Tumour microenvironment and metabolic plasticity in cancer and cancer stem cells: Perspectives on metabolic and immune regulatory signatures in chemoresistant ovarian cancer stem cells

Ahmed, Nuzhat; Escalona, Ruth; Leung, Dilys T.H.; Chan, Emily; Kannourakis, George

doi:10.1016/j.semcancer.2018.10.002

Cited by 123 publications

(123 citation statements)

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“…The mRNA expression of Magmas, ERCC1 and OCT4 in SKOV3 and OVCAR5 ovarian cancer cell lines. Magmas, ERCC1 and OCT4 mRNA expression in SKOV3 and OVCAR5 cells were performed after treatment with IC 50 doses of cisplatin or paclitaxel as described previously [83,123]. The relative expression of gene of interest was normalized to housekeeping 18S gene.…”

Section: Figurementioning

confidence: 99%

“…These observations require future studies to develop CSC-associated immunotherapy. This is especially important in the scenario of OC dissemination where downregulation of HLA class 1 antigen, interferon induced pathway and upregulation of immune inhibitory PD-L1 is evident on tumour cells after chemotherapy treatment [123].…”

Section: Csc-based Therapymentioning

confidence: 99%

“…The metabolic profile of OC cells and ovarian CSCs has been described in a recent review [123]. It is becoming obvious that ovarian CSCs sustain a malleable metabolism, which depends on their nutritional requirement and the stimulus they receive from the tumour microenvironment [231].…”

Section: Metabolic Targeting Of Ovarian Cscsmentioning

confidence: 99%

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Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ahmed

Kadife²,

Raza

et al. 2020

Cells

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Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes significant impediments in effectively treating patients, resulting in a dismal prognosis. Disease progression is predominantly influenced by the peritoneal tumour microenvironment rather than properties of the tumor and is the major contributor to prognosis. Standard treatment of OC patients consists of debulking surgery, followed by chemotherapy, which in most cases end in recurrent chemoresistant disease. This review discusses the different origins of high-grade serous ovarian cancer (HGSOC), the major sub-type of EOC. Tumour heterogeneity, genetic/epigenetic changes, and cancer stem cells (CSC) in facilitating HGSOC progression and their contribution in the circumvention of therapy treatments are included. Several new treatment strategies are discussed including our preliminary proof of concept study describing the role of mitochondria-associated granulocyte macrophage colony-stimulating factor signaling protein (Magmas) in HGSOC and its unique potential role in chemotherapy-resistant disease. of 35have been observed in OC patients but not in patients with benign and borderline tumours, and this hypomethylation correlates with advanced-stage disease and poor prognosis [48,49]. A genome-wide methylation profiling of blood cells from healthy controls and age-matched untreated OC patients identified CpG methylation of 2714 cancer-related genes, of which 56% were hypomethylated [50]. Ovarian Cancer Stem CellsCellular heterogeneity associated with genetic and epigenetic changes in tumours are linked with the initiation and expansion of CSCs, a population of cells within the tumour, which initiate tumour growth through self-renewal and differentiation processes [51,52]. These cells are more adaptive to the changing tumour microenvironment and tend to be more resistant to treatment. CSCs are highly plastic and a few numbers of isolated CSCs have been shown to be responsible for tumorgenesis and are more chemotherapy and radiation resistant due to their dormant state and a high expression of drug efflux pumps [53,54]. As a result, CSCs are able to adapt to different tumour microenvironments and survive due to their efficient DNA repair mechanisms and their capacity to evade host immune surveillance [55][56][57]. These inherent properties of CSCs suggest an active role in tumour relapse and emphasize the need to develop effective targeted therapies to improve clinical outcomes in patients [51][52][53][54][55][56][57].Stem cells have been identified in ovaries and fallopian tubes [58,59]. These cells express proteins including aldehyde dehydrogenase family 1 A2 (ALDH1A2), homeobox protein NANOG, LIM homeobox protein 9 (LHX9) and frizzled-related protein 1 (SRFP1) and have been observed in OSE, CIC and fimbria [2,[58][59][60][61][62]. In a...

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Section: Figurementioning

confidence: 99%

Section: Csc-based Therapymentioning

confidence: 99%

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Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ahmed

Kadife²,

Raza

et al. 2020

Cells

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“…glucose, iron, zinc), fundamental for optimal lymphocyte activity. Overall, the above events determine a condition of energy deficiency, which, in turn, represses T‐cell receptor (TCR) ‐related signaling, IFN‐ γ production, cytotoxicity and motility of Tconv cells with detrimental effects on the immune antineoplastic response …”

Section: Highlighting the Role Of Energy/oxidative Metabolic Changes mentioning

confidence: 99%

“…Overall, the above events determine a condition of energy deficiency, which, in turn, represses T-cell receptor (TCR) -related signaling, IFN-c production, cytotoxicity and motility of Tconv cells with detrimental effects on the immune antineoplastic response. 52 Among the changes induced by chronic inflammation and macrophage activation in the tumor microenvironment, oxidative stress plays a key role in negatively affecting the immune response. When ROS is produced excessively, as in chronic inflammation, exceeding the neutralization rate achieved by intracellular antioxidants (mainly glutathione), T cells experience oxidative stress whose persistence may alter their function and blunt effector T-cell responses.…”

Section: Role Of Macrophage Activation With Treg Reprogrammingmentioning

confidence: 99%

Blocking inflammation to improve immunotherapy of advanced cancer

Macciò

Madeddu

2019

Immunology

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The ability to induce functional reprogramming of regulatory T (Treg) cells in the tumor microenvironment is an extremely important therapeutic opportunity. However, when discussing such an approach, the opposing effect that the activation of the Treg cell compartments may have in inducing the immune inflammatory response and its link with the efficacy of immunotherapy should be considered. In fact, Treg reprogramming has a dual effect: immediate, with mechanisms that activate immunosurveillance, and late, mediated by the macrophage activation that yields an inflammatory status that is deleterious for the antineoplastic efficiency of the immune system response. Persistence of the inflammatory response is associated with specific changes of oxidative and glycolytic metabolic pathways that interfere with conventional T‐cell activation and function and may be one of the reasons for the failure of immunotherapy in advanced cancer patients. Therefore, in addition to modulating Treg cell action, the combined use of drugs able to block chronic inflammation mediated mainly by macrophages, to counteract the oxidative stress, and to positively regulate the metabolic derangements, could improve the effectiveness of modern immunotherapy. In conclusion, reprogramming of Treg cells may be an appropriate strategy for treating early stages of neoplastic diseases, whereas other immunosuppressive mechanisms should be the target of a combined immunotherapy approach in more advanced phases of cancer.

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Intracellular Glucose‐Depriving Polymer Micelles for Antiglycolytic Cancer Treatment

et al. 2023

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A new anticancer strategy to exploit abnormal metabolism of cancer cells rather than to merely control the drug release or rearrange the tumor microenvironment is reported. An antiglycolytic amphiphilic polymer, designed considering the unique metabolism of cancer cells (Warburg effect) and aimed at the regulation of glucose metabolism, is synthesized through chemical conjugation between glycol chitosan (GC) and phenylboronic acid (PBA). GC‐PBA derivatives form stable micellar structures under physiological conditions and respond to changes in glucose concentration. Once the micelles accumulate at the tumor site, intracellular glucose capture occurs, and the resultant energy deprivation through the inhibition of aerobic glycolysis remarkably suppresses tumor growth without significant side effects in vivo. This strategy highlights the need to develop safe and effective cancer treatment without the use of conventional anticancer drugs.

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Tumour microenvironment and metabolic plasticity in cancer and cancer stem cells: Perspectives on metabolic and immune regulatory signatures in chemoresistant ovarian cancer stem cells

Cited by 123 publications

References 234 publications

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Blocking inflammation to improve immunotherapy of advanced cancer

Intracellular Glucose‐Depriving Polymer Micelles for Antiglycolytic Cancer Treatment

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