The role of cellular quiescence in cancer - beyond a quiet passenger.

Quiescence, the ability to temporarily halt proliferation, is a conserved process that initially allowed survival of unicellular organisms during inhospitable times and later contributed to the rise of multicellular organisms, becoming key for cell differentiation, size control and tissue homeostasis. In this Review, we explore the concept of cancer as a disease that involves abnormal regulation of cellular quiescence at every step, from malignant transformation to metastatic outgrowth. Indeed, disrupted quiescence regulation can be linked to each of the so-called 'hallmarks of cancer'. As we argue here, quiescence induction contributes to immune evasion and resistance against cell death. In contrast, loss of quiescence underlies sustained proliferative signalling, evasion of growth suppressors, pro-tumorigenic inflammation, angiogenesis and genomic instability. Finally, both acquisition and loss of quiescence are involved in replicative immortality, metastasis and deregulated cellular energetics. We believe that a viewpoint that considers quiescence abnormalities that occur during oncogenesis might change the way we ask fundamental questions and the experimental approaches we take, potentially contributing to novel discoveries that might help to alter the course of cancer therapy.

Novel radiation and targeted therapy combinations for improving rectal cancer outcomes.

Neoadjuvant radiotherapy (RT) is commonly used as standard treatment for rectal cancer. However, response rates are variable and survival outcomes remain poor, highlighting the need to develop new therapeutic strategies. Research is focused on identifying novel methods for sensitising rectal tumours to RT to enhance responses and improve patient outcomes. This can be achieved through harnessing tumour promoting effects of radiation or preventing development of radio-resistance in cancer cells. Many of the approaches being investigated involve targeting the recently published new dimensions of cancer hallmarks. This review article will discuss key radiation and targeted therapy combination strategies being investigated in the rectal cancer setting, with a focus on exploitation of mechanisms which target the hallmarks of cancer.

Current and Emerging Treatment Paradigms in Colorectal Cancer: Integrating Hallmarks of Cancer.

The treatment of unresectable metastatic colorectal cancer has evolved over the last two decades, as knowledge of cancer biology has broadened and new targets have emerged. 'The Hallmarks of Cancer' illustrate the crucial capabilities acquired by cells to become malignant and represent the evolution of knowledge of tumor biology. This review integrates these novel targets and therapies into selected hallmarks: sustaining proliferative signaling, inducing vasculature, avoiding immune destruction, genome instability and mutation, reprogramming cellular metabolism, and resisting cell death. The different strategies and combinations under study are based on treatments with anti-EGFR, anti-VEGF, and anti-HER2 agents, KRAS G12C inhibitors, BRAF and MEK inhibitors, and immune checkpoint inhibitors. However, new approaches are emerging, including vaccines, WEE1 inhibitors, and PARP inhibitors, among others. The further deciphering of cancer biology will unravel new targets, develop novel therapies, and improve patients' outcomes.

Y-Box Binding Protein 1: Unraveling the Multifaceted Role in Cancer Development and Therapeutic Potential.

Y-box binding protein 1 (YBX1), a member of the Cold Shock Domain protein family, is overexpressed in various human cancers and is recognized as an oncogenic gene associated with poor prognosis. YBX1's functional diversity arises from its capacity to interact with a broad range of DNA and RNA molecules, implicating its involvement in diverse cellular processes. Independent investigations have unveiled specific facets of YBX1's contribution to cancer development. This comprehensive review elucidates YBX1's multifaceted role in cancer across cancer hallmarks, both in cancer cell itself and the tumor microenvironment. Based on this, we proposed YBX1 as a potential target for cancer treatment. Notably, ongoing clinical trials addressing YBX1 as a target in breast cancer and lung cancer have showcased its promise for cancer therapy. The ramp up in in vitro research on targeting YBX1 compounds also underscores its growing appeal. Moreover, the emerging role of YBX1 as a neural input is also proposed where the high level of YBX1 was strongly associated with nerve cancer and neurodegenerative diseases. This review also summarized the up-to-date advanced research on the involvement of YBX1 in pancreatic cancer.

The role of transcription factors in the acquisition of the four latest proposed hallmarks of cancer and corresponding enabling characteristics.

With the recent description of the molecular and cellular characteristics that enable acquisition of both core and new hallmarks of cancer, the consequences of transcription factor dysregulation in the hallmarks scheme has become increasingly evident. Dysregulation or mutation of transcription factors has long been recognized in the development of cancer where alterations in these key regulatory molecules can result in aberrant gene expression and consequential blockade of normal cellular differentiation. Here, we provide an up-to-date review of involvement of dysregulated transcription factor networks with the most recently reported cancer hallmarks and enabling characteristic properties. We present some illustrative examples of the impact of dysregulated transcription factors, specifically focusing on the characteristics of phenotypic plasticity, non-mutational epigenetic reprogramming, polymorphic microbiomes, and senescence. We also discuss how new insights into transcription factor dysregulation in cancer is contributing to addressing current therapeutic challenges.

Obesity: a perfect storm for carcinogenesis.

Obesity-related cancers account for 40% of the cancer cases observed in the USA and obesity is overtaking smoking as the most widespread modifiable risk factor for carcinogenesis. Here, we use the hallmarks of cancer framework to delineate how obesity might influence the carcinogenic hallmarks in somatic cells. We discuss the effects of obesity on (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) resisting cell death; (d) enabling replicative immortality; (e) inducing angiogenesis; (f) activating invasion and metastasis; (g) reprogramming energy metabolism; and (h) avoiding immune destruction, together with its effects on genome instability and tumour-promoting inflammation. We present the current understanding and controversies in this evolving field, and highlight some areas in need of further cross-disciplinary focus. For instance, the relative importance of the many potentially causative obesity-related factors is unclear for each type of malignancy. Even within a single tumour type, it is currently unknown whether one obesity-related factor consistently plays a predominant role, or if this varies between patients or, even in a single patient with time. Clarifying how the hallmarks are affected by obesity may lead to novel prevention and treatment strategies for the increasingly obese population.

Oncogenic functions of the FOXC2 transcription factor: a hallmarks of cancer perspective.

Epigenetic regulation of gene expression is a fundamental determinant of molecular and cellular function, and epigenetic reprogramming in the context of cancer has emerged as one of the key enabling characteristics associated with acquisition of the core hallmarks of this disease. As such, there has been renewed interest in studying the role of transcription factors as epigenetic regulators of gene expression in cancer. In this review, we discuss the current state of knowledge surrounding the oncogenic functions of FOXC2, a transcription factor that frequently becomes dysregulated in a variety of cancer types. In addition to highlighting the clinical impact of aberrant FOXC2 activity in cancer, we discuss mechanisms by which this transcription factor becomes dysregulated in both tumor and tumor-associated cells, placing particular emphasis on the ways in which FOXC2 promotes key hallmarks of cancer progression. Finally, we bring attention to important issues related to the oncogenic dysregulation of FOXC2 that must be addressed going forward in order to improve our understanding of FOXC2-mediated cancer progression and to guide prognostic and therapeutic applications of this knowledge in clinical settings.

The hallmarks of cancer in pituitary tumors?

Over 20 years ago, Hanahan and Weinberg published a seminal review that addressed the biological processes that underly malignant transformation. This classical review, along with two revisions published in 2011 and 2022, has remain a classic of the oncology literature. Since many of the addressed biological processes may apply to non-malignant tumorigenesis, we evaluated to what extent these hallmarks pertain to the development of pituitary adenomas.Some of the biological processes analyzed in this review include genome instability generated by somatic USP8 and GNAS mutations in Cushing's diseases and acromegaly respectively; non-mutational epigenetic reprograming through changes in methylation; induction of angiogenesis through alterations of VEGF gene expression; promotion of proliferative signals mediated by EGFR; evasion of growth suppression by disrupting cyclin dependent kinase inhibitors; avoidance of immune destruction; and the promotion of inflammation mediated by alteration of gene expression of immune check points. We also elaborate further on the existence of oncogene induced senescence in pituitary tumors. We conclude that a better understanding of these processes can help us dilucidated why pituitary tumors are so resistant to malignant transformation and can potentially contribute to the development of novel anticancer treatments.

Approaches for the setting of occupational exposure limits (OELs) for carcinogens.

This article addresses issues of importance for occupational exposure limits (OELs) and chemical carcinogens with a focus on non-threshold carcinogens. It comprises scientific as well as regulatory issues. It is an overview, not a comprehensive review. A central topic is mechanistic research and insights, and its implications for cancer risk assessment. Alongside scientific advancements, the approaches of hazard identification and qualitative and quantitative risk assessment have developed over the years. The key steps in a quantitative risk assessment are outlined, with special attention given to the dose-response assessment and the derivation of an OEL using risk calculations or default assessment factors. The work procedures of several bodies performing cancer hazard identifications and quantitative risk assessments, as well as regulatory procedures to derive OELs for non-threshold carcinogens, are presented. Non-threshold carcinogens for which the European Union (EU) introduced binding OELs in 2017-2019 serve as illustrations together with some currently used strategies in the EU and elsewhere. Available knowledge supports the derivation of health-based OELs (Hb-OELs) for non-threshold carcinogens, and the use of a risk-based approach with low-dose linear extrapolation (linear non-threshold, LNT) as the default for non-threshold carcinogens. However, there is a need to develop methods that allow recent years' advances in cancer research to be used for improving risk estimates. It is recommended that defined risk levels (terminology and numerical values) are harmonised, and that both collective and individual risks are considered and clearly communicated. Socioeconomic aspects should be dealt with transparently and separated from the scientific health risk assessment.

Current landscape of miRNAs and TGF-ß signaling in lung cancer progression and therapeutic targets.

Lung cancer (LC) is the primary reason for cancer-associated fatalities globally. Due to both tumor-suppressing and tumor-promoting activities, the TGF-ß family of growth factors is extremely essential to tumorigenesis. A non-coding single-stranded short RNA called microRNA (miRNA), which is made up of about 22 nt and is encoded by endogenous genes, can control normal and pathological pathways in various kinds of cancer, including LC. Recent research demonstrated that the TGF-ß signaling directly can affect the synthesis of miRNAs through suppressor of mothers against decapentaplegic (SMAD)-dependent activity or other unidentified pathways, which could generate allostatic feedback as a result of TGF-ß signaling stimulation and ultimately affect the destiny of cancer tissues. In this review, we emphasize the critical functions of miRNAs in lung cancer progression and, more critically, how they affect the TGF-ß signaling pathway, and explore the role of both the TGF-ß signaling pathway and miRNAs as potential therapeutic targets for improving the treatments of LC patients.

Potassium channels activity unveils cancer vulnerability.

"No cell could exist without ion channels" (Clay Armstrong; 1999). Since the discovery in the early 1950s, that ions move across biological membranes, the idea that changes of ionic gradients can generate biological signals has fascinated scientists in any fields. Soon later (1960s) it was found that ionic flows were controlled by a class of specific and selective proteins called ion channels. Thus, it became clear that the concerted activities of these proteins can initiate, arrest, and finely tune a variety of biochemical cascades which offered the opportunity to better understand both biology and pathology. Cancer is a disease that is notoriously difficult to treat due its heterogeneous nature which makes it the deadliest disease in the developed world. Recently, emerging evidence has established that potassium channels are critical modulators of several hallmarks of cancer including tumor growth, metastasis, and metabolism. Nevertheless, the role of potassium ion channels in cancer biology and the therapeutic potential offered by targeting these proteins has not been explored thoroughly. This chapter is addressed to both cancer biologists and ion channels scientists and it aims to shine a light on the established and potential roles of potassium ion channels in cancer biology and on the therapeutic benefit of targeting potassium channels with activator molecules.

MammaPrint and BluePrint comprehensively capture the cancer hallmarks in early-stage breast cancer patients.

MammaPrint® (MP) is a 70-gene signature that stratifies early-stage breast cancer patients into low- and high risk of distant relapse. Further stratification of MP risk results identifies four risk subgroups, ultra-low (UL), low, high 1, and high 2, with specific prognostic and predictive outcomes. BluePrint® (BP) is an 80-gene signature that classifies breast tumors as basal, luminal, or HER2 molecular subtype. To gain insight into their biological significance, we annotated the MP 70- and BP 80-genes with respect to the 10 hallmarks of cancer (HoC). Furthermore, we related gene expression profiles of the extreme ends of the MP low- and high-risk patients (here called, ultra-low (UL) and ultra-high (UH) or High2, respectively), to the 10 HoC per BP subtype by differential gene expression and pathway analysis. MP and BP gene functions reflected all 10 HoCs. Most MP and BP genes were associated with sustaining proliferative signaling, followed by genome instability and mutation categories. Based on the gene expression profiles, UL and UH subgroup pathways were down -or upregulated, respectively, reflecting proliferative and metastatic features, such as G2M checkpoint, DNA repair, oxidative phosphorylation, immune invasion, PI3K/AKT/mTOR signaling, and hypoxia pathways. Notably, the UH HER2-type was enriched in several immune signaling pathways, such as IL2/STAT5 signaling and TNFα signaling via NFκB. Our results show that MP and BP gene signatures represent and capture all 10 HoCs and highlight underlying biological processes of MP extreme samples, which might guide treatment decisions as the signature captures the full spectrum of early breast cancers.

[Development and Application of Ontology of Cancer Hallmarks].

Objective To develop a traceable cancer hallmark ontology with terminology including gene mutation,cancer hallmark,and cell line for knowledge integration,standardization,correlation,and discovery.Methods The Ontology Development 101 and the current ontology development methods were employed to determine the content coverage,structural layers,reusable terms,and new terms of the cancer hallmark ontology.Taking colorectal cancer as a study case,we extracted the knowledge related with colorectal cancer hallmarks using text mining and text classification technology from PubMed,and then formalized the extracted knowledge into the cancer hallmark ontology.Moreover,we made use of existing cancer hallmark evidence in Catalogue of Somatic Mutations in Cancer and further semantic retrieval to discover new knowledge.Results The established cancer hallmark ontology comprised 9910 classes and 6138 instances,which realized the semantic representation of 2310 article abstracts about colorectal cancer and 26 pieces of evidence about genes and their cancer hallmarks.Compared with the Catalogue of Somatic Mutations in Cancer,new evidence for more genes associated with colorectal cancer hallmarks was found based on cancer hallmark ontology.Conclusion This study is of great significance to the research on the cancer pathogenesis at the molecular level,the revealing of specific roles of genes and mutations in the occurrence of cancer,and the rapid knowledge discovery of cancer hallmarks.

Notch-associated lncRNAs profiling circuiting epigenetic modification in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent digestive cancers, ranking the 2nd cause of cancer-related fatality worldwide. The worldwide burden of CRC is predicted to rise by 60% by 2030. Environmental factors drive, first, inflammation and hence, cancer incidence increase. MAIN: The Notch-signaling system is an evolutionarily conserved cascade, has role in the biological normal developmental processes as well as malignancies. Long non-coding RNAs (LncRNAs) have become major contributors in the advancement of cancer by serving as signal pathways regulators. They can control gene expression through post-translational changes, interactions with micro-RNAs or down-stream effector proteins. Recent emerging evidence has emphasized the role of lncRNAs in controlling Notch-signaling activity, regulating development of several cancers including CRC. CONCLUSION: Notch-associated lncRNAs might be useful prognostic biomarkers or promising potential therapeutic targets for CRC treatment. Therefore, here-in we will focus on the role of "Notch-associated lncRNAs in CRC" highlighting "the impact of Notch-associated lncRNAs as player for cancer induction and/or progression."

Acute vs. chronic vs. intermittent hypoxia in breast Cancer: a review on its application in in vitro research.

Hypoxia has been linked to elevated instances of therapeutic resistance in breast cancer. The exposure of proliferating cancer cells to hypoxia has been shown to induce an aggressive phenotype conducive to invasion and metastasis. Regions of the primary tumors in the breast may be exposed to different types of hypoxia including acute, chronic or intermittent. Intermittent hypoxia (IH), also called cyclic hypoxia, is caused by exposure to cycles of hypoxia and reoxygenation (H-R cycles). Importantly, there is currently no consensus amongst the scientific community on the total duration of hypoxia, the oxygen level, and the possible presence of H-R cycles. In this review, we discuss current methods of hypoxia research, to explore how exposure regimes used in experiments are connected to signaling by different hypoxia inducible factors (HIFs) and to distinct cellular responses in the context of the hallmarks of cancer. We highlight discrepancies in the existing literature on hypoxia research within the field of breast cancer in particular and propose a clear definition of acute, chronic, and intermittent hypoxia based on HIF activation and cellular responses: (i) acute hypoxia is when the cells are exposed for no more than 24 h to an environment with 1% O2 or less; (ii) chronic hypoxia is when the cells are exposed for more than 48 h to an environment with 1% O2 or less and (iii) intermittent hypoxia is when the cells are exposed to at least two rounds of hypoxia (1% O2 or less) separated by at least one period of reoxygenation by exposure to normoxia (8.5% O2 or higher). Our review provides for the first time a guideline for definition of hypoxia related terms and a clear foundation for hypoxia related in vitro (breast) cancer research.

Hypoxia-induced alternative splicing in human diseases: the pledge, the turn, and the prestige.

Maintenance of oxygen homeostasis is an indispensable criterion for the existence of multicellular life-forms. Disruption of this homeostasis due to inadequate oxygenation of the respiring tissues leads to pathological hypoxia, which acts as a significant stressor in several pathophysiological conditions including cancer, cardiovascular defects, bacterial infections, and neurological disorders. Consequently, the hypoxic tissues develop necessary adaptations both at the tissue and cellular level. The cellular adaptations involve a dramatic alteration in gene expression, post-transcriptional and post-translational modification of gene products, bioenergetics, and metabolism. Among the key responses to oxygen-deprivation is the skewing of cellular alternative splicing program. Herein, we discuss the current concepts of oxygen tension-dependent alternative splicing relevant to various pathophysiological conditions. Following a brief description of cellular response to hypoxia and the pre-mRNA splicing mechanism, we outline the impressive number of hypoxia-elicited alternative splicing events associated with maladies like cancer, cardiovascular diseases, and neurological disorders. Furthermore, we discuss how manipulation of hypoxia-induced alternative splicing may pose promising strategies for novel translational diagnosis and therapeutic interventions.

YB-1 Protein in Breast Cancer (Scientific and Personal Meetings with Professor Ovchinnikov).

In the article, the author examines the properties of Y-box-binding protein (YB-1) and expression of the YBX-1 gene in various malignant tumors and provides the data from her own prospective study in breast cancer patients. YB-1 is a member of the highly conserved family of cold shock proteins with multiple functions in the cytoplasm and cell nucleus. YB-1 is involved in embryogenesis; it ensures cell proliferation and protects cell from the action of various aggressive environmental factors. In adult organisms, YB-1 is involved in a variety of cellular functions that regulate malignant phenotype in several types of tumors. YB-1 is a molecular marker of tumor progression that can be used in clinical practice as both prognostic factor and a target for anticancer therapy. Our prospective clinical study showed that expression of YB-1 mRNA is an independent prognostic factor, as breast cancer patients expressing YB-1 have a lower disease-free survival rate, regardless of the tumor stage and biological subtype. We recommend determining the level of YB-1 mRNA expression as a prognostic test in breast cancer patients.

Machine Learning Using Gene-Sets to Infer miRNA Function.

miRNA are regulators of cell phenotype, and there is clear evidence that these small posttranscriptional modifiers of gene expression are involved in defining a cellular response across states of development and disease. Classical methods for elucidating the repressive effect of a miRNA on its targets involve controlling for the many factors influencing miRNA action, and this can be achieved in cell lines, but misses tissue and organism level context which are key to a miRNA function. Also, current technology to carry out this validation is limited in both generalizability and throughput. Methodologies with greater scalability and rapidity are required to better understand the function of these important species of RNA. To this end, there is an increasing store of RNA expression level data incorporating both miRNA and mRNA, and in this chapter, we describe how to use machine learning and gene-sets to translate the knowledge of phenotype defined by mRNA to putative roles for miRNA. We outline our approach to this process and highlight how it was done for our miRNA annotation of the hallmarks of cancer using the Cancer Genome Atlas (TCGA) dataset. The concepts we present are applicable across datasets and phenotypes, and we highlight potential pitfalls and challenges that may be faced as they are used.

An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation.

We propose an overview of the molecular cues and their intracellular signaling involved in the crosstalk between cancer and the nervous system. While "cancer neuroscience" as a field is still in its infancy, the relation between cancer and the nervous system has been known for a long time, and a huge body of experimental data provides evidence that tumor-nervous system connections are widespread. They encompass different mechanisms at different tumor progression steps, are multifaceted, and display some intriguing analogies with the nervous system's physiological processes. Overall, we can say that many of the paradigmatic "hallmarks of cancer" depicted by Weinberg and Hanahan are affected by the nervous system in a variety of manners.

The Kv10.1 Channel: A Promising Target in Cancer.

Carcinogenesis is a multistage process involving the dysregulation of multiple genes, proteins, and pathways that make any normal cell acquire a cancer cell phenotype. Therefore, it is no surprise that numerous ion channels could be involved in this process. Since their discovery and subsequent cloning, ion channels have been established as therapeutic targets in excitable cell pathologies (e.g., cardiac arrhythmias or epilepsy); however, their involvement in non-excitable cell pathologies is relatively recent. Among all ion channels, the voltage-gated potassium channels Kv10.1 have been established as a promising target in cancer treatment due to their high expression in tumoral tissues compared to low levels in healthy tissues.