Exercise training improves radiotherapy efficiency in a murine model of prostate cancer.

Engaging in exercise while undergoing radiotherapy (RT) has been reported to be safe and achievable. The impact of exercise training (ET) on RT efficiency is however largely unknown. Our study aims to investigate the interactions between ET and RT on prostate cancer growth. Athymic mice received a subcutaneous injection of PPC-1 cells and were randomly assigned to either cancer control, cancer ET, cancer RT, or cancer RT combined with ET (CaRT-ET). Mice were sacrificed 24 days post-injection. All three intervention groups had reduced tumor size, the most important decrease being observed in CaRT-ET mice. Apoptotic marker cleaved caspase-3 was not modified by ET, but enhanced with RT. Importantly, this increase was the highest when the two strategies were combined. Furthermore, NK1.1 staining and gene expression of natural killer (NK) cell receptors Klrk1 and Il2rß were not affected by ET alone but were increased with RT, this effect being potentiated when combined with ET. Overall, our study shows that (a) ET enhances RT efficiency by potentiating NK cell infiltration, and (b) while ET alone and ET combined with RT both reduce tumor growth, the mechanisms mediating these effects are different.

Interleukin-6, C/EBP-ß and PPAR-γ expression correlates with intramuscular liposarcoma growth in mice: The impact of voluntary physical activity levels.

IL-6 is an axial cytokine overexpressed in cancer to promote growth and increase resistance to anti-cancer therapies. As the application of IL-6-targeting therapies are still limited, alternative non-aggressive and adjuvant approaches, like physical activity (PA) could be useful to reverse IL-6 effects. To get more insights into liposarcoma (LS) pathophysiology, we investigated potential molecular links between IL-6 and LS growth and we tested the impact of PA on such mechanism in an orthotopic model of intramuscular LS. Initially active nude mice have received an intramuscular injection of either human SW872 cells or vehicle, then were respectively randomized into voluntary-active or inactive mice with open or restricted access to activity-wheels. We found that LS-bearing mice exhibited ∼6 fold increase in circulating IL-6 comparing to controls, with a concomitant decrease in hepatic drug-metabolizing enzymes expression. Circulating IL-6 levels were positively correlated with intra-tumor IL-6 expression (r = 0.85, P < 0.01). Interestingly, intra-tumor IL-6, C/EBP-α/ß and PPAR-γ expression were correlated together and with greater tumor mass and autophagy markers, notably, GABARAPL-1. Intriguingly, we found that maintaining a spontaneous PA after tumor injection did not reduce the levels of IL-6, but even enhanced tumor growth, induced body weight loss and increased the risk of developing lung metastasis. Our findings suggest that (1) IL-6, C/EBP-ß and PPAR-γ exert a potential role in promoting growth of dedifferentiated LS and (2) that PA failed to mechanistically interfere with these factors, but enhanced LS growth via other independent-mechanisms. The preclinical data reported here could be helpful in the sub-molecular classification of LS patients to improve diagnosis and design a low-risk treatment. Circulating IL-6 could serve as an indicator for treatment follow-up and, perhaps, for infra-radiologic LS relapses.

Combined effects of exercise and immuno-chemotherapy treatments on tumor growth in MC38 colorectal cancer-bearing mice.

Acute exercise induces transient modifications in the tumor microenvironment and has been linked to reduced tumor growth along with increased infiltration of immune cells within the tumor in mouse models. In this study, we aimed to evaluate the impact of acute exercise before treatment administration on tumor growth in a mice model of MC38 colorectal cancer receiving an immune checkpoint inhibitor (ICI) and chemotherapy. Six-week-old mice injected with colorectal cancer cells (MC38) were randomized in 4 groups: control (CTRL), immuno-chemotherapy (TRT), exercise (EXE) and combined intervention (TRT/EXE). Both TRT and TRT-EXE received ICI: anti-PD1-1 (1 injection/week) and capecitabine + oxaliplatin (5 times a week) for 1 week (experimentation 1), 3 weeks (experimentation 2). TRT-EXE and EXE groups were submitted to 50 minutes of treadmill exercise before each treatment administration. Over the protocol duration, tumor size has been monitored daily. Tumor growth and microenvironment parameters were measured after the intervention on Day 7 (D7) and Day 16 (D16). From day 4 to day 7, tumor volumes decreased in the EXE/TRT group while remaining stable in the TRT group (p=0.0213). From day 7 until day 16 tumor volume decreased with no significant difference between TRT and TRT/EXE. At D7 the TRT/EXE group exhibited a higher total infiltrate T cell (p=0.0118) and CD8+ cytotoxic T cell (p=0.0031). At D16, tumor marker of apoptosis, vascular integrity and inflammation were not significantly different between TRT and TRT/EXE. Our main result was that acute exercise before immuno-chemotherapy administration significantly decreased early-phase tumor growth (D0 to D4). Additionally, exercise led to immune cell infiltration changes during the first week after exercise, while no significant molecular alterations in the tumor were observed 3 weeks after exercise.

Sphingolipids and response to chemotherapy.

Chemotherapy is frequently used to treat primary or metastatic cancers, but intrinsic or acquired drug resistance limits its efficiency. Sphingolipids are important regulators of various cellular processes including proliferation, apoptosis, differentiation, angiogenesis, stress, and inflammatory responses which are linked to various aspects of cancer, like tumor growth, neoangiogenesis, and response to chemotherapy. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative and proapoptotic functions, whereas sphingosine-1-phosphate and other derivatives have opposing effects. Among the variety of enzymes that control ceramide generation, acid or neutral sphingomyelinases and ceramide synthases are important targets to allow killing of cancer cells by chemotherapeutic drugs. On the contrary, glucosylceramide synthase, ceramidase, and sphingosine kinase are other targets driving cancer cell resistance to chemotherapy. This chapter focuses on ceramide-based mechanisms leading to cancer therapy sensitization or resistance which could have some impacts on the development of novel cancer therapeutic strategies.

Effects of Active Video Games in Patients With Cancer: Systematic Review.

BACKGROUND: Physical activity (PA) is now considered an adjuvant therapy in cancer treatment; nevertheless, multiple barriers could reduce PA engagement during treatment. Active video games (AVGs) lead to the achievement of mild- to moderate-intensity PA and represent a promising tool for regular movement and exercise. OBJECTIVE: This paper aims to review the current literature and provide updated content on the physiological and psychological effects of AVG-based interventions in patients with cancer undergoing treatment. METHODS: Four electronic databases were investigated. Studies reporting on AVG interventions delivered to patients undergoing treatment were included. A total of 21 articles (17 interventions) were identified for data extraction and quality assessment. RESULTS: A total of 362 patients with cancer participated in the studies (number of participants 3-70). The majority underwent treatment for breast, lung, prostate, hematologic, or oral or laryngeal cancer. The types and stages of cancer varied in all studies. Participants ranged in age from 3 to 93 years. Four studies included patients with pediatric cancer. The duration of interventions ranged from 2 to 16 weeks, with a minimum of 2 sessions per week and a maximum of 1 daily session. Sessions were supervised in 10 studies, and 7 included home-based interventions. AVG interventions improved endurance, quality of life, cancer-related fatigue, and self-efficacy. Effects were mixed on strength, physical function, and depression. AVGs did not affect activity level, body composition, or anxiety. Compared with standard physiotherapy, physiological effects were lower or similar, and psychological effects were higher or similar. CONCLUSIONS: Overall, our results suggest that AVGs can be recommended to patients undergoing cancer treatment, given the physiological and psychological benefits. When AVGs are proposed, supervision of the sessions should be considered as it can limit dropouts. In the future, it is important to develop AVGs that combine endurance and muscle strengthening, with the possibility of achieving moderate to high exercise intensity, depending on the physical abilities of the patients, as indicated in the World Health Organization's recommendations.

A pharmacological strategy to recapitulate exercise-induced antitumoral immunity.

The antitumor activity of exercise by means of enhanced immune activation is documented, but better identification of the underlying mechanisms is required to develop new therapeutic strategies. Recent work from the Dr Bar-Sagi group reveals that exercise engages IL-15 signaling and pharmacological activation of the IL-15/IL-15R axis mimics the exercise-driven immune cell-mediated cytotoxicity in pancreatic cancer.

Modulating Tumour Hypoxia in Prostate Cancer Through Exercise: The Impact of Redox Signalling on Radiosensitivity.

Prostate cancer is a complex disease affecting millions of men globally. Radiotherapy (RT) is a common treatment modality although treatment efficacy is dependent upon several features within the tumour microenvironment (TME), especially hypoxia. A hypoxic TME heightens radioresistance and thus disease recurrence and treatment failure continues to pose important challenges. However, the TME evolves under the influence of factors in systemic circulation and cellular crosstalk, underscoring its potential to be acutely and therapeutically modified. Early preclinical evidence suggests exercise may affect tumour growth and some of the benefits drawn, could act to radiosensitise tumours to treatment. Intracellular perturbations in skeletal muscle reactive oxygen species (ROS) stimulate the production of numerous factors that can exert autocrine, paracrine, and endocrine effects on the prostate. However, findings supporting this notion are limited and the associated mechanisms are poorly understood. In light of this preclinical evidence, we propose systemic changes in redox signalling with exercise activate redox-sensitive factors within the TME and improve tumour hypoxia and treatment outcomes, when combined with RT. To this end, we suggest a connection between exercise, ROS and tumour growth kinetics, highlighting the potential of exercise to sensitise tumour cells to RT, and improve treatment efficacy.

Exercise training as a modulator of epigenetic events in prostate tumors.

BACKGROUND: Exercise is increasingly recognized as an effective strategy to improve cancer prevention and prognosis. Several biological mechanisms mediating these benefits have been proposed, but the role of epigenetics remains largely unknown. Since epigenetics is highly susceptible to lifestyle factors, we hypothesized that exercise could affect the epigenome landscape in cancer tissues. METHODS: Rats implanted with AT1 prostate tumors were randomized to either control or exercise training. microRNA expression, DNA methylation and histone acetylation were analyzed in the tumor tissue. RESULTS: MiR-27a-5p appeared to be differently expressed between sedentary and trained rats. Furthermore, exercise increased global DNA methylation and decreased DNA methyltransferases mRNA expression in the tumor tissue. Histone acetylation however remained unaltered. CONCLUSION: Overall, exercise might reverse some of the cancer-related epigenetic alterations in the prostate tumor tissue.

Oxidative and glycolytic skeletal muscles deploy protective mechanisms to avoid atrophy under pathophysiological iron overload.

BACKGROUND: Iron excess has been proposed as an essential factor in skeletal muscle wasting. Studies have reported correlations between muscle iron accumulation and atrophy, either through ageing or by using experimental models of secondary iron overload. However, iron treatments performed in most of these studies induced an extra-pathophysiological iron overload, more representative of intoxication or poisoning. The main objective of this study was to determine the impact of iron excess closer to pathophysiological conditions on structural and metabolic adaptations (i) in differentiated myotubes and (ii) in skeletal muscle exhibiting oxidative (i.e. the soleus) or glycolytic (i.e. the gastrocnemius) metabolic phenotypes. METHODS: The impact of iron excess was assessed in both in vitro and in vivo models. Murine differentiated myotubes were exposed to ferric ammonium citrate (FAC) (i.e. 10 and 50 µM) for the in vitro component. The in vivo model was achieved by a single iron dextran subcutaneous injection (1 g/kg) in mice. Four months after the injection, soleus and gastrocnemius muscles were harvested for analysis. RESULTS: In vitro, iron exposure caused dose-dependent increases of iron storage protein ferritin (P < 0.01) and dose-dependent decreases of mRNA TfR1 levels (P < 0.001), which support cellular adaptations to iron excess. Extra-physiological iron treatment (50 µM FAC) promoted myotube atrophy (P = 0.018), whereas myotube size remained unchanged under pathophysiological treatment (10 µM FAC). FAC treatments, whatever the doses tested, did not affect the expression of proteolytic markers (i.e. NF-κB, MurF1, and ubiquitinated proteins). In vivo, basal iron content and mRNA TfR1 levels were significantly higher in the soleus compared with the gastrocnemius (+130% and +127%; P < 0.001, respectively), supporting higher iron needs in oxidative skeletal muscle. Iron supplementation induced muscle iron accumulation in the soleus and gastrocnemius muscles (+79%, P < 0.001 and +34%, P = 0.002, respectively), but ferritin protein expression only increased in the gastrocnemius (+36%, P = 0.06). Despite iron accumulation, muscle weight, fibre diameter, and myosin heavy chain distribution remained unchanged in either skeletal muscle. CONCLUSIONS: Together, these data support that under pathophysiological conditions, skeletal muscle can protect itself from the related deleterious effects of excess iron.

Effects of exercise training combined with insulin treatment on cardiac NOS1 signaling pathways in type 1 diabetic rats.

This study examined the effects of a dual treatment combining insulin treatment and exercise training on basal cardiac function and signaling pathways involving ß3-AR, NOS1, and RyR2 in type 1 diabetic rats. Male Wistar rats were assigned into a diabetic group receiving no treatment (D), an insulin-treated diabetic (Ins), a trained diabetic (TD), and a trained insulin-treated diabetic (TIns) group. Control group (C) was included in order to confirm the deleterious effects of diabetes. Insulin treatment and/or treadmill exercise training were conducted for 8 weeks. Basal cardiac function was evaluated by Langendorff technique. Cardiac protein expression of ß3-AR, NOS1, and RyR2 was assessed using Western blots. Diabetes induced a decrease of both basal diastolic and systolic (±dP/dt) cardiac function (P < 0.05). Moreover, diabetes was associated with an increase of ß3-AR and NOS1 and a decrease of RyR2 expression (P < 0.05). Although combined treatment was not able to normalize -dP/dt, it succeeded to normalize +dP/dt of diabetic rats. Combined treatment led to an overexpression of RyR2. Effects of this combined treatment on +dP/dt and RyR2 were greater than the effects of insulin and exercise training, applied solely. Treatments, applied solely or in combination, resulted in a complete normalization of ß3-AR and in a down-regulation of NOS1 because this protein expression in all treated diabetic rats became lower than control values (P < 0.01). Our study shows that unlike single treatments, dual treatment combining insulin treatment and exercise training was able to normalize basal systolic function of diabetic rats by a specific regulation of ß3-AR-NOS1-RyR2 signaling pathways.

Chronic Fatigue in Cancer, Brain Connectivity and Reluctance to Engage in Physical Activity: A Mini-Review.

A large amount of evidence shows that after a cancer diagnosis, patients significantly reduce their level of physical activity. Usually, this reduction is attributed to cancer-related fatigue. However, to our knowledge, no study has clearly demonstrated that fatigue alters effort-based decision-making in cancer. This mini-review aimed to provide evidence that chronic fatigue in cancer patients causes changes in brain connectivity that impact effort-based decision-making. Indeed, three patterns of activation to compensate for dysfunctional networks have been reported: greater variability in the executive network and hyperactivation in the executive network, which account for less efficient and costly processes in the frontal cortex, and reduced deactivation in the default mode network. Nevertheless, these activation patterns are also observed with other factors, such as anticipatory stressors (worry, rumination or sleep loss), that might also cause reluctance to engage in physical activity. Effort-based decision-making involving weighing costs against benefits and physical activity interventions should increase immediate benefits to facilitate engagement in effortful activities.

Voluntary Wheel Running Does Not Enhance Radiotherapy Efficiency in a Preclinical Model of Prostate Cancer: The Importance of Physical Activity Modalities?

Physical activity is increasingly recognized as a strategy able to improve cancer patient outcome, and its potential to enhance treatment response is promising, despite being unclear. In our study we used a preclinical model of prostate cancer to investigate whether voluntary wheel running (VWR) could improve tumor perfusion and enhance radiotherapy (RT) efficiency. Nude athymic mice were injected with PC-3 cancer cells and either remained inactive or were housed with running wheels. Apparent microbubble transport was enhanced with VWR, which we hypothesized could improve the RT response. When repeating the experiments and adding RT, however, we observed that VWR did not influence RT efficiency. These findings contrasted with previous results and prompted us to evaluate if the lack of effects observed on tumor growth could be attributable to the physical activity modality used. Using PC-3 and PPC-1 xenografts, we randomized mice to either inactive controls, VWR, or treadmill running (TR). In both models, TR (but not VWR) slowed down tumor growth, suggesting that the anti-cancer effects of physical activity are dependent on its modalities. Providing a better understanding of which activity type should be recommended to cancer patients thus appears essential to improve treatment outcomes.

Exercise shapes redox signaling in cancer.

In this paper of the special issue dedicated for the Olympics 2020, we put the light on an exciting facet of exercise-oncology, which may still be unknown to some audience. Accumulating convincing evidences show that exercise reduces cancer progression and recurrence mainly in colon and breast cancer patients. Interestingly, the positive effects of exercise on cancer outcomes were mainly observed when patients practiced vigorous exercise of 6 METs or more. At the molecular level, experimental studies highlighted that regular vigorous exercise could reduce tumor growth by driving changes in immune system, metabolism, hormones, systemic inflammation, angiogenesis and redox status. In the present review, we describe the main redox-sensitive mechanisms mediated by exercise. These redox mechanisms are of particular therapeutic interest as they may explain the emerging preclinical findings proving that the association of vigorous exercise with chemotherapy or radiotherapy improves the anti-cancer responses of both interventions. Clinical and preclinical studies converge to support the practice of exercise as an adjuvant therapy that improves cancer outcomes. The understanding of the underpinning molecular mechanisms of exercise in cancer can open new avenues to improve cancer care in patients.

Localization of Fas/CD95 into the lipid rafts on down-modulation of the phosphatidylinositol 3-kinase signaling pathway.

Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is known to protect tumor cells from apoptosis and more specifically from the Fas-mediated apoptotic signal. The antitumoral agent edelfosine sensitizes leukemic cells to death by inducing the redistribution of the apoptotic receptor Fas into plasma membrane subdomains called lipid rafts. Herein, we show that inhibition of the PI3K signal by edelfosine triggers a Fas-mediated apoptotic signal independently of the Fas/FasL interaction. Furthermore, similarly to edelfosine, blockade of the PI3K activity, using specific inhibitors LY294002 and wortmannin, leads to the clustering of Fas whose supramolecular complex is colocalized within the lipid rafts. These findings indicate that the antitumoral agent edelfosine down-modulates the PI3K signal to sensitize tumor cells to death through the redistribution of Fas into large platform of membrane rafts.

Ethanol induces oxidative stress in primary rat hepatocytes through the early involvement of lipid raft clustering.

UNLABELLED: The role of the hepatocyte plasma membrane structure in the development of oxidative stress during alcoholic liver diseases is not yet fully understood. Previously, we have established the pivotal role of membrane fluidity in ethanol-induced oxidative stress, but no study has so far tested the involvement of lipid rafts. In this study, methyl-beta-cyclodextrin or cholesterol oxidase, which were found to disrupt lipid rafts in hepatocytes, inhibited both reactive oxygen species production and lipid peroxidation, and this suggested a role for these microstructures in oxidative stress. By immunostaining of lipid raft components, a raft clustering was detected in ethanol-treated hepatocytes. In addition, we found that rafts were modified by formation of malondialdehyde adducts and disulfide bridges. Interestingly, pretreatment of cells by 4-methyl-pyrazole (to inhibit ethanol metabolism) and various antioxidants prevented the ethanol-induced raft aggregation. In addition, treatment of hepatocytes by a stabilizing agent (ursodeoxycholic acid) or a fluidizing compound [2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate] led to inhibition or enhancement of raft clustering, respectively, which pointed to a relationship between membrane fluidity and lipid rafts during ethanol-induced oxidative stress. We finally investigated the involvement of phospholipase C in raft-induced oxidative stress upon ethanol exposure. Phospholipase C was shown to be translocated into rafts and to participate in oxidative stress by controlling hepatocyte iron content. CONCLUSION: Membrane structure, depicted as membrane fluidity and lipid rafts, plays a key role in ethanol-induced oxidative stress of the liver, and its modulation may be of therapeutic relevance.

TRAIL induces receptor-interacting protein 1-dependent and caspase-dependent necrosis-like cell death under acidic extracellular conditions.

Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent that induces apoptosis in cancer cells but not in most normal cells. How tumor physiology, particularly acidic extracellular pH (pH(e)), would modify sensitivity of cancer cells to TRAIL-induced cell death is not known. We have previously shown that cancer cells, resistant to TRAIL-induced apoptosis at physiologic pH(e) (7.4), could be sensitized to TRAIL at acidic pH(e) (6.5). However, at this acidic pH(e), cell death was necrotic. We show here that, in spite of a necrosis-like cell death morphology, caspases are activated and are necessary for TRAIL-induced cell death at acidic pH(e) in HT29 human colon cancer cells. Furthermore, we observed that, whereas receptor-interacting protein (RIP) was cleaved following TRAIL treatment at physiologic pH(e) (7.4), it was not cleaved following TRAIL treatment at acidic pH(e) (6.5). Moreover, RIP degradation by geldanamycin or decrease expression of RIP by small RNA interference transfection inhibited TRAIL-induced necrosis at acidic pH(e), showing that RIP was necessary for this necrotic cell death pathway. We also show that RIP kinase activity was essential for this cell death pathway. Altogether, we show that, under acidic pH(e) conditions, TRAIL induces a necrosis-like cell death pathway that depends both on caspases and RIP kinase activity. Thus, our data suggest for the first time that RIP-dependent necrosis might be a major death pathway in TRAIL-based therapy in solid tumors with acidic pH(e).

Cisplatin-induced apoptosis involves membrane fluidification via inhibition of NHE1 in human colon cancer cells.

We have previously shown that cisplatin triggers an early acid sphingomyelinase (aSMase)-dependent ceramide generation concomitantly with an increase in membrane fluidity and induces apoptosis in HT29 cells. The present study further explores the role and origin of membrane fluidification in cisplatin-induced apoptosis. The rapid increase in membrane fluidity following cisplatin treatment was inhibited by membrane-stabilizing agents such as cholesterol or monosialoganglioside-1. In HT29 cells, these compounds prevented the early aggregation of Fas death receptor and of membrane lipid rafts on cell surface and significantly inhibited cisplatin-induced apoptosis without altering drug intracellular uptake or cisplatin DNA adducts formation. Early after cisplatin treatment, Na+/H+ membrane exchanger-1 (NHE1) was inhibited leading to intracellular acidification, aSMase was activated, and ceramide was detected at the cell membrane. Treatment of HT29 cells with Staphylococcus aureus sphingomyelinase increased membrane fluidity. Moreover, pretreatment with cariporide, a specific inhibitor of NHE1, inhibited cisplatin-induced intracellular acidification, aSMase activation, ceramide membrane generation, membrane fluidification, and apoptosis. Finally, NHE1-expressing PS120 cells were more sensitive to cisplatin than NHE1-deficient PS120 cells. Altogether, these findings suggest that the apoptotic pathway triggered by cisplatin involves a very early NHE1-dependent intracellular acidification leading to aSMase activation and increase in membrane fluidity. These events are independent of cisplatin-induced DNA adducts formation. The membrane exchanger NHE1 may be another potential target of cisplatin, increasing cell sensitivity to this compound.

Cisplatin cytotoxicity: DNA and plasma membrane targets.

Most current anticancer therapies induce tumor cell death through apoptosis where its specific involved pathways are poorly understood. For example, for many DNA-damaging agents, the specific biochemical lesions (DNA adducts) are associated with the induction of apoptosis via the mitochondria death pathway. However, several of these DNA-damaging agents like cisplatin induce apoptosis through plasma membrane disruption, triggering the Fas death receptor pathway. In this review, we focus on the role of early plasma membrane events in cisplatin-induced apoptosis. Special attention is given to changes in plasma membrane fluidity, inhibition of NHE1 exchanger, activation of acid sphingomyelinase and their consequences on the Fas death pathway in response to cisplatin.

A Review of Physical Activity and Circulating miRNA Expression: Implications in Cancer Risk and Progression.

The role of circulating miRNAs (c-miRNAs) in carcinogenesis has garnered considerable scientific interest. miRNAs may contribute actively to cancer development and progression, making them potential targets for cancer prevention and therapy. Lifestyle factors such as physical activity (PA) have been shown to alter c-miRNA expression, but the subsequent impact on cancer risk and prognosis is unknown. To provide a better understanding of how PA reduces the risk of cancer incidence and improves patient outcomes, we conducted a review of the impact of PA on c-miRNA expression, which includes a comprehensive synthesis of studies examining the impacts of acute and chronic exercise on expression of c-miRNAs. While the variability in methods used to assess miRNA expression creates challenges in comparing and/or synthesizing the literature, results to date suggest that the circulating form of several miRNAs known for playing a role in cancer (c-miR-133, c-miR-221/222, c-miR-126, and c-let-7) are altered by both acute and chronic PA. Additional research should develop standardized procedures for assessing both c-miRNA and PA measurement to improve the comparability of research results regarding the direction and amplitude of changes in c-miRNAs in response to PA. Cancer Epidemiol Biomarkers Prev; 27(1); 11-24. ©2017 AACR.

The Practice of Physical Activity in the Setting of Lower-Extremities Sarcomas: A First Step toward Clinical Optimization.

Lower-extremities sarcoma patients, with bone tumor and soft-tissue sarcoma, are a unique population at high risk of physical dysfunction and chronic heart diseases. Thus, providing an adequate physical activity (PA) program constitutes a primary part of the adjuvant treatment, aiming to improve patients' quality of life. The main goal of this paper is to offer clear suggestions for clinicians regarding PA around the time between diagnosis and offered treatments. These preliminary recommendations reflect our interpretation of the clinical and preclinical data published on this topic, after a systematic search on the PubMed database. Accordingly, patients could be advised to (1) start sessions of supportive rehabilitation and low-intensity PA after surgery and (2) increase PA intensities progressively during home stay. The usefulness of PA during the preoperative period remains largely unknown but emerging preclinical data on mice bearing intramuscular sarcoma are most likely discouraging. However, efforts are still needed to in-depth elucidate the impact of PA before surgery completion. PA should be age-, sex-, and treatment-adapted, as young/adolescent, women and patients receiving platinum-based chemotherapy are more susceptible to physical quality deterioration. Concerning PA intensity, the practice of moderate-intensity resistance and endurance exercises (30-60 min/day) are safe after surgery, even when receiving adjuvant chemo/radiotherapy. The general PA recommendations for cancer patients, 150 min/week of combined moderate-intensity endurance/resistance exercises, could be feasible after 18-24 months of rehabilitation. We believe that these suggestions will help clinicians to design a low-risk and useful PA program.