The Brain Microenvironment Induces DNMT1 Suppression and Indolence of Metastatic Cancer Cells

Hirata, Eishu; Ishibashi, Kojiro; Shinjo, Keiko; Kojima, Shinya; Kondo, Yutaka; Mano, Hiroyuki; Yano, Seiji; Kiyokawa, Etsuko

doi:10.1016/j.isci.2020.101480

Cited by 22 publications

(18 citation statements)

References 49 publications

(64 reference statements)

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“…In the early stage of brain metastasis, when the survival of cancer cells is unstable, it has been reported that cancer cells slow down cell cycle progression and enhance apoptosis-resistant survival signals. This switching is thought to involve a mechanism in which a component secreted by peripheral astrocytes suppresses DNMT1, a methyltransferase of cancer cells [ 21 ]. It is suggested that there is a mechanism by which the responsiveness of peripheral astrocytes is dynamically altered upon some stimuli or oxidative stress loading and that such changes are first manifested in metabolomic shifts.…”

Section: Discussionmentioning

confidence: 99%

Metabolome Shift in Both Metastatic Breast Cancer Cells and Astrocytes Which May Contribute to the Tumor Microenvironment

Sato

Shimizu

Okawa

et al. 2021

IJMS

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The role of astrocytes in the periphery of metastatic brain tumors is unclear. Since astrocytes regulate central nervous metabolism, we hypothesized that changes in astrocytes induced by contact with cancer cells would appear in the metabolome of both cells and contribute to malignant transformation. Coculture of astrocytes with breast cancer cell supernatants altered glutamate (Glu)-centered arginine–proline metabolism. Similarly, the metabolome of cancer cells was also altered by astrocyte culture supernatants, and the changes were further amplified in astrocytes exposed to Glu. Inhibition of Glu uptake in astrocytes reduces the variability in cancer cells. Principal component analysis of the cancer cells revealed that all these changes were in the first principal component (PC1) axis, where the responsible metabolites were involved in the metabolism of the arginine–proline, pyrimidine, and pentose phosphate pathways. The contribution of these changes to the tumor microenvironment needs to be further pursued.

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Section: Discussionmentioning

confidence: 99%

Metabolome Shift in Both Metastatic Breast Cancer Cells and Astrocytes Which May Contribute to the Tumor Microenvironment

Sato

Shimizu

Okawa

et al. 2021

IJMS

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“…However, the dysregulation of these cells can promote tumor growth and metastasis. Recent studies demonstrate that the relationships between cancer cells and their surrounding microenvironments affect cancer cell survival, growth, proliferation, epithelial-mesenchymal transition (EMT), and metastasis ( 4 ). Thus, the modulation of the TME as a target for clinical applications is an area of interest in cancer treatments.…”

Section: Introductionmentioning

confidence: 99%

The Role of Tumor Necrosis Factor in Manipulating the Immunological Response of Tumor Microenvironment

Laha¹,

Grant²,

Mishra³

et al. 2021

Front. Immunol.

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The tumor microenvironment (TME) is an intricate system within solid neoplasms. In this review, we aim to provide an updated insight into the TME with a focus on the effects of tumor necrosis factor-α (TNF-α) on its various components and the use of TNF-α to improve the efficiency of drug delivery. The TME comprises the supporting structure of the tumor, such as its extracellular matrix and vasculature. In addition to cancer cells and cancer stem cells, the TME contains various other cell types, including pericytes, tumor-associated fibroblasts, smooth muscle cells, and immune cells. These cells produce signaling molecules such as growth factors, cytokines, hormones, and extracellular matrix proteins. This review summarizes the intricate balance between pro-oncogenic and tumor-suppressive functions that various non-tumor cells within the TME exert. We focused on the interaction between tumor cells and immune cells in the TME that plays an essential role in regulating the immune response, tumorigenesis, invasion, and metastasis. The multifunctional cytokine, TNF-α, plays essential roles in diverse cellular events within the TME. The uses of TNF-α in cancer treatment and to facilitate cancer drug delivery are discussed. The effects of TNF-α on tumor neovasculature and tumor interstitial fluid pressure that improve treatment efficacy are summarized.

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“…A recent study showed that astrocytes and the soft surrounding microenvironment suppressed DNA methyltransferase 1 and kept cancer cells in dormant states. 26 These mechanisms could be related to our model. Moreover, our results showed that varied cell cycle patterns of metastatic tumors were observed in the same organ.…”

Section: Discussionmentioning

confidence: 72%

Visualization of the cancer cell cycle by tissue‐clearing technology using the Fucci reporter system

et al. 2021

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Characteristics of cancer cells are considered to be determined by gene alterations in the cancer cells as well as by the effects of the surrounding tumor microenvironment. 1 Uncontrolled cell proliferation is one of the important characteristics of cancer cells, and dormant cancer cells might contribute to relapse of cancer after antitumor drug treatments. 2,3 Therefore, controlling the cell cycle is important for cancer treatment, and various regulators of the cell cycle have been determined. 4 However, the effects of the tumor microenvironment on the cancer cell cycle are yet to be fully understood. Tissue-clearing technology has developed dramatically during the last couple of decades in neuroscience research, and has recently started to be utilized in cancer research. 5 We previously reported that the tissue-clearing technology termed CUBIC is useful for monitoring cancer metastasis in various mouse tumor models. 6

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The Brain Microenvironment Induces DNMT1 Suppression and Indolence of Metastatic Cancer Cells

Cited by 22 publications

References 49 publications

Metabolome Shift in Both Metastatic Breast Cancer Cells and Astrocytes Which May Contribute to the Tumor Microenvironment

Metabolome Shift in Both Metastatic Breast Cancer Cells and Astrocytes Which May Contribute to the Tumor Microenvironment

The Role of Tumor Necrosis Factor in Manipulating the Immunological Response of Tumor Microenvironment

Visualization of the cancer cell cycle by tissue‐clearing technology using the Fucci reporter system

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