Cure Alveolar Soft Part Sarcoma International (iCureASPS)

“Daily rhythms of light/darkness, activity/rest and feeding/fasting are important in human physiology and their disruption (for example by frequent changes between day and night shifts) increases the risk of disease. Many of the diseases found to be associated with such disrupted circadian lifestyles, including cancer, cardiovascular diseases, metabolic disorders and neurological diseases, depend on pathological de-regulation of angiogenesis, suggesting that disrupting the circadian clock will impair the physiological regulation of angiogenesis leading to development and progression of these diseases. Today there is little known regarding circadian regulation of pathological angiogenesis but there is some evidence that supports both direct and indirect regulation of angiogenic factors by the cellular circadian clock machinery, as well as by circulating circadian factors, important for coordinating circadian rhythms in the organism. Through highlighting recent advances both in pre-clinical and clinical research on various diseases including cancer, cardiovascular disorders and obesity, we will here present an overview of the available knowledge on the importance of circadian regulation of angiogenesis and discuss how the circadian clock may provide alternative targets for pro-or anti-angiogenic therapy in the future.”

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“Introduction

Daily cycles of light and darkness on Earth have led to the development of highly conserved anticipatory signalling processes, which are crucial to prepare most organisms from bacteria to human beings for the coming of the day and the night (1). These processes couple environmental light/darkness to biological functions and are naturally oscillating with a period of close to 24 h, thus collectively known as circadian rhythms (circa: about; diem: a day). Multiple aspects of mammalian physiology are under circadian regulation. The most obvious circadian rhythms in humans are perhaps those of activity/rest (2) and feeding/fasting (3). However, these rhythms are tightly coupled to a number of enabling physiological processes, such as regulation of blood pressure (4), heart rate (5), ventilation rate (6), metabolism (3), kidney and intestinal activity (7) and production of hormones that modulate these processes (8).

The importance of circadian signalling for maintaining our health is underscored by increased disease risk in people who frequently change their activity pattern from being awake during the day or during the night, such as people engaged in shift-work (9). Because of increased globalization and the 24-h lifestyle found in most major cities today, we are experiencing a drastic increase in the number of people on shifting working schedules submitting themselves to disrupted circadian rhythms (10). Epidemiologic studies have shown that such disruptions are coupled to an increased risk of cancer, including breast (11), prostate (12) and colorectal cancer (13), metabolic disorders including obesity (14), diabetes (15) and cardiovascular disorder (16) as well as psychiatric disorders including depression and various other diseases (17, 18). These diseases are for the most part driven by pathological changes to the vasculature (19–23) – in particular pathological angiogenesis, i.e., the growth of new blood vessels from an existing vasculature – which therefore has become a major research focus of the medical industry in recent years (24). In adults the healthy vasculature in most tissues is quiescent, presumably owing to the presence of high levels of endogenous angiogenesis inhibitors relative to pro-angiogenic factors. However, this intimate balance can easily be tipped in favor of angiogenesis – a process known as the angiogenic switch – which often will lead to rapidly progressive disease (21). As such, angiogenesis is crucial for solid tumor growth (22), obesity (25–27), arteriosclerotic plaque growth and instability (28), regeneration of heart or brain tissue following myocardial infarction (28) or stroke (29), as well as for chronic inflammatory diseases such as rheumatoid arthritis (19) and neurodegenerative diseases (30) and retinopathies, including age-related macular degeneration (31) and diabetic retinopathy (32). This realization has led to a surge in the clinical development and use of drugs targeting the angiogenic switch and in particular the factor vascular endothelial growth factor (VEGF) as an anti-angiogenic therapy in cancer and retinopathies (31, 33, 34). While such an approach has led to some progress in the management of these diseases, it is clear that more targets are needed in order to overcome resistance and increase the response to anti-angiogenic therapy (35). The angiogenic switch is regulated at multiple levels, and as we will discuss in more detail below, also by circadian clock factors. It is therefore pertinent to elucidate how circadian rhythms may influence angiogenesis and how this process could be targeted in order to prevent development and progression of angiogenesis-dependent diseases“

“Introduction

Daily cycles of light and darkness on Earth have led to the development of highly conserved anticipatory signalling processes, which are crucial to prepare most organisms from bacteria to human beings for the coming of the day and the night (1). These processes couple environmental light/darkness to biological functions and are naturally oscillating with a period of close to 24 h, thus collectively known as circadian rhythms (circa: about; diem: a day). Multiple aspects of mammalian physiology are under circadian regulation. The most obvious circadian rhythms in humans are perhaps those of activity/rest (2) and feeding/fasting (3). However, these rhythms are tightly coupled to a number of enabling physiological processes, such as regulation of blood pressure (4), heart rate (5), ventilation rate (6), metabolism (3), kidney and intestinal activity (7) and production of hormones that modulate these processes (8).

The importance of circadian signalling for maintaining our health is underscored by increased disease risk in people who frequently change their activity pattern from being awake during the day or during the night, such as people engaged in shift-work (9). Because of increased globalization and the 24-h lifestyle found in most major cities today, we are experiencing a drastic increase in the number of people on shifting working schedules submitting themselves to disrupted circadian rhythms (10). Epidemiologic studies have shown that such disruptions are coupled to an increased risk of cancer, including breast (11), prostate (12) and colorectal cancer (13), metabolic disorders including obesity (14), diabetes (15) and cardiovascular disorder (16) as well as psychiatric disorders including depression and various other diseases (17, 18). These diseases are for the most part driven by pathological changes to the vasculature (19–23) – in particular pathological angiogenesis, i.e., the growth of new blood vessels from an existing vasculature – which therefore has become a major research focus of the medical industry in recent years (24). In adults the healthy vasculature in most tissues is quiescent, presumably owing to the presence of high levels of endogenous angiogenesis inhibitors relative to pro-angiogenic factors. However, this intimate balance can easily be tipped in favor of angiogenesis – a process known as the angiogenic switch – which often will lead to rapidly progressive disease (21). As such, angiogenesis is crucial for solid tumor growth (22), obesity (25–27), arteriosclerotic plaque growth and instability (28), regeneration of heart or brain tissue following myocardial infarction (28) or stroke (29), as well as for chronic inflammatory diseases such as rheumatoid arthritis (19) and neurodegenerative diseases (30) and retinopathies, including age-related macular degeneration (31) and diabetic retinopathy (32). This realization has led to a surge in the clinical development and use of drugs targeting the angiogenic switch and in particular the factor vascular endothelial growth factor (VEGF) as an anti-angiogenic therapy in cancer and retinopathies (31, 33, 34). While such an approach has led to some progress in the management of these diseases, it is clear that more targets are needed in order to overcome resistance and increase the response to anti-angiogenic therapy (35). The angiogenic switch is regulated at multiple levels, and as we will discuss in more detail below, also by circadian clock factors. It is therefore pertinent to elucidate how circadian rhythms may influence angiogenesis and how this process could be targeted in order to prevent development and progression of angiogenesis-dependent diseases“

“Organization of the circadian clock

Light and food are the principal agents responsible for coordinating circadian rhythms (36). Light is detected by non-vision forming retinal ganglion cells in the retina, which convey such day/night information to the suprachiasmatic nucleus (SCN) via the retino-hypothalamic tract (37). In the SCN, the signals are amplified and coordinated, and from here neuronal and humoral cues are generated which sets the pace for the coordinated rhythmic functions of the rest of the organism (38). Thus the SCN is considered to be the master clock and pacemaker. Food, the second major circadian timing factor or zeitgeber, is crucial for rhythm generation in the liver, which in turn regulate metabolic activities in the rest of our organism (39). Interestingly, many recent studies have also found circadian clocks in many other cell types, which may be regulated both by SCN- or liver-derived signals as well as other circadian mediators (40, 41). While, the cellular clocks within each cell of a tissue are usually coordinated, they may be out of sync with clocks in other tissues if timing cues are not coordinated with each other. As such, the vascular clock may be regulated differently by central and peripheral circadian clocks in different vasculatures, for example as a result of pathological disruption of blood pressure rhythms (42), differences in sympathetic innervation (43) or expression of receptors for endocrine circadian modulators (44), due to disrupted rhythms of blood sugar levels (45, 46) or in other ways, which all could be important in causing diseases.

Regardless of the input (light, endocrine entraining factor or other) the molecular clock-work of all cells is organized in a very similar fashion (47) and build on a remarkably simple transcription-translation feedback loop (see Figure 1). Bmal1 is a key element of the positive limb of the loop. Bmal1, a member of the basic helix-loop-helix, PAS-domain containing family of transcription factors interacts with other members of this family, usually CLOCK or Npas2 to form a heterodimeric transcriptional activator, which drives transcription through binding to E-boxes in the promoters of target genes (48). Among these are members of the Period and Cryptochrome families (49, 50), which act as transcriptional repressors, inhibiting transcription at both their own promoters as well as those of other circadian output genes. This simple organization is referred to as the core loop, but it is regulated by a number of associated pathways that strengthen the system (38). These include ROR/Rev-Erb factors, D-box and F-box binding factors, protein kinases, ubiquitin ligases and multiple co-activators or -repressors, etc., factors that are important for conferring the right timing on the system, but are not involved in generating rhythmicity per se.”

“Mechanisms of angiogenesis”

“The development and growth of the vascular system is mainly achieved through angiogenesis – the sprouting and growth of new blood vessels from an existing vasculature (23), as opposed to vasculogenesis, which refers to the de novo formation of blood vessels and which is principally involved in formation of the first major vessels during early development (51). Angiogenesis is also important in adults during the female reproductive cycle (52), in wound healing/regeneration (53, 54) and in tissue (i.e. adipose or muscle) growth (55). However, in most adult tissues, the vasculature is quiescent and non-growing, but can be induced to grow in response to, for example, local tissue inflammation (56), hypoxia (21, 57–59) or other cues that induce the production of angiogenic factors. Angiogenesis is a multi-step process (60), starting with the destabilization of the vascular wall by degradation of the basement membrane and detachment of vascular mural cells such as smooth muscle cells and pericytes. This exposes the abluminal side of the endothelium on which a few leading tip cells emerge, start to move toward the angiogenic signal and thus form a sprout. Cells located behind the tip-cell and thus preserving the connection to the original vessel, also known as stalk cells, proliferate, form a lumen and start to mature by recruiting new vascular mural cells and make the new vessel ready for perfusion once the tip-cell has found and anastomosed with a second existing or new vessel and thereby established a circulation loop (60, 61). Each of these steps is regulated by various angiogenic or vascular maturation factors. For example, basement membrane degradation is achieved by production and secretion of matrix metallo-proteinases (62), whereas VEGF and Dll4/Notch signalling are important for regulating organized sprouting (63–65). Patterning factors such as netrins and plexins are important for the guidance of the growing vessels (66, 67) and PDGF-B is considered a major factor involved in vessel maturation and stabilization by recruiting new mural cells to the endothelium (68). There are however many other angiogenic and vascular maturation factors that are important [see Cao et al. (24) for a recent excellent review on this subject].”

“The role of the circadian clock in human tumor angiogenesis”

“Disruption of circadian rhythms during cancer treatment is clinically relevant. Approximately 50% of colorectal cancer patients, for instance, experience disruption of circadian rhythms during chemotherapy treatment. Patients with disrupted circadian rhythms as measured by actigraphs (wristwatch-style motion detectors) had significantly shorter survival times than those with normal circadian rhythms (87). Fatigue and weight loss were also higher in patients with disrupted circadian rhythms. In another study, colorectal cancer patients receiving chemotherapy who had good performance status and normal circadian rhythms had better survival and response to treatment, as well as less fatigue and better quality of life (88). Lifestyle adaptations may help patients to entrain circadian rhythms of sleep and food intake to normal 24-h cycles; these include timing and composition of meals; regulation of consumption of herbal sedatives and stimulants and alcohol; timing of exercise and morning exposure to sunlight; and mind-body programs that diminish sleep-disturbing stress, as well as therapies like cognitive-behavioral treatment for insomnia that promote sleep (89, 90).

From a molecular point of view, and in agreement with the findings from pre-clinical models, CLOCK was reported to be significantly up-regulated and Per2 was down-regulated in human colorectal cancer tumors compared to adjacent healthy tissue and the levels of CLOCK from different patients strongly correlated with the level of VEGF detected in their tumor biopsies as well as degree of metastatic dissemination of tumor cells and poor prognosis (91, 92). In addition, other angiogenic factors have been found to oscillate in a circadian fashion, including bFGF, EGF and IGFBP in breast cancer patients, where peak plasma levels are generally found during the day and low levels in the night (93). Even in non-malignant disorders, VEGF levels have been found to oscillate in a similar manner as in cancer patients (94). As such, plasma VEGF levels in a patient with POEMS exhibited circadian oscillations with the highest levels found at night, resulting in night-time peripheral oedema, which subsided during the day, when VEGF levels had normalized (94). Interestingly, in the non-vascularized cornea, anti-angiogenic angiostatin is increasing during the dark-phase, in which the eye is closed and therefore particularly sensitive to hypoxia-induced angiogenesis (95). This may in such tissues be an intrinsic mechanism to prevent angiogenesis during the night.”