor (AR) signaling pathway that facilitates the development and progression of castration resistant PCa. Several enzymes namely, CYP17A1, HSD17B, and SRD5A are essential to furnishing DHT from dehydroepiandrosterone in the classical pathway while DHT is formed from androstanediol in the backdoor pathway. The advancement in delineating the molecular heterogeneity of PCa has been possible through the development of several in vitro and in vivo research models. Generally, tissue culture models are advantageous to understand PCa biology and investigate the efficacy and toxicity of novel agents; nevertheless, animal models are indispensable to studying the PCa etiology and treatment since they can simulate the tumor microenvironment that plays a central role in initiation and progression of the disease. Moreover, the availability of several genetically engineered mouse models has made it possible to study the metastasis process. However, the conventional models are not devoid of limitations. For example, the lack of heterogeneity in tissue culture models and the variation of metastatic characteristics in xenograft models are obviously challenging. Additionally, due to the racial and ethnic disparities in PCa pathophysiology, a new model that can represent PCa encompassing different ethnicities is urgently needed. New models should continue to evolve to address the genetic and molecular complexities as well as to further elucidate the finer details of the steroidogenic pathway associated with PCa.

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Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance

Cited by 67 publications

References 139 publications

EZH2 as a Prognostic Factor and Its Immune Implication with Molecular Characterization in Prostate Cancer: An Integrated Multi-Omics in Silico Analysis

EZH2 as a Prognostic Factor and Its Immune Implication with Molecular Characterization in Prostate Cancer: An Integrated Multi-Omics in Silico Analysis

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

Preclinical and Clinical Research Models of Prostate Cancer: A Brief Overview

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