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Developmental Cell May 2021Tumors undergo metabolic transformations to sustain uncontrolled proliferation, avoid cell death, and seed in secondary organs. An increased focus on cancer lipid... (Review)
Review
Tumors undergo metabolic transformations to sustain uncontrolled proliferation, avoid cell death, and seed in secondary organs. An increased focus on cancer lipid metabolism has unveiled a number of mechanisms that promote tumor growth and survival, many of which are independent of classical cellular bioenergetics. These mechanisms include modulation of ferroptotic-mediated cell death, support during tumor metastasis, and interactions with the cells of the tumor microenvironment. As such, targeting lipid metabolism for anti-cancer therapies is attractive, with recent work on small-molecule inhibitors identifying compounds to target lipid metabolism. Here, we discuss these topics and identify open questions.
Topics: Animals; Diet; Ferroptosis; Humans; Lipid Metabolism; Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 33945792
DOI: 10.1016/j.devcel.2021.04.013 -
Expert Reviews in Molecular Medicine Mar 2021Methylation at DNA, RNA and protein levels plays critical roles in many cellular processes and is associated with diverse differentiation events, physiological... (Review)
Review
Methylation at DNA, RNA and protein levels plays critical roles in many cellular processes and is associated with diverse differentiation events, physiological activities and human diseases. To aid in the diagnostic and therapeutic design for cancer treatment utilising methylation, this review provides a boutique yet comprehensive overview on methylation at different levels including the mechanisms, cross-talking and clinical implications with a particular focus on cancers. We conclude that DNA methylation is the sole type of methylation that has been largely translated into clinics and used for, mostly, early diagnosis. Translating the onco-therapeutic and prognostic values of RNA and protein methylations into clinical use deserves intensive efforts. Simultaneous examination of methylations at multiple levels or together with other forms of molecular markers represents an interesting research direction with profound clinical translational potential.
Topics: DNA Methylation; Humans; Neoplasms; Protein Processing, Post-Translational
PubMed: 33787478
DOI: 10.1017/erm.2021.4 -
Trends in Cancer Oct 2020Several cancer interventions induce DNA damage and promote senescence in cancer and nonmalignant cells. Senescent cells secrete a collection of proinflammatory factors... (Review)
Review
Several cancer interventions induce DNA damage and promote senescence in cancer and nonmalignant cells. Senescent cells secrete a collection of proinflammatory factors collectively termed the senescence-associated secretory phenotype (SASP). SASP factors are able to potentiate various aspects of tumorigenesis, including proliferation, metastasis, and immunosuppression. Moreover, the accumulation and persistence of therapy-induced senescent cells can promote tissue dysfunction and the early onset of various age-related symptoms in treated cancer patients. Here, we review in detail the mechanisms by which cellular senescence contributes to cancer development and the side effects of cancer therapies. We also review how pharmacological interventions to eliminate senescent cells or inhibit SASP production can mitigate these negative effects and propose therapeutic strategies based on the age of the patient.
Topics: Carcinogenesis; Cellular Senescence; Humans; Neoplasms
PubMed: 32482536
DOI: 10.1016/j.trecan.2020.05.004 -
Cancer Letters May 2023Patient-derived organoids (PDO) are a new biomedical research model that can reconstruct phenotypic and genetic characteristics of the original tissue and are useful for... (Review)
Review
Patient-derived organoids (PDO) are a new biomedical research model that can reconstruct phenotypic and genetic characteristics of the original tissue and are useful for research on pathogenesis and drug screening. To introduce the progression in this field, we review the key factors of constructing organoids derived from epithelial tissues and cancers, covering culture medium and matrix, morphological characteristics, genetic profiles, high-throughput drug screening, and application potential. We also discuss the co-culture system of cancer organoids with tumor microenvironment (TME) associated cells. The co-culture system is widely used in evaluating crosstalk of cancer cells with TME components, such as fibroblasts, endothelial cells, immune cells, and microorganisms. The article provides a prospective for standardized cultivation mode, automatic morphological evaluation, and drug sensitivity screening using high-throughput methods.
Topics: Humans; Drug Evaluation, Preclinical; Endothelial Cells; Prospective Studies; Neoplasms; Organoids; Tumor Microenvironment
PubMed: 37061121
DOI: 10.1016/j.canlet.2023.216180 -
Trends in Cell Biology Jan 2022Aberrancy in cell cycle progression is one of the fundamental mechanisms underlying tumorigenesis, making regulators of the cell cycle machinery rational anticancer... (Review)
Review
Aberrancy in cell cycle progression is one of the fundamental mechanisms underlying tumorigenesis, making regulators of the cell cycle machinery rational anticancer therapeutic targets. A growing body of evidence indicates that the cell cycle regulatory pathway integrates into other hallmarks of cancer, including metabolism remodeling and immune escape. Thus, therapies against cell cycle machinery components can not only repress the division of cancer cells, but also reverse cancer metabolism and restore cancer immune surveillance. Besides the ongoing effects on the development of small molecule inhibitors (SMIs) of the cell cycle machinery, proteolysis targeting chimeras (PROTACs) have recently been used to target these oncogenic proteins related to cell cycle progression. Here, we discuss the rationale of cell cycle targeting therapies, particularly PROTACs, to more efficiently retard tumorigenesis.
Topics: Carcinogenesis; Cell Cycle; Cell Transformation, Neoplastic; Humans; Neoplasms; Proteolysis
PubMed: 34304958
DOI: 10.1016/j.tcb.2021.07.001 -
The Quarterly Journal of Nuclear... Jun 2020Current cancer classification is based on intrinsic tumor parameters such as characteristic of tumor cells, tumor progression, tumor invasion and the presence of distant... (Review)
Review
Current cancer classification is based on intrinsic tumor parameters such as characteristic of tumor cells, tumor progression, tumor invasion and the presence of distant metastases, as summarized by the AJCC/UICC-TNM stratification system. There is currently no immune-based classification of cancer. We provided evidence that the immune contexture, as defined by the type, density, functional immune orientation and the location of immune cells within tumor, strongly influences the outcome of colorectal cancer (CRC) patients. To translate this information to the clinic, we developed an immunohistochemistry and digital pathology-based assay named Immunoscore that allows the quantification of two T cell subsets (CD3 and CD8) in two tumor regions (core and invasive margin of tumors). We have demonstrated that the standardized consensus Immunoscore has a prognostic value superior and independent to the one of the traditional TNM system in an international study in stage I-III colon cancer patients, therefore validating the Immunoscore as the first immune-based scoring system. In additional analyses, we showed the prognostic value of Immunoscore for stage II-IV CRC patients, as well as the predictive value of Immunoscore in stage III colon cancer patients. The Immunoscore may help predict and stratify patients who will benefit from adjuvant chemotherapy. Moreover, the Immunoscore allows the classification of tumors from hot to cold categories, and could consequently guide clinical decision for the choice of treatment.
Topics: Clinical Decision-Making; Humans; Neoplasms
PubMed: 32107902
DOI: 10.23736/S1824-4785.20.03249-5 -
Cancer Cell Jun 2020The concept that dietary changes could improve the response to cancer therapy is extremely attractive to many patients, who are highly motivated to take control of at... (Review)
Review
The concept that dietary changes could improve the response to cancer therapy is extremely attractive to many patients, who are highly motivated to take control of at least some aspect of their treatment. Growing insight into cancer metabolism is highlighting the importance of nutrient supply to tumor development and therapeutic response. Cancers show diverse metabolic requirements, influenced by factors such as tissue of origin, microenvironment, and genetics. Dietary modulation will therefore need to be matched to the specific characteristics of both cancers and treatment, a precision approach requiring a detailed understanding of the mechanisms that determine the metabolic vulnerabilities of each cancer.
Topics: Diet; Humans; Neoplasms; Nutritional Status
PubMed: 32413275
DOI: 10.1016/j.ccell.2020.04.005 -
EBioMedicine Nov 2021Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the... (Review)
Review
Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the tumour microenvironment (TME). Excessive lactate secreted by metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source by shuttling between different cell populations, and inhibiting the mechanistic (previously 'mammalian') target of rapamycin (mTOR) pathway in immune cells. This review focuses on recent advances in the regulation of immune responses by lactate, as well as therapeutic strategies targeting lactate anabolism and transport in the TME, such as those involving glycolytic enzymes and monocarboxylate transporter inhibitors. Considering the multifaceted roles of lactate in cancer metabolism, a comprehensive understanding of how lactate and lactate-targeting therapies regulate immune responses in the TME will provide insights into the complex relationships between metabolism and antitumour immunity.
Topics: Animals; Biological Transport; Biomarkers; Disease Management; Disease Susceptibility; Energy Metabolism; Glycolysis; Humans; Immunomodulation; Immunotherapy; Lactic Acid; Metabolic Networks and Pathways; Neoplasms; Tumor Microenvironment
PubMed: 34656878
DOI: 10.1016/j.ebiom.2021.103627 -
Molecular Cell Oct 2020Cancer immunotherapies enhance anti-tumor immune responses using checkpoint inhibitors, such as PD-1 or PD-L1 inhibitors. Recent studies, however, have extended the... (Review)
Review
Cancer immunotherapies enhance anti-tumor immune responses using checkpoint inhibitors, such as PD-1 or PD-L1 inhibitors. Recent studies, however, have extended the scope of immunotherapeutics by unveiling DNA damage-induced innate immunity as a novel target for cancer treatment. Elucidating the interplay among the DNA damage response (DDR), cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation, and anti-tumoral immunity is critical for the development of effective cancer immunotherapies. Here, we discuss the current understanding of the mechanisms by which DNA damage activates immune responses that target and eradicate cancer cells. Yet, understanding how cancer cells can escape this immune surveillance and promote tumor progression represents an outstanding challenge. We highlight the most recent clinical advances, in particular how pharmacological fine-tuning of innate/adaptive immunity and its combination with DDR inhibitors, ionizing radiation (IR), and chemotherapy can be exploited to improve cancer treatment.
Topics: DNA Damage; Genomic Instability; Humans; Immunity, Innate; Immunotherapy; Membrane Proteins; Neoplasms
PubMed: 32810436
DOI: 10.1016/j.molcel.2020.07.026