Cancer Cell Dormancy: Potential Therapeutic Targets To Eradicate Cancer Cells Within the Niche

2013 ◽  
pp. 559-571
Author(s):  
Jessian L. Munoz ◽  
Jacqueline M. Park ◽  
Sarah A. Bliss ◽  
Pranela Rameshwar
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Therapeutic Targets ◽  
Cell Dormancy

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

Gut ◽  
2019 ◽  
Vol 69 (2) ◽  
pp. 243-251 ◽  
Author(s):  
Masahiro Maeda ◽  
Hideyuki Takeshima ◽  
Naoko Iida ◽  
Naoko Hattori ◽  
Satoshi Yamashita ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cell ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Stem Cell Niche ◽  
Therapeutic Targets ◽  
Prognostic Impact ◽  
Cell Growth And Migration ◽  
Cell Niche

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 asWNT5A,GREM1,NOGandIGF2. 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.

scholarly journals Mesenchymal stem cell-derived extracellular vesicles may promote breast cancer cell dormancy

2018 ◽  
Vol 9 ◽  
pp. 204173141881009 ◽  
Author(s):  
Jake Casson ◽  
Owen G Davies ◽  
Carol-Anne Smith ◽  
Matthew J Dalby ◽  
Catherine C Berry
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Extracellular Vesicles ◽  
Breast Cancer Cells ◽  
Cell Dormancy

Disseminated breast cancer cells have the capacity to metastasise to the bone marrow and reside in a dormant state within the mesenchymal stem cell niche. Research has focussed on paracrine signalling factors, such as soluble proteins, within the microenvironment. However, it is now clear extracellular vesicles secreted by resident mesenchymal stem cells into this microenvironment also play a key role in the initiation of dormancy. Dormancy encourages reduced cell proliferation and migration, while upregulating cell adhesion, thus retaining the cancer cells within the bone marrow microenvironment. Here, MCF7 breast cancer cells were treated with mesenchymal stem cell–derived extracellular vesicles, resulting in reduced migration in two-dimensional and three-dimensional culture, with reduced cell proliferation and enhanced adhesion, collectively supporting cancer cell dormancy.

scholarly journals The mTOR Pathway in Pluripotent Stem Cells: Lessons for Understanding Cancer Cell Dormancy

Membranes ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 858
Author(s):  
Bashar A. Alhasan ◽  
Sergeiy A. Gordeev ◽  
Aleksandra R. Knyazeva ◽  
Kseniia V. Aleksandrova ◽  
Boris A. Margulis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Pluripotent Stem Cells ◽  
Embryonic Stem ◽  
Mtor Pathway ◽  
Dormant State ◽  
Correct Understanding ◽  
Cell Dormancy ◽  
Autophagy Activity

Currently, the success of targeted anticancer therapies largely depends on the correct understanding of the dormant state of cancer cells, since it is increasingly regarded to fuel tumor recurrence. The concept of cancer cell dormancy is often considered as an adaptive response of cancer cells to stress, and, therefore, is limited. It is possible that the cancer dormant state is not a privilege of cancer cells but the same reproductive survival strategy as diapause used by embryonic stem cells (ESCs). Recent advances reveal that high autophagy and mTOR pathway reduction are key mechanisms contributing to dormancy and diapause. ESCs, sharing their main features with cancer stem cells, have a delicate balance between the mTOR pathway and autophagy activity permissive for diapause induction. In this review, we discuss the functioning of the mTOR signaling and autophagy in ESCs in detail that allows us to deepen our understanding of the biology of cancer cell dormancy.

scholarly journals MicroRNAs’ control of cancer cell dormancy

Cell Division ◽  
2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Tatiana G. Ruksha
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Pi3k Pathway ◽  
Chemotherapeutic Agents ◽  
Quiescent State ◽  
Cell Cycle Regulators ◽  
Phosphoinositide 3 Kinase ◽  
Cells Of The Microenvironment ◽  
Tumor Types ◽  
Cell Dormancy

Abstract ‘Dormancy’, in the context of carcinogenesis, is a biological phenomenon of decreased cancer cell proliferation and metabolism. In view of their ability to remain quiescent, cancer cells are able to avoid cell death induced by chemotherapeutic agents, and thereby give rise to tumor relapse at a later stage. Being a dynamic event, the dormant state is controlled by several epigenetic mechanisms, including the action of microRNAs. The present review highlights microRNAs that have been shown to be dysregulated in dormant cancer cells among different tumor types. MicroRNAs accomplish their control of cancer cell quiescence by targeting cell cycle regulators and signaling pathways involved in cell growth maintenance, including the AKT/phosphoinositide 3-kinase (PI3K) pathway. MicroRNAs, as components of intercellular vesicles, enable interactions to occur between cancer cells and cells of the microenvironment, resulting in the cancer cells either acquiring the quiescent state or, oppositely, stimulating them to proliferate. Taken together, the evidence obtained to date has collectively confirmed the involvement of microRNAsin cancer cell dormancy. Modulation of the various processes may enable optimization of the treatment of metastatic tumors.

Blockade of IDO-kynurenine-AhR pathway promotes cell apoptosis in carboxyamidotriazole-induced tumor cell dormancy-apoptosis oscillation

2020 ◽  
Author(s):  
Jing Shi ◽  
Qingzhu Wang ◽  
Lixing Yang ◽  
Qin Liu ◽  
Rui Ju ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Nuclear Translocation ◽  
Cell Cycle Distribution ◽  
Colorectal Cancer Cells ◽  
Proliferation Response ◽  
Cell Dormancy

Abstract Background: Some cancer cells may reshape their genetic make-up, adopt a special metabolism mode and undergo dormancy to endure drug attacks. Blocking survival signals in dormant cancer cells that survive a certain anticancer therapy and eradicating them while dormant may help prevent tumor recurrence and metastasis.Methods: Two colorectal cancer cell lines C26 and HCT116 were treated with carboxyamidotriazole. Sulforhodamine B assay and Ki67 staining were conducted to detect the cells proliferation response. Cell cycle distribution was measured with BrdU staining. Then treated with CAI, DMF, 1-MT or a combination and analyzed the apoptosis. The in vivo anti-tumor effects of each monotherapy or combination therapy were assessed according to their capability to slow tumor growth and extend the life span of tumor-bearing mice. Results: The colorectal cancer cells slow growth to escape the pressure of the anti-tumor drug CAI. Blocking the IDO-kynurenine-AhR pathway could promote CRC cells apoptosis in CAI-induced tumor cell dormancy-apoptosis oscillation, facilitating their eradication.Conclusion: The combination of 1-MT or DMF with CAI may prompt dormant cancer cell to enter an apoptotic state, which is triggered by STAT1 nuclear translocation but obscured by the dormancy-permissive metabolic fitness signals when the tumor cells are exposed to CAI alone.

N-hexane Extract and Fraction of Green Tea as Antiproliferation of MCM-B2 Breast Cancer Cells In Vitro

2020 ◽  
Vol 6 (2) ◽  
Author(s):  
Lisni Noraida Waruwu ◽  
Maria Bintang ◽  
Bambang Pontjo Priosoeryanto
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Green Tea ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Green Tea Extract ◽  
Hexane Fraction ◽  
Phytochemical Screening ◽  
Tea Extract

Green tea (Camellia sinensis) is one of traditional plants that have the potential as an anticancer. The sample used in this research commercial green tea extract. The purpose of this study was to test the antiproliferation activity of green tea extract on breast cancer cell MCM-B2 in vitro. Green tea extract fractionated using three solvents, ie water, ethanol 70%, and n-hexane. Extract and fraction of green tea water have value Lethality Concentration 50 (LC50) more than 1000 ppm. The fraction of ethanol 70% and n-hexane had an LC50 value of 883.48 ppm and 600.56 ppm, respectively. The results of the phytochemical screening of green tea extract are flavonoids, tannins, and saponins, while the phytochemical screening results of n-hexane fraction are flavonoids and tannins. Antiproliferation activity was tested on breast cancer cells MCM-B2 and normal cells Vero by trypan blue staining method. The highest MCM-B2 cell inhibitory activity was achieved at a concentration of 13000 ppm green tea extract and 1000 ppm of n-hexane fraction, 59% and 59%, respectively. The extract and n-hexane fraction of green tea are not toxic to normal Vero cells characterized by not inhibiting normal cell proliferation. Keywords: antiproliferative, cancer cell MCM-B2, commercial green tea, cytotoxicity

Synthesis and Characterization of Quinoline-3-Carboxamide Derivatives as Inhibitors of the ATM Kinase

2020 ◽  
Vol 20 (23) ◽  
pp. 2070-2079
Author(s):  
Srimadhavi Ravi ◽  
Sugata Barui ◽  
Sivapriya Kirubakaran ◽  
Parul Duhan ◽  
Kaushik Bhowmik
Keyword(s):  
Western Blot ◽  
Cancer Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Cancer Cell Lines ◽  
Atm Kinase ◽  
Cytotoxicity Studies

Background: The importance of inhibiting the kinases of the DDR pathway for radiosensitizing cancer cells is well established. Cancer cells exploit these kinases for their survival, which leads to the development of resistance towards DNA damaging therapeutics. Objective: In this article, the focus is on targeting the key mediator of the DDR pathway, the ATM kinase. A new set of quinoline-3-carboxamides, as potential inhibitors of ATM, is reported. Methods: Quinoline-3-carboxamide derivatives were synthesized and cytotoxicity assay was performed to analyze the effect of molecules on different cancer cell lines like HCT116, MDA-MB-468, and MDA-MB-231. Results: Three of the synthesized compounds showed promising cytotoxicity towards a selected set of cancer cell lines. Western Blot analysis was also performed by pre-treating the cells with quercetin, a known ATM upregulator, by causing DNA double-strand breaks. SAR studies suggested the importance of the electron-donating nature of the R group for the molecule to be toxic. Finally, Western-Blot analysis confirmed the down-regulation of ATM in the cells. Additionally, the PTEN negative cell line, MDA-MB-468, was more sensitive towards the compounds in comparison with the PTEN positive cell line, MDA-MB-231. Cytotoxicity studies against 293T cells showed that the compounds were at least three times less toxic when compared with HCT116. Conclusion: In conclusion, these experiments will lay the groundwork for the evolution of potent and selective ATM inhibitors for the radio- and chemo-sensitization of cancer cells.

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

2018 ◽  
Vol 18 (17) ◽  
pp. 1483-1493
Author(s):  
Ricardo Imbroisi Filho ◽  
Daniel T.G. Gonzaga ◽  
Thainá M. Demaria ◽  
João G.B. Leandro ◽  
Dora C.S. Costa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Hepatic Function ◽  
Anticancer Properties ◽  
Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

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