Special Issue "mTOR Pathway in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2017)

Special Issue Editors

Guest Editor
Dr. Andrew R. Tee

Division of Cancer and Genetics, Cardiff University, Cardiff, Wales CF10 3AT, UK
Website | E-Mail
Interests: mTOR; protein translation; hypoxia; Tuberous Sclerosis Complex; autophagy, cancer; signalling; protein kinases; angiogenesis; mitochondrial biogenesis
Guest Editor
Dr. James Murray

School of Biochemistry & Immunology, Trinity College Dublin, Dublin, Ireland
Website | E-Mail
Interests: autophagy; reversible phosphorylation; protein and lipid kinases; cancer; neurodegenerative diseases; diabetes

Special Issue Information

Dear Colleagues,

Mechanistic target of rapamycin (mTOR) is often referred to as a master regulator of cell growth control and is aberrantly activated in many cancers. As well as enhancing tumour growth and proliferative rate, mTOR is also involved in metabolic transformation, neovascularisation and metastasis. Regulation of tumour growth by mTOR involves protein translation, hypoxia signalling, autophagy and synthetic anabolic pathways in the pentose phosphate pathway that builds tumour mass while maintaining energy and nutrient homeostasis. mTOR is also a critical driver of epithelial–mesenchymal transition, necessary for cancer cell differentiation status, cancer stem-cells, drug resistance, motility and metastasis. Our knowledge of mTOR signalling has been markedly accelerated by research on rare genetic disorders where patients are predisposed to tumours. Given the plethora of activities that mTOR is involved in, it is not surprising that mTOR is upregulated during cancer progression. mTOR activation often correlates with metastasis, poor patient survival and resistance to anticancer agents such as chemotherapy. Consequently, the mTOR signalling pathway has received a lot of clinical interest. The use of rapalogues and ATP-competitive inhibitors of mTOR have shown clinical promise for the treatment of a range of cancers. In summary, this Special Issue will review the complexity of mTOR signalling, its involvement in cancer progression, how mTOR inhibitors have made a clinical impact and future research directions.

Dr. Andrew Tee
Dr. James Murray
Gueat Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Editorial

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Open AccessEditorial Mechanistic Target of Rapamycin (mTOR) in the Cancer Setting
Cancers 2018, 10(6), 168; https://doi.org/10.3390/cancers10060168
Received: 23 May 2018 / Accepted: 24 May 2018 / Published: 30 May 2018
PDF Full-text (159 KB) | HTML Full-text | XML Full-text
Abstract
This special issue on mammalian target of rapamycin (mTOR) explores the importance of mTOR in cell growth control and cancer. Cancer cells often exploit mTOR as a mechanism to enhance their capacity to grow. While protein synthesis is by far the best-characterized mTOR-driven [...] Read more.
This special issue on mammalian target of rapamycin (mTOR) explores the importance of mTOR in cell growth control and cancer. Cancer cells often exploit mTOR as a mechanism to enhance their capacity to grow. While protein synthesis is by far the best-characterized mTOR-driven process, this special issue also describes a wider array of mTOR-driven biological processes that cancer cells benefit from, including autophagy, cell cycle control, metabolic transformation, angiogenic signaling, and anabolic processes such as nucleotide biosynthesis and ribosomal biogenesis. Other areas of mTOR signaling covered in these reviews delve into cell migration, inflammation, and regulation of transcription factors linked to cancer progression. Full article
(This article belongs to the Special Issue mTOR Pathway in Cancer)

Review

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Open AccessReview mTOR Cross-Talk in Cancer and Potential for Combination Therapy
Received: 19 December 2017 / Revised: 15 January 2018 / Accepted: 16 January 2018 / Published: 19 January 2018
Cited by 16 | PDF Full-text (3712 KB) | HTML Full-text | XML Full-text
Abstract
The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 [...] Read more.
The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy. Full article
(This article belongs to the Special Issue mTOR Pathway in Cancer)
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Open AccessReview mTOR Pathways in Cancer and Autophagy
Received: 4 December 2017 / Revised: 22 December 2017 / Accepted: 9 January 2018 / Published: 12 January 2018
Cited by 35 | PDF Full-text (645 KB) | HTML Full-text | XML Full-text
Abstract
TOR (target of rapamycin), an evolutionarily-conserved serine/threonine kinase, acts as a central regulator of cell growth, proliferation and survival in response to nutritional status, growth factor, and stress signals. It plays a crucial role in coordinating the balance between cell growth and cell [...] Read more.
TOR (target of rapamycin), an evolutionarily-conserved serine/threonine kinase, acts as a central regulator of cell growth, proliferation and survival in response to nutritional status, growth factor, and stress signals. It plays a crucial role in coordinating the balance between cell growth and cell death, depending on cellular conditions and needs. As such, TOR has been identified as a key modulator of autophagy for more than a decade, and several deregulations of this pathway have been implicated in a variety of pathological disorders, including cancer. At the molecular level, autophagy regulates several survival or death signaling pathways that may decide the fate of cancer cells; however, the relationship between autophagy pathways and cancer are still nascent. In this review, we discuss the recent cellular signaling pathways regulated by TOR, their interconnections to autophagy, and the clinical implications of TOR inhibitors in cancer. Full article
(This article belongs to the Special Issue mTOR Pathway in Cancer)
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Open AccessReview Oncogenic Signalling through Mechanistic Target of Rapamycin (mTOR): A Driver of Metabolic Transformation and Cancer Progression
Received: 5 December 2017 / Revised: 27 December 2017 / Accepted: 28 December 2017 / Published: 3 January 2018
Cited by 11 | PDF Full-text (1624 KB) | HTML Full-text | XML Full-text
Abstract
Throughout the years, research into signalling pathways involved in cancer progression has led to many discoveries of which mechanistic target of rapamycin (mTOR) is a key player. mTOR is a master regulator of cell growth control. mTOR is historically known to promote cell [...] Read more.
Throughout the years, research into signalling pathways involved in cancer progression has led to many discoveries of which mechanistic target of rapamycin (mTOR) is a key player. mTOR is a master regulator of cell growth control. mTOR is historically known to promote cell growth by enhancing the efficiency of protein translation. Research in the last decade has revealed that mTOR’s role in promoting cell growth is much more multifaceted. While mTOR is necessary for normal human physiology, cancer cells take advantage of mTOR signalling to drive their neoplastic growth and progression. Oncogenic signal transduction through mTOR is a common occurrence in cancer, leading to metabolic transformation, enhanced proliferative drive and increased metastatic potential through neovascularisation. This review focuses on the downstream mTOR-regulated processes that are implicated in the “hallmarks” of cancer with focus on mTOR’s involvement in proliferative signalling, metabolic reprogramming, angiogenesis and metastasis. Full article
(This article belongs to the Special Issue mTOR Pathway in Cancer)
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Open AccessReview Eukaryotic Elongation Factor 2 Kinase (eEF2K) in Cancer
Cancers 2017, 9(12), 162; https://doi.org/10.3390/cancers9120162
Received: 18 October 2017 / Revised: 24 November 2017 / Accepted: 25 November 2017 / Published: 27 November 2017
Cited by 4 | PDF Full-text (863 KB) | HTML Full-text | XML Full-text
Abstract
Eukaryotic elongation factor 2 kinase (eEF2K) is a highly unusual protein kinase that negatively regulates the elongation step of protein synthesis. This step uses the vast majority of the large amount of energy and amino acids required for protein synthesis. eEF2K activity is [...] Read more.
Eukaryotic elongation factor 2 kinase (eEF2K) is a highly unusual protein kinase that negatively regulates the elongation step of protein synthesis. This step uses the vast majority of the large amount of energy and amino acids required for protein synthesis. eEF2K activity is controlled by an array of regulatory inputs, including inhibition by signalling through mammalian target of rapamycin complex 1 (mTORC1). eEF2K is activated under conditions of stress, such as energy depletion or nutrient deprivation, which can arise in poorly-vascularised tumours. In many such stress conditions, eEF2K exerts cytoprotective effects. A growing body of data indicates eEF2K aids the growth of solid tumours in vivo. Since eEF2K is not essential (in mice) under ‘normal’ conditions, eEF2K may be a useful target in the treatment of solid tumours. However, some reports suggest that eEF2K may actually impair tumorigenesis in some situations. Such a dual role of eEF2K in cancer would be analogous to the situation for other pathways involved in cell metabolism, such as autophagy and mTORC1. Further studies are needed to define the role of eEF2K in different tumour types and at differing stages in tumorigenesis, and to assess its utility as a therapeutic target in oncology. Full article
(This article belongs to the Special Issue mTOR Pathway in Cancer)
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Open AccessFeature PaperReview Evolving Significance and Future Relevance of Anti-Angiogenic Activity of mTOR Inhibitors in Cancer Therapy
Cancers 2017, 9(11), 152; https://doi.org/10.3390/cancers9110152
Received: 4 September 2017 / Revised: 23 October 2017 / Accepted: 27 October 2017 / Published: 1 November 2017
Cited by 7 | PDF Full-text (1089 KB) | HTML Full-text | XML Full-text
Abstract
mTOR inhibitors have demonstrated remarkable anti-tumor activity in experimental models, mainly by reducing cancer cell growth and tumor angiogenesis. Their use in cancer patients as monotherapy has, however, generated only limited benefits, increasing median overall survival by only a few months. Likewise, in [...] Read more.
mTOR inhibitors have demonstrated remarkable anti-tumor activity in experimental models, mainly by reducing cancer cell growth and tumor angiogenesis. Their use in cancer patients as monotherapy has, however, generated only limited benefits, increasing median overall survival by only a few months. Likewise, in other targeted therapies, cancer cells develop resistance mechanisms to overcome mTOR inhibition. Hence, novel therapeutic strategies have to be designed to increase the efficacy of mTOR inhibitors in cancer. In this review, we discuss the present and future relevance of mTOR inhibitors in cancer therapy by focusing on their effects on tumor angiogenesis. Full article
(This article belongs to the Special Issue mTOR Pathway in Cancer)
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Open AccessFeature PaperReview Regulation of mTOR, Metabolic Fitness, and Effector Functions by Cytokines in Natural Killer Cells
Cancers 2017, 9(10), 132; https://doi.org/10.3390/cancers9100132
Received: 31 August 2017 / Revised: 22 September 2017 / Accepted: 23 September 2017 / Published: 28 September 2017
Cited by 5 | PDF Full-text (417 KB) | HTML Full-text | XML Full-text
Abstract
The control of cellular metabolism is now recognized as key to regulate functional properties of immune effectors such as T or Natural Killer (NK) cells. During persistent infections or in the tumor microenvironment, multiple metabolic changes have been highlighted in T cells that [...] Read more.
The control of cellular metabolism is now recognized as key to regulate functional properties of immune effectors such as T or Natural Killer (NK) cells. During persistent infections or in the tumor microenvironment, multiple metabolic changes have been highlighted in T cells that contribute to their dysfunctional state or exhaustion. NK cells may also undergo major phenotypic and functional modifications when infiltrating tumors that could be linked to metabolic alterations. The mammalian target of rapamycin (mTOR) kinase is a central regulator of cellular metabolism. mTOR integrates various extrinsic growth or immune signals and modulates metabolic pathways to fulfill cellular bioenergetics needs. mTOR also regulates transcription and translation thereby adapting cellular pathways to the growth or activation signals that are received. Here, we review the role and regulation of mTOR in NK cells, with a special focus on cytokines that target mTOR such as IL-15 and TGF-β. We also discuss how NK cell metabolic activity could be enhanced or modulated to improve their effector anti-tumor functions in clinical settings. Full article
(This article belongs to the Special Issue mTOR Pathway in Cancer)
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