The Cancer Clock Is (Not) Ticking: Links between Circadian Rhythms and Cancer

Circadian rhythms regulate many physiological and behavioral processes, including sleep, metabolism and cell division, which have a 24-h oscillation pattern. Rhythmicity is generated by a transcriptional–translational feedback loop in individual cells, which are synchronized by the central pacemaker in the brain and external cues. Epidemiological and clinical studies indicate that disruption of these rhythms can increase both tumorigenesis and cancer progression. Environmental changes (shift work, jet lag, exposure to light at night), mutations in circadian regulating genes, and changes to clock gene expression are recognized forms of disruption and are associated with cancer risk and/or cancer progression. Experimental data in animals and cell cultures further supports the role of the cellular circadian clock in coordinating cell division and DNA repair, and disrupted cellular clocks accelerate cancer cell growth. This review will summarize studies linking circadian disruption to cancer biology and explore how such disruptions may be further altered by common characteristics of tumors including hypoxia and acidosis. We will highlight how circadian rhythms might be exploited for cancer drug development, including how delivery of current chemotherapies may be enhanced using chronotherapy. Understanding the role of circadian rhythms in carcinogenesis and tumor progression will enable us to better understand causes of cancer and how to treat them.

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Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction

The Scientific World JOURNAL ◽

10.1100/tsw.2007.213 ◽

2007 ◽

Vol 7 ◽

pp. 194-202 ◽

Cited By ~ 65

Author(s):

Colleen A. McClung

Keyword(s):

Circadian Rhythms ◽

Drug Addiction ◽

Molecular Mechanisms ◽

Dopaminergic System ◽

Treatment Options ◽

Drug Induced ◽

Circadian Genes ◽

Dopaminergic Transmission ◽

Central Pacemaker

Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.

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Breast Cancer Cells in Microgravity: New Aspects for Cancer Research

International Journal of Molecular Sciences ◽

10.3390/ijms21197345 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7345 ◽

Cited By ~ 1

Author(s):

Mohamed Zakaria Nassef ◽

Daniela Melnik ◽

Sascha Kopp ◽

Jayashree Sahana ◽

Manfred Infanger ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Cancer Biology ◽

Breast Cancer Cells ◽

De Novo ◽

Tumor Model ◽

Cancer Drug ◽

Cancer Therapies

Breast cancer is the leading cause of cancer death in females. The incidence has risen dramatically during recent decades. Dismissed as an “unsolved problem of the last century”, breast cancer still represents a health burden with no effective solution identified so far. Microgravity (µg) research might be an unusual method to combat the disease, but cancer biologists decided to harness the power of µg as an exceptional method to increase efficacy and precision of future breast cancer therapies. Numerous studies have indicated that µg has a great impact on cancer cells; by influencing proliferation, survival, and migration, it shifts breast cancer cells toward a less aggressive phenotype. In addition, through the de novo generation of tumor spheroids, µg research provides a reliable in vitro 3D tumor model for preclinical cancer drug development and to study various processes of cancer progression. In summary, µg has become an important tool in understanding and influencing breast cancer biology.

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Biological mechanisms linked to inflammation in cancer: Discovery of tumor microenvironment-related biomarkers and their clinical application in solid tumors

The International Journal of Biological Markers ◽

10.1177/1724600820906155 ◽

2020 ◽

Vol 35 (1_suppl) ◽

pp. 8-11 ◽

Cited By ~ 3

Author(s):

Paola Nisticò ◽

Gennaro Ciliberto

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Cancer Progression ◽

Cancer Biology ◽

Tumor Development ◽

Short Paper ◽

Great Relevance ◽

Cellular Components ◽

The Relationship

Our view of cancer biology radically shifted from a “cancer-cell-centric” vision to a view of cancer as an organ disease. The concept that genetic and/or epigenetic alterations, at the basis of cancerogenesis, are the main if not the exclusive drivers of cancer development and the principal targets of therapy, has now evolved to include the tumor microenvironment in which tumor cells can grow, proliferate, survive, and metastasize only within a favorable environment. The interplay between cancer cells and the non-cellular and cellular components of the tumor microenvironment plays a fundamental role in tumor development and evolution both at the primary site and at the level of metastasis. The shape of the tumor cells and tumor mass is the resultant of several contrasting forces either pro-tumoral or anti-tumoral which have at the level of the tumor microenvironment their battle field. This crucial role of tumor microenvironment composition in cancer progression also dictates whether immunotherapy with immune checkpoint inhibitor antibodies is going to be efficacious. Hence, tumor microenvironment deconvolution has become of great relevance in order to identify biomarkers predictive of efficacy of immunotherapy. In this short paper we will briefly review the relationship between inflammation and cancer, and will summarize in 10 short points the key concepts learned so far and the open challenges to be solved.

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Clinical, Pathological, and Ethical Considerations for the Conduct of Clinical Trials in Dogs with Naturally Occurring Cancer: A Comparative Approach to Accelerate Translational Drug Development

ILAR Journal ◽

10.1093/ilar/ily019 ◽

2018 ◽

Vol 59 (1) ◽

pp. 99-110 ◽

Cited By ~ 5

Author(s):

Daniel Regan ◽

Kelly Garcia ◽

Douglas Thamm

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Translational Research ◽

Cancer Biology ◽

Comparative Approach ◽

Cancer Drug ◽

Comparative Oncology ◽

Pet Dogs ◽

Naturally Occurring

Abstract The role of comparative oncology in translational research is receiving increasing attention from drug developers and the greater biomedical research community. Pet dogs with spontaneous cancer are important and underutilized translational models, owing to dogs’ large size and relative outbreeding, combined with their high incidence of certain tumor histotypes with significant biological, genetic, and histological similarities to their human tumor counterparts. Dogs with spontaneous tumors naturally develop therapy resistance and spontaneous metastasis, all in the context of an intact immune system. These fundamental features of cancer biology are often lacking in induced or genetically engineered preclinical tumor models and likely contribute to their poor predictive value and the associated overall high failure rate in oncology drug development. Thus, the conduct of clinical trials in pet dogs with naturally occurring cancer represents a viable surrogate and valuable intermediary step that should be increasingly incorporated into the cancer drug discovery and development pipeline. The development of molecular-targeted therapies has resulted in an expanded role of the pathologist in human oncology trials, and similarly the expertise of veterinary pathologists will be increasingly valuable to all phases of comparative oncology trial design and conduct. In this review, we provide a framework of clinical, ethical, and pathology-focused considerations for the increasing integration of translational research investigations in dogs with spontaneous cancer as a means to accelerate clinical cancer discovery and drug development.

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Undervalued ubiquitous proteins

4open ◽

10.1051/fopen/2019002 ◽

2019 ◽

Vol 2 ◽

pp. 7 ◽

Cited By ~ 4

Author(s):

Björn L.D.M. Brücher ◽

Ijaz S. Jamall

Keyword(s):

Cancer Progression ◽

Cancer Biology ◽

Life Forms ◽

Intercellular Signaling ◽

Peptide Bonds ◽

True Nature ◽

The Stability ◽

Quantitative Contribution ◽

Ubiquitous Proteins

The role of ubiquitous proteins (UPs) and their corresponding enzymes have been underestimated in carcinogenesis as the focus of much research revolved around measuring mutations and/or other genetic epiphenomena as surrogate markers of cancer and cancer progression. Over the past three decades, the scientific community has come to realize that the concentration on microdissection of cancer cells without accounting for the neighborhood in which these cells reside, i.e., the stroma, fails to reflect the true nature of cancer biology. UPs are fundamental for cellular homeostasis and phylogenetic development as well as for the integrity of the cytoskeleton and for the stability of cells and tissues in regards to intercellular signaling, cell shape and mobility, apoptosis, wound healing, and cell polarity. Corresponding enzymes are used by microorganisms to gain entry into the host by degradation of UPs and play a role to cleave peptide bonds for killing disease-causing life forms along for the creation of the precancerous niche (PCN) during carcinogenesis, cancer invasion, and in metastasis. The language used by such proteins as well as their complementary enzymes with its influence on multiple pathways and the cross-linked extracellular matrix is incompletely understood. The role of UPs in the disruption of signaling homeostasis and resulting interference with crosstalk in carcinogenesis appears sufficiently delineated to warrant a much more refined examination of their qualitative and quantitative contribution to the development of cancer and cancer therapy.

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Multifaced roles of PLAC8 in cancer

Biomarker Research ◽

10.1186/s40364-021-00329-1 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Misha Mao ◽

Yifan Cheng ◽

Jingjing Yang ◽

Yongxia Chen ◽

Ling Xu ◽

...

Keyword(s):

Cell Growth ◽

Tumor Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Molecular Function ◽

Cancer Cell Growth ◽

The Impact ◽

Functional Output

AbstractThe role of PLAC8 in tumorigenesis has been gradually elucidated with the development of research. Although there are common molecular mechanisms that enforce cell growth, the impact of PLAC8 is varied and can, in some instances, have opposite effects on tumorigenesis. To systematically understand the role of PLAC8 in tumors, the molecular functions of PLAC8 in cancer will be discussed by focusing on how PLAC8 impacts tumorigenesis when it arises within tumor cells and how these roles can change in different stages of cancer progression with the ultimate goal of suppressing PLAC8-relevant cancer behavior and related pathologies. In addition, we highlight the diversity of PLAC8 in different tumors and its functional output beyond cancer cell growth. The comprehension of PLAC8’s molecular function might provide new target and lead to the development of novel anticancer therapies.

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Genetic and Epigenetic Events Generate Multiple Pathways in Colorectal Cancer Progression

Pathology Research International ◽

10.1155/2012/509348 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 55

Author(s):

Massimo Pancione ◽

Andrea Remo ◽

Vittorio Colantuoni

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Cancer Biology ◽

Current Knowledge ◽

Alternative Pathway ◽

Epigenetic Events ◽

Cells Of Origin ◽

Common Causes ◽

Colorectal Cancer Progression

Colorectal cancer (CRC) is one of the most common causes of death, despite decades of research. Initially considered as a disease due to genetic mutations, it is now viewed as a complex malignancy because of the involvement of epigenetic abnormalities. A functional equivalence between genetic and epigenetic mechanisms has been suggested in CRC initiation and progression. A hallmark of CRC is its pathogenetic heterogeneity attained through at least three distinct pathways: a traditional (adenoma-carcinoma sequence), an alternative, and more recently the so-called serrated pathway. While the alternative pathway is more heterogeneous and less characterized, the traditional and serrated pathways appear to be more homogeneous and clearly distinct. One unsolved question in colon cancer biology concerns the cells of origin and from which crypt compartment the different pathways originate. Based on molecular and pathological evidences, we propose that the traditional and serrated pathways originate from different crypt compartments explaining their genetic/epigenetic and clinicopathological differences. In this paper, we will discuss the current knowledge of CRC pathogenesis and, specifically, summarize the role of genetic/epigenetic changes in the origin and progression of the multiple CRC pathways. Elucidation of the link between the molecular and clinico-pathological aspects of CRC would improve our understanding of its etiology and impact both prevention and treatment.

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The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms20143602 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3602 ◽

Cited By ~ 15

Author(s):

Magdalena Rudzińska ◽

Alessandro Parodi ◽

Surinder M. Soond ◽

Andrey Z. Vinarov ◽

Dmitry O. Korolev ◽

...

Keyword(s):

Drug Resistance ◽

Cancer Progression ◽

Cancer Biology ◽

Lysosomal Enzymes ◽

Tumor Biology ◽

Therapeutic Strategies ◽

Cysteine Cathepsins ◽

Aggressive Tumor ◽

Tumor Phenotypes

Cysteine cathepsins are lysosomal enzymes belonging to the papain family. Their expression is misregulated in a wide variety of tumors, and ample data prove their involvement in cancer progression, angiogenesis, metastasis, and in the occurrence of drug resistance. However, while their overexpression is usually associated with highly aggressive tumor phenotypes, their mechanistic role in cancer progression is still to be determined to develop new therapeutic strategies. In this review, we highlight the literature related to the role of the cysteine cathepsins in cancer biology, with particular emphasis on their input into tumor biology.

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Circadian Rhythms of the Hypothalamus: From Function to Physiology

Clocks & Sleep ◽

10.3390/clockssleep3010012 ◽

2021 ◽

Vol 3 (1) ◽

pp. 189-226

Author(s):

Rachel Van Drunen ◽

Kristin Eckel-Mahan

Keyword(s):

Circadian Rhythms ◽

Energy Homeostasis ◽

Environmental Changes ◽

Neurological Diseases ◽

Epidemiological Studies ◽

Internal Clock ◽

The Body ◽

Hypothalamic Nuclei ◽

Increased Risk

The nearly ubiquitous expression of endogenous 24 h oscillations known as circadian rhythms regulate the timing of physiological functions in the body. These intrinsic rhythms are sensitive to external cues, known as zeitgebers, which entrain the internal biological processes to the daily environmental changes in light, temperature, and food availability. Light directly entrains the master clock, the suprachiasmatic nucleus (SCN) which lies in the hypothalamus of the brain and is responsible for synchronizing internal rhythms. However, recent evidence underscores the importance of other hypothalamic nuclei in regulating several essential rhythmic biological functions. These extra-SCN hypothalamic nuclei also express circadian rhythms, suggesting distinct regions that oscillate either semi-autonomously or independent of SCN innervation. Concurrently, the extra-SCN hypothalamic nuclei are also sensitized to fluctuations in nutrient and hormonal signals. Thus, food intake acts as another powerful entrainer for the hypothalamic oscillators’ mediation of energy homeostasis. Ablation studies and genetic mouse models with perturbed extra-SCN hypothalamic nuclei function reveal their critical downstream involvement in an array of functions including metabolism, thermogenesis, food consumption, thirst, mood and sleep. Large epidemiological studies of individuals whose internal circadian cycle is chronically disrupted reveal that disruption of our internal clock is associated with an increased risk of obesity and several neurological diseases and disorders. In this review, we discuss the profound role of the extra-SCN hypothalamic nuclei in rhythmically regulating and coordinating body wide functions.

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Biological Functions of Gasdermins in Cancer: From Molecular Mechanisms to Therapeutic Potential

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.638710 ◽

2021 ◽

Vol 9 ◽

Author(s):

Man Wang ◽

Xinzhe Chen ◽

Yuan Zhang

Keyword(s):

Cell Death ◽

Cancer Cell ◽

Cancer Progression ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Effector Proteins ◽

Biological Functions ◽

Cancer Cell Growth ◽

Cancer Pathogenesis

Pyroptosis is a type of lytic programmed cell death triggered by various inflammasomes that sense danger signals. Pyroptosis has recently attracted great attention owing to its contributory role in cancer. Pyroptosis plays an important role in cancer progression by inducing cancer cell death or eliciting anticancer immunity. The participation of gasdermins (GSDMs) in pyroptosis is a noteworthy recent discovery. GSDMs have emerged as a group of pore-forming proteins that serve important roles in innate immunity and are composed of GSDMA-E and Pejvakin (PJVK) in human. The N-terminal domains of GSDMs, expect PJVK, can form pores on the cell membrane and function as effector proteins of pyroptosis. Remarkably, it has been found that GSDMs are abnormally expressed in several forms of cancers. Moreover, GSDMs are involved in cancer cell growth, invasion, metastasis and chemoresistance. Additionally, increasing evidence has indicated an association between GSDMs and clinicopathological features in cancer patients. These findings suggest the feasibility of using GSDMs as prospective biomarkers for cancer diagnosis, therapeutic intervention and prognosis. Here, we review the progress in unveiling the characteristics and biological functions of GSDMs. We also focus on the implication and molecular mechanisms of GSDMs in cancer pathogenesis. Investigating the relationship between GSDMs and cancer biology could assist us to explore new therapeutic avenues for cancer prevention and treatment.

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