904 research outputs found
Cancer as a tool for preclinical psychoneuroimmunology
No full textCancer represents a novel homeostatic challenge to the host system. How the brain senses and responds to changes in peripheral physiology elicited by tumor growth is a largely untapped area of research. This is especially relevant given the widespread prevalence of systemic problems that people with various types of cancer experience. These include disruptions in sleep/wake cycles, cognitive function, depression, and changes in appetite/food intake, among others. Critically, many of these problems are evident prior to diagnosis, indicating that their etiology is potentially distinct from the effects of cancer treatment or the stress of a cancer diagnosis. Psychoneuroimmunology (PNI) is well equipped to tackle these types of problems, as it uses approaches from multiple disciplines to understand how specific stimuli (endogenous and environmental) are transduced into neural, endocrine, and immune signals that ultimately regulate health and behavior. In this article, I first provide a brief historical perspective of cancer and PNI, introduce the idea of cancer as a systemic homeostatic challenge, and provide examples from preclinical literature supporting this hypothesis. Given the rise of advanced tools in neuroscience (e.g., calcium imaging), we can now monitor and manipulate genetically defined neural circuits over the extended time scales necessary to disentangle distal communication between peripheral tumors and the brai
A vindication of the Reasons and Defence, &c. Part 1. [electronic resource] : Being a reply to the first part of No sufficient reason for restoring some prayers and directions of King Edward Vi's first Liturgy. By the author of the Reasons and Defence.
No full textThe author of the Reasons = Jeremy Collier.Also issued as part of: 'A collection of tracts written by the late Reverend .. Jeremy Collier, ..', London, 1736.With a half-title.Electronic reproduction.English Short Title Catalog,Reproduction of original from British Library
Central regulation of breast cancer growth and metastasis
No full textCancer is a systemic disease. In order to fully understand it, we must take a holistic view on how cancer interacts with its host. The brain monitors and responds to natural and aberrant signals arriving from the periphery, particularly those of metabolic or immune origin. As has been well described, a hallmark of cancer is marked disruption of metabolic and inflammatory processes. Depending on the salience and timing of these inputs, the brain responds via neural and humoral routes to alter whole-body physiology. These responses have consequences for tumor growth and metastasis, directly influencing patient quality of life and subsequent mortality. Additionally, environmental inputs such as light, diet, and stress, can promote inappropriate neural activity that benefits cancer. Here, I discuss evidence for brain-tumor interactions, with special emphasis on subcortical neuromodulator neural populations, and potential ways of harnessing this cross-talk as a novel approach for cancer treatment
Sleep Disruption and Cancer: Chicken or the Egg?
No full textSleep is a nearly ubiquitous phenomenon across the phylogenetic tree, highlighting its essential role in ensuring fitness across evolutionary time. Consequently, chronic disruption of the duration, timing, or structure of sleep can cause widespread problems in multiple physiological systems, including those that regulate energy balance, immune function, and cognitive capacity, among others. Many, if not all these systems, become altered throughout the course of cancer initiation, growth, metastatic spread, treatment, and recurrence. Recent work has demonstrated how changes in sleep influence the development of chronic diseases, including cancer, in both humans and animal models. A common finding is that for some cancers (e.g., breast), chronic disruption of sleep/wake states prior to disease onset is associated with an increased risk for cancer development. Additionally, sleep disruption after cancer initiation is often associated with worse outcomes. Recently, evidence suggesting that cancer itself can affect neuronal circuits controlling sleep and wakefulness has accumulated. Patients with cancer often report difficulty falling asleep, difficulty staying asleep, and severe fatigue, during and even years after treatment. In addition to the psychological stress associated with cancer, cancer itself may alter sleep homeostasis through changes to host physiology and via currently undefined mechanisms. Moreover, cancer treatments (e.g., chemotherapy, radiation, hormonal, and surgical) may further worsen sleep problems through complex biological processes yet to be fully understood. This results in a “chicken or the egg” phenomenon, where it is unclear whether sleep disruption promotes cancer or cancer reciprocally disrupts sleep. This review will discuss existing evidence for both hypotheses and present a framework through which the interactions between sleep and cancer can be dissociated and causally investigated
Cancer as a homeostatic challenge: the role of the hypothalamus
No full textThe initiation, progression, and metastatic spread of cancer elicits diverse changes in systemic physiology. In this way, cancer represents a novel homeostatic challenge to the host system. Here, we discuss how the hypothalamus, a critical brain region involved in homeostasis senses, integrates, and responds to cancer-induced changes in physiology. Through this lens, cancer-associated changes in behavior (e.g., sleep disruption) and physiology (e.g., glucocorticoid dysregulation) can be viewed as the result of an inability to re-establish homeostasis. We provide examples at each level (receptor sensing, integration of systemic signals, and efferent regulatory pathways) of how homeostatic organization becomes disrupted across different cancers. Finally, we lay out predictions of this hypothesis, and highlight outstanding questions that aim to guide further work in this area
Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4
No full textBackground: cyclin-dependent kinases 2, 4 and 6 (Cdk2, Cdk4, Cdk6) are closely structurally homologous proteins which are classically understood to control the transition from the G1 to the S-phases of the cell cycle by combining with their appropriate cyclin D or cyclin E partners to form kinase-active holoenzymes. Deregulation of Cdk4 is widespread in human cancer, CDK4 gene knockout is highly protective against chemical and oncogene-mediated epithelial carcinogenesis, despite the continued presence of CDK2 and CDK6; and overexpresssion of Cdk4 promotes skin carcinogenesis. Surprisingly, however, Cdk4 kinase inhibitors have not yet fulfilled their expectation as 'blockbuster' anticancer agents. Resistance to inhibition of Cdk4 kinase in some cases could potentially be due to a non-kinase activity, as recently reported with epidermal growth factor receptor. Results: a search for a potential functional site of non-kinase activity present in Cdk4 but not Cdk2 or Cdk6 revealed a previously-unidentified loop on the outside of the C'-terminal non-kinase domain of Cdk4, containing a central amino-acid sequence, Pro-Arg-Gly-Pro-Arg-Pro (PRGPRP). An isolated hexapeptide with this sequence and its cyclic amphiphilic congeners are selectively lethal at high doses to a wide range of human cancer cell lines whilst sparing normal diploid keratinocytes and fibroblasts. Treated cancer cells do not exhibit the wide variability of dose response typically seen with other anticancer agents. Cancer cell killing by PRGPRP, in a cyclic amphiphilic cassette, requires cells to be in cycle but does not perturb cell cycle distribution and is accompanied by altered relative Cdk4/Cdk1 expression and selective decrease in ATP levels. Morphological features of apoptosis are absent and cancer cell death does not appear to involve autophagy. Conclusion: these findings suggest a potential new paradigm for the development of broad-spectrum cancer specific therapeutics with a companion diagnostic biomarker and a putative functional site for kinase-unrelated activities of Cdk4
Molecular Mechanisms of Cancer-Induced Sleep Disruption
No full textSleep is essential for health. Indeed, poor sleep is consistently linked to the development of systemic disease, including depression, metabolic syndrome, and cognitive impairments. Further evidence has accumulated suggesting the role of sleep in cancer initiation and progression (primarily breast cancer). Indeed, patients with cancer and cancer survivors frequently experience poor sleep, manifesting as insomnia, circadian misalignment, hypersomnia, somnolence syndrome, hot flushes, and nightmares. These problems are associated with a reduction in the patients' quality of life and increased mortality. Due to the heterogeneity among cancers, treatment regimens, patient populations and lifestyle factors, the etiology of cancer-induced sleep disruption is largely unknown. Here, we discuss recent advances in understanding the pathways linking cancer and the brain and how this leads to altered sleep patterns. We describe a conceptual framework where tumors disrupt normal homeostatic processes, resulting in aberrant changes in physiology and behavior that are detrimental to health. Finally, we discuss how this knowledge can be leveraged to develop novel therapeutic approaches for cancer-associated sleep disruption, with special emphasis on host-tumor interactions
Lateral Hypothalamic Control of Sleep in the Context of Cancer
No full textSleep plays a vital role in health and well-being. Its conservation along nearly all branches of the phylogenetic tree suggests that sleep serves an essential biological function. Disrupted or truncated sleep is consistently linked to heart disease, depression, obesity, and more recently, cancer. Indeed, chronic sleep disturbance affects 10%-20% of the population in the developed world, representing a substantial public health problem that translates into an estimated financial burden in the hundreds of billions of dollars annually. Poor sleep is a strong predictor of subsequent mortality in cancer patients even when taking into consideration other risk factors including age, hormone receptor status, cortisol concentrations, depression, and metastatic spread. Despite the prevalence of these problems, the underlying mechanisms mediating cancer-associated changes in sleep are unknown. Here, we discuss recent evidence supporting a cross-talk among tumors in the periphery, the nervous, endocrine, metabolic, and immune systems leading to sleep and systemic disruption. Special emphasis is given to the lateral hypothalamus, which contains many neural populations that couple sleep to metabolic state, immune status, and the environment. Among these, hypocretin/orexin neurons have been the most well characterized. We further lay down logical "next-steps" in this research area that are likely to drive the development of novel treatments for cancer-associated sleep disruption
Neuropeptides in Cancer: Friend and Foe?
No full textNeuropeptides are small regulatory molecules found throughout the body, most notably in the nervous, cardiovascular, and gastrointestinal systems. They serve as neurotransmitters or hormones in the regulation of diverse physiological processes. Cancer cells escape normal growth control mechanisms by altering their expression of growth factors, receptors, or intracellular signals, and neuropeptides have recently been recognized as mitogens in cancer growth and development. Many neuropeptides and their receptors exist in multiple subtypes, coupling with different downstream signaling pathways and playing distinct roles in cancer progression. The consideration of neuropeptide/receptor systems as anticancer targets is already leading to new biological and diagnostic knowledge that has the potential to enhance the understanding and treatment of cancer. In this review, recent discoveries regarding neuropeptides in a wide range of cancers, emphasizing their mechanisms of action, signaling cascades, regulation, and therapeutic potential, are discussed. Current technologies used to manipulate and analyze neuropeptides/receptors are described. Applications of neuropeptide analogs and their receptor inhibitors in translational studies and radio-oncology are rapidly increasing, and the possibility for their integration into therapeutic trials and clinical treatment appears promising
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