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Exercise And The Hallmarks Of Cancer Pdf

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James E.

Sign up to an individual subscription to the Oxford Textbook of Oncology. Eight chapters have had content updated to include the latest information on evidence, research, recommendations, and treatment, and the terminology and references have been amended where relevant. Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct.

Exercise attenuates the major hallmarks of aging.

Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients.

The etiology of the effects of exercise on tumor progression are unclear, as are the cellular actors involved. Exercise affects almost all tissues in the body, and scientists have found that being physically active can reduce the risk of several types of cancer as well as improving outcomes for cancer patients.

However, it is still unknown how exercise exerts its protective effects. One of the hallmarks of cancer is the ability of cancer cells to evade detection by the immune system, which can in some cases stop the body from eliminating tumor cells. Rundqvist et al. Additionally, Rundqvist et al. Next, immune cells from mice that had exercised frequently were transferred into mice that had not exercised, where they were more effective against tumor cells than the immune cells from untrained mice.

The ability of T cells to identify and eliminate cancer cells is essential to avoid tumor growth, and is one of the foundations of current immune therapy treatments.

Exercise could improve the outcome of these treatments by increasing the activation of the immune system, making tumor-fighting cells more effective. In humans, exercising cohorts have lower rates of cancer incidence Moore et al.

The mechanisms underlying these observations have remained elusive, although recent work has indicated a relationship between immune response and exercise-induced changes in malignant progression Pedersen et al. The metabolic demands of strenuous physical exertion generally induce significant changes in nutrient utilization, principally via central carbon metabolism Brooks, These exercise-induced alterations in metabolism change the ratios of energy substrates utilized, and can shift intramuscular metabolite profiles.

These shifts are reflected in systemic metabolite availability, which in turn modifies energy production throughout the body Henderson et al. It is clear that cytotoxic T cells play a crucial role in controlling tumor growth. By recognizing mutation-derived neoantigens, T cells can identify and eliminate malignant cells in a process known as immunosurveillance Dunn et al.

Escape from immune control is a critical step toward progressive malignant growth in many cancers, and tumors achieve this in a number of ways, amongst them the dampening of antitumor T cell responses Dunn et al. The activity of immune cells is tightly linked with their metabolism O'Neill et al.

Many aspects of immune cell energetics are likely sensitive to the metabolic changes induced by exercise Henderson et al. Exercise is known to affect immune cell function, and an altered immune response has been suggested as a mechanism underlying effects of exercise on cancer risk and progression Christensen et al.

To address this, we undertook studies of exercise-induced changes in tumor progression, and asked what metabolites are released in response to exercise; as well as whether metabolites produced by exercise can alter cytotoxic T-cell function. We found that exercise itself can modify cytotoxic T-cell metabolism, and that exercise-induced effects on tumor growth are dependent on cytotoxic T-cell activity.

To address the role of immunity on the effects of exercise in neoplasia, we first assessed how repeated voluntary exertion influenced tumor progression in mice, using a genetic model of mammary cancer induced by the MMTV-PyMT transgene on the FVB inbred strain background Figure 1—figure supplement 1A.

FVB inbred mice are enthusiastic runners relative to most other inbred strains Avila et al. Contrary to what was previously shown Goh et al. This indicates that exercise in this tumor model modulates the infiltration of cytotoxic lymphocytes.

Given that infiltration of cytotoxic T cells is linked to a favorable prognosis in many human neoplasms and in some animal tumor models Savas et al. In this cell-line-driven model, allowing animals to exercise significantly reduced tumor growth and increased survival times Figure 1B relative to animals not given access to an exercise wheel.

B Mean tumor volume and SEM over time left and survival right. C—E Flow cytometry determined frequency of lymphocytic populations within I3TC tumor, spleen and lymph nodes LN at day 55 after inoculation. To determine whether immune cell populations were also affected by exercise in the subcutaneous I3TC tumor model, we carried out flow cytometric analyses of single-cell suspensions of inoculated tumors, spleens, and tumor-draining lymph nodes of running versus non-running animals.

This depletion study demonstrates a clear role for cytotoxic T-cells in the suppression of tumor growth by exercise in this model. Acute exercise induces changes in several known metabolic mediators of immune responses Henderson et al. To investigate how the systemic availability of metabolites can change in response to exercise, we undertook a metabolomic investigation of muscle and plasma in response to exercise.

After habituation, an exhaustive endurance test was performed on wild-type mice on the FVB background, and following exercise, skeletal muscle and plasma were harvested immediately, snap frozen and analyzed by mass spectrometry GC-MS Figure 2—figure supplement 1A-C. This is in line with mitochondrial metabolism being rate-limiting in high-intensity exertion Brooks, Interestingly, the TCA metabolites citric acid, malic acid and alpha ketoglutaric acid aKG were all higher in plasma after exertion Figure 2—figure supplement 1C , suggesting release of these metabolites from muscle into plasma Figure 2—figure supplement 1D.

Contribution of muscle citrate to plasma has previously been shown; for example, by femoral arterio-venous sampling during exercise in human subjects Nielsen and Thomsen, ; Schranner et al. To extend the information to include the lymphoid organs, an additional set of exhaustive endurance tests was performed on mice followed by immediate harvest of skeletal muscle, plasma, spleen, and muscle draining axillary and non-draining inguinal lymph nodes.

In addition, human plasma was harvested before pre-exercise , directly after post-exercise and 1 hr 1 hr post after an intense endurance exercise session in sedentary individuals Figure 2—figure supplement 1E. As well as altering the intramuscular Figure 2B and circulating levels of the TCA metabolites Figure 2C and D , acute exercise in these experiments also introduced shifts in the metabolic profiles of lymphoid organs, supporting the notion that acute exercise alters the metabolic environment of lymphoid organs Figure 2E—G.

Notably, the number of significantly increased metabolites was markedly higher in the muscle draining lymph nodes when compared to non-draining lymph nodes Figure 2F and G , respectively.

This indicates that changes seen in draining lymph nodes are likely attributable to muscle metabolite production. Interestingly, plasma, draining lymph nodes, and non-draining lymph nodes all showed higher levels of corticosterone after exercise Figure 2H.

Changes in amino acid and fatty acid levels were also identified in multiple organs Figure 2—figure supplement 1H. Muscle, plasma, spleen, muscle draining, and non-draining lymph nodes were collected from exercising and control mice immediately after the exercise. Samples were analyzed on the Precision Metabolomics mass spectrometry platform. Data is provided as Figure 2—source data 1. B—G Volcano plots of differentially induced metabolites per mouse tissue and human plasma.

TCA metabolites are colored blue. Glycolytic metabolites are colored orange. H Heatmap of exercise-induced changes in metabolite concentrations in human and mouse plasma and tissues. However, the single most profound metabolic change induced by exertion is the transient increase in circulating lactate. Circulating lactate levels rise very rapidly during exercise, and can in response to high intensity exertion increase up to fold in skeletal muscle Bonen et al.

The rapid postmortem accumulation of systemic lactate in response to global oxygen deprivation made us unable to differentiate the lactate levels in murine organ samples Donaldson and Lamont, ; Keltanen et al. An increase in lactate as well as TCA cycle metabolites was however seen in human plasma post-exercise Figure 2D and when measuring lactate in blood from the tail vein in live animals directly after an acute treadmill exercise Figure 2—figure supplement 1G.

In the human samples, these returned to close to resting levels 1 hr after exercise Figure 2—figure supplement 1F , indicating that the changes in central carbon availability are likely conserved between mice and humans. Given that metabolism and T-cell differentiation are tightly linked O'Neill et al. Reference human resting serum levels are provided in Figure 3—figure supplement 1A.

For this reason, lactate produced during exercise does not significantly alter circulating plasma pH levels unlike the acidification seen in, for example, solid tumors Brand et al. We therefore, adjusted pH to 7. TCA metabolites can be transported across the plasma membrane with sodium carboxylate cotransporters Markovich, Although none of the metabolites provided proliferative advantages after 3 days of activation, malate, succinate, and aKG were notably well tolerated by the T-cells at high doses Figure 3A , Figure 3—figure supplement 1B-C.

C Granzyme B median fluorescence intensity MFI at day 3 of culture with increasing concentrations of central carbon metabolites. Loss of CD62L surface expression is induced in response to TCR activation and instrumental for the migratory capacity of cells localized in secondary lymphoid organs. Based on the data from the metabolite screen, TCA metabolites appear to enhance the loss of CD62L in response to activation. The effect of sodium L-lactate could be detected starting at concentrations of approximately 6 mM.

The [U- 13 C 6 ]glucose was introduced after warm up on a treadmill for 10 min at low speed, so as to ensure maximal glucose uptake by the skeletal muscle at the time of injection. The spleens were harvested at 20 min post-exercise and at the equivalent time point in the resting animals.

On day 2 and 3 after vaccination, 10 mg of [U- 13 C 6 ]glucose was introduced to the mice prior to a treadmill exercise. Data is provided as Figure 4—source data 1.

Following the transfer of T-cells to non-exercising mice, tumor growth was monitored for 40 days. Blood profiles on day 10 following transfer confirmed the expansion of the OT-1 population in the recipient mice, and also showed a significant increase in expression of iCOS in the cells transferred from exercising donors Figure 5C and D.

The sedentary recipient animals that received T-cells from exercising donors showed an enhanced survival and reduced rate of tumor growth, when compared to sedentary animals receiving T-cells from sedentary donors Figure 5E—G. Peripheral blood was sampled 10 days after adoptive transfer and tumor volume monitored. B Flow cytometry analysis of OT-I T cell expansion in peripheral blood 10 days after adoptive transfer.

Adoptive cells were distinguished from endogenous immune cells by expression of the CD Therefore, we performed daily infusions of sodium L-lactate into tumor-bearing animals at doses that result in plasma lactate levels similar to those seen during intensive exercise approximately 10—20 mM.

Following this dose, levels subside to 4 mM within 60 min; the expected time to reach baseline values from this magnitude of spike is approximately min post-injection Lezi et al. This dose was chosen as an approximation of the levels and persistence of rises in plasma lactate that occur following intense short-term periods of exercise.

Lower doses of lactate 0. The frequency of tumor-infiltrating NK cells was reduced. Daily sodium L-lactate injections were continued throughout the experiment. Graphs show tumor volume mean and SEM over time and survival.

B Flow cytometric characterization of I3TC tumor infiltrating immune cell populations. Injections were continued throughout the experiment. Here, we show that exercise requires cytotoxic T cells to affect tumor growth. Recent studies suggest that exercise reduces cancer recurrence and mortality, and the effect of exercise on tumorigenic progression has now been documented in a range of animal models Ruiz-Casado et al.

Previously proposed underlying mechanisms for the anti-neoplastic effects of exercise include effects on weight control and endocrine hormone levels, as well as altered tumor vascularization Betof et al. Exercise has been shown to reduce systemic inflammation Gleeson et al. There is evidence that these immune cells populations exhibit an effector phenotype Campbell et al. Exercise is a multimodal stimulus.

In a recent study, Hojman et al. However, in the mouse models employed here we found limited infiltration and no effect of exercise on the CD3- NK1. Immune cells patrol all corners of the body and can reside in niches with highly differential metabolic profiles.

Recent findings have provided evidence that these different environments can instruct effector functions of immune cells Buck et al. In the current study, we show how exercise modulates metabolic parameters significantly beyond local skeletal muscle.

Cytotoxic T-cells mediate exercise-induced reductions in tumor growth

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Cancer cells must rewire cellular metabolism to satisfy the demands of unbridled growth and proliferation. As such, most human cancers differ from normal counterpart tissues by a plethora of energetic and metabolic reprogramming. Oncogenic levels of MYC regulates almost every aspect of cellular metabolism, a recently revisited hallmark of cancer development.

Exercise and the Hallmarks of Cancer. Trends Cancer. Jun;3(6) doi: /drugtruthaustralia.org Epub Jun 3.

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

The scientific interest of exercise medicine for the treatment of cancer is ever expanding. These guidelines provide physicians and therapists with a comprehensive and detailed overview about the beneficial effects of exercise training and, more so, summarize the evidence on potential dose—response mechanisms, including pathways of exercise-induced stimuli to counteract tumour microenvironmental pathologies. However, the most optimal types and doses of exercise training across the cancer disease and treatment continuum are yet to be determined. Therefore, the purpose of this narrative review was to illustrate the current implications but also limitations of exercise training during the different stages of cancer therapy, as well as to discuss necessary future directions. As a second purpose, special attention will be given to the current role of exercise in the treatment of cancer in Germany.

The cancer process

The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors. The resource takes advantage of a curation effort aimed at embedding a large fraction of the gene products that are found altered in cancer cells into a network of causal protein relationships. Graph algorithms, in turn, allow to infer likely paths of causal interactions linking cancer associated genes to cancer phenotypes thus offering a rational framework for the design of strategies to revert disease phenotypes. The ability to sequence a whole genome in a day at a cost that compares favorably with traditional diagnostic approaches has contributed to assemble large collections of cancer genomes that are freely accessible in public repositories 1.

World population has been continuously increasing and progressively aging. Aging is characterized by a complex and intraindividual process associated with nine major cellular and molecular hallmarks, namely, genomic instability, telomere attrition, epigenetic alterations, a loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. This review exposes the positive antiaging impact of physical exercise at the cellular level, highlighting its specific role in attenuating the aging effects of each hallmark. Exercise should be seen as a polypill, which improves the health-related quality of life and functional capabilities while mitigating physiological changes and comorbidities associated with aging.