Epigenetic Control of the Tumor Microenvironment

Marks, David L.; Olson, Rachel; Fernández-Zapico, Martín E.

doi:10.2217/epi-2016-0110

Cited by 66 publications

(58 citation statements)

References 138 publications

(165 reference statements)

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“…confirm the importance of tumor microenvironment, which comprises prominent components of cancer progression within the immediate vicinity of tumor cells such as fibroblasts, immune cells and the extracellular matrix 25,26. The results demonstrate that there must exist intracellular reductants in tissue other than the reduced nicotinamide adenine dinucleotide (NADH) (present in the growing medium in cell culturing) that contribute to Cyt c activity.…”

supporting

confidence: 56%

Redox state changes of mitochondrial cytochromes in brain and breast cancers by Raman spectroscopy and imaging

Abramczyk

Surmacki

Brożek-Płuska

2020

Preprint

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This paper presents a non-invasive approach to study redox status of cytochromes in vitro human brain cells of normal astrocytes (NHA), astrocytoma (CRL-1718), glioblastoma (U87-MG) and medulloblastoma (Daoy), and human breast cells of normal cells (MCF10A), slightly malignant cells (MCF7) and highly aggressive cells (MDA-MB-231), in vivo animal models, and ex vivo brain and breast tissues surgically resected human specimens by means of Raman microspectroscopy at 355 nm, 532 nm, 785 nm and endospectroscopic Raman probe at 785 nm.Here we show that the amount of reduced cytochrome becomes abnormally high in human brain tumors and breast cancers. In contrast, the amount of reduced cytochrome c is lower in cancer cells when compared to the normal one at in vitro conditions when the effect of microenvironment is eliminated. Mitochondrial dysfunction and alterations in the chemical composition of the nucleus, mitochondria, lipid droplets, cytoplasm in single cells have been detected by Raman imaging. Incubation in vitro with retinoic acid increases the amount of reduced cytochrome c.

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supporting

confidence: 56%

Redox state changes of mitochondrial cytochromes in brain and breast cancers by Raman spectroscopy and imaging

Abramczyk

Surmacki

Brożek-Płuska

2020

Preprint

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“…There are several ongoing clinical trials of EZH2 inhibitors for not only haematological malignancies but solid tumours (ClinicalTrials.gov: https://clinicaltrials.gov/), and the their efficacy in vivo cannot be fully explained by only the epigenetic reprogramming of cancer cells 51. Therefore, their effects on cancer stromal cells may be a concomitant mode of action of epigenetic drugs 52. The possibility of stroma-targeting therapy, namely epigenetic reprogramming of CAFs needs to be explored.…”

Section: Discussionmentioning

confidence: 99%

Cancer cell niche factors secreted from cancer-associated fibroblast by loss of H3K27me3

Maeda

Takeshima²,

Iida³

et al. 2019

Gut

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ObjectiveCancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells.DesignTwelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database.ResultsCAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal–epithelial interactions, such as WNT5A, GREM1, NOG and IGF2. Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration.ConclusionsH3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.

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“…Moreover, one of the most important constituents of the tumor microenvironment is the ECM, a meshwork of proteins and glycosaminoglycans surrounding tumor cells [12]. ECM provides the biochemical and mechanical support for tumor progression [12,27,28]. The expression of several ECM proteins has been shown to be upregulated in tumors, of which, the most abundant is type I collagen [29].…”

Section: Structural Proteins and Ecm Stiffnessmentioning

confidence: 99%

Esophageal Cancer Development: Crucial Clues Arising from the Extracellular Matrix

Palumbo

Costa

Pontes

et al. 2020

Cells

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In the last years, the extracellular matrix (ECM) has been reported as playing a relevant role in esophageal cancer (EC) development, with this compartment being related to several aspects of EC genesis and progression. This sounds very interesting due to the complexity of this highly incident and lethal tumor, which takes the sixth position in mortality among all tumor types worldwide. The well-established increase in ECM stiffness, which is able to trigger mechanotransduction signaling, is capable of regulating several malignant behaviors by converting alteration in ECM mechanics into cytoplasmatic biochemical signals. In this sense, it has been shown that some molecules play a key role in these events, particularly the different collagen isoforms, as well as enzymes related to its turnover, such as lysyl oxidase (LOX) and matrix metalloproteinases (MMPs). In fact, MMPs are not only involved in ECM stiffness, but also in other events related to ECM homeostasis, which includes ECM remodeling. Therefore, the crucial role of distinct MMPs isoform has already been reported, especially MMP-2, -3, -7, and -9, along EC development, thus strongly associating these proteins with the control of important cellular events during tumor progression, particularly in the process of invasion during metastasis establishment. In addition, by distinct mechanisms, a vast diversity of glycoproteins and proteoglycans, such as laminin, fibronectin, tenascin C, galectin, dermatan sulfate, and hyaluronic acid exert remarkable effects in esophageal malignant cells due to the activation of oncogenic signaling pathways mainly involved in cytoskeleton alterations during adhesion and migration processes. Finally, the wide spectrum of interactions potentially mediated by ECM may represent a singular intervention scenario in esophageal carcinogenesis natural history and, due to the scarce knowledge on the cellular and molecular mechanisms involved in EC development, the growing body of evidence on ECM’s role along esophageal carcinogenesis might provide a solid base to improve its management in the future.

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Epigenetic Control of the Tumor Microenvironment

Cited by 66 publications

References 138 publications

Redox state changes of mitochondrial cytochromes in brain and breast cancers by Raman spectroscopy and imaging

Redox state changes of mitochondrial cytochromes in brain and breast cancers by Raman spectroscopy and imaging

Cancer cell niche factors secreted from cancer-associated fibroblast by loss of H3K27me3

Esophageal Cancer Development: Crucial Clues Arising from the Extracellular Matrix

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