Exercise and colorectal cancer: prevention and molecular mechanisms

Exercise and physical activity have been shown to be strongly associated with a decreased incidence rate of various chronic diseases especially numerous human malignancies. A huge number of clinical trials and meta-analysis have demonstrated that exercise is significantly effective in lowering the risk of colorectal cancer. In addition, it is suggested as an effective therapeutic modality against this cancer type. Therefore, in this review, we will review comprehensibly the effects of exercise in preventing, treating, and alleviating the adverse effects of conventional therapeutic options in colorectal cancer. Moreover, the possible mechanisms underlying the positive effects of exercise and physical activity in colorectal cancer, including regulation of inflammation, apoptosis, growth factor axis, immunity, epigenetic, etc. will be also discussed. Exercise is an effective post-treatment management program in colorectal cancer survivals Exercise improves muscle strength, cardiorespiratory fitness, emotional distress, physical activity, fatigue, and sleep quality in colorectal patients undergoing chemotherapy Targeting and modulating insulin-like growth factor (IGF) system, inflammation, apoptosis, immunity, epigenetic, Leptin and Ghrelin, and signaling pathways are major underlying mechanisms for preventive effects of exercise in colorectal cancer Exercise is an effective post-treatment management program in colorectal cancer survivals Exercise improves muscle strength, cardiorespiratory fitness, emotional distress, physical activity, fatigue, and sleep quality in colorectal patients undergoing chemotherapy Targeting and modulating insulin-like growth factor (IGF) system, inflammation, apoptosis, immunity, epigenetic, Leptin and Ghrelin, and signaling pathways are major underlying mechanisms for preventive effects of exercise in colorectal cancer


Introduction
Colorectal cancer (CRC) is one the most frequently occurred cancer types among various populations. Its incidence rate is increasing every day, such that it is estimated that the number of CRC survival will grow to 2.5 million in 2035 [1,2]. There is a great variation in the incidence patterns of CRC among world regions. More importantly, in the past few decades, multiple factors as three important and well-studied underlying mechanisms for the initiation and development of CRC [6,7]. However, due to the high complexity of CRC development, the participation of various genetic and environmental factors and mechanistic pathways in this process, CRC etiology is still unknown and needs further studies [8,9].
There are various therapeutic strategies such ad surgery, chemotherapy, and radiotherapy for combating CRC [10]. However, their limitations such as severe side effects, tumor recurrence, and developing resistance, more importantly, the presence of metastatic disease at the time of diagnosis, result in urgent need for developing novel therapeutic modalities that effectively remove tumors and increase patient's survival and prognosis [10]. In recent years, an accumulating number of studies have focused on the preventive and therapeutic effects of exercise and physical training, as one of the major lifestyle factors in numerous human malignancies [11]. Completed clinical trials and meta-analysis have reported that physical activity and exercise are significantly effective in lowering the risk of various human malignancies such as breast, proximal and distal colon, gastroesophageal, endometrial, ovarian, prostate, renal, pancreatic, and lung cancer [12,13]. In addition to preventive effects, physical activity also has been reported to be an effective therapeutic modality against colorectal cancer (Table 1). This review tries to have a comprehensive and up-to-date overview of the exercise and physical training as a preventive and thematic strategy against colorectal cancer, as well as the underlying molecular mechanisms with special attention to animal and human studies, as well as clinical trials.

Exercise and cancer
There are various mechanisms responsible for the preventive and therapeutic effects of exercise and physical activity on cancer [30]. One of the most significant mechanisms is the modulation of proliferative signaling pathways. Disruption of proliferative signaling pathways decreases the likelihood that cellular malignant transformation will occur [30,31]. Studies in animal models of multiple cancer types have shown decreased levels of various mitogenic hormones such as insulin growth factor-1 (IGF-1) and their downstream signaling pathways with potent proliferative and anti-apoptotic effects, including Ras-mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-Akt and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling transductions prevent cancer initiation and progression [32][33][34][35]. More interestingly, exercise also results in alteration of serum factors, which leads to the upregulation of p53 and activation of downstream anticancer signaling [36]. Another major mechanism in developing cancers is the inactivation of tumor suppressor genes [37]. Exercise is reported to upregulate the expression levels of important tumor suppressor genes, including p53, p21, insulin-like growth factor-binding protein (IGFBP) -3, programmed cell death (PDCD)-4, and phosphatase and tensin homolog (PTEN) [37]. In the murine model of mammary carcinogenesis, exercise resulted in decreased levels of hyper-phosphorylated retinoblastoma protein [38,39]. Exercise is also reported to downregulate miR-21 and the anti-apoptotic protein Bcl-2 and increase the expression levels of the tumor suppressor PDCD4 in an animal model of breast cancer [40]. Resistance to apoptosis along with disruption in the proliferative pathway is common events in tumor formation [41]. In animal models of pancreatic, prostate, skin, and breast cancers, it was found that physical activity and exercise effectively inhibited tumor growth and induced apoptosis through activation of caspase-3 and p53 and inhibition of Bcl-2 [41][42][43][44][45]. Higgins et al. demonstrated that exercise led to significant upregulation of p53, as well as increased expression levels of pro-apoptotic proteins, Bax and Bak, hence delay of lung adenocarcinoma tumor growth [46]. Exercise is indicted to play an active role in modulating the expression levels of angiogenesis-related genes, hence regulating angiogenesis and metastasis processes during cancer progression [47]. Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1a) are two major players of angiogenesis in the tumor microenvironment that are upregulated by exercise in various animal models of cancer [47]. Therefore, exerciser training results in the suppression of invasion and metastasis of cancer cells through normalization of the tumor microenvironment [47][48][49][50][51][52].
The preventive functions of exercise and physical activity and their effects on reducing the incidence risk of various human malignancies are the most studies areas of cancer treatment [53]. These effects are more prominent in the case of colorectal and breast cancer, such that there are more than one hundred studies only for investigating the effects of exercise on reducing the risk of CRC [54]. An accumulating number of these studies have convincingly reported an approximately 24-40% decrease in the CRC risk in physically active individuals in comparison to the least active [54][55][56][57][58][59][60]. Despite extensive investigation, however, there are still some unrevealed aspects of the association between physical activity and reduced risk of colorectal cancer [21]. Two important issues in this field are the timing and intensity of physical activity in relation to CRC risk, which will comprehensively discuss in the following paragraphs (Fig. 1).

Timing of exercise
Results from various investigations about the appropriate age periods, in which physical activity exerts more potent preventive effects in CRC patients, have found that being active and exercise in any age periods of life, including 30-39, 40-49, and + 50 years has a strong association with the reduced risk of CRC. In other words, exercise during the 30-50 years of a person's life is more consistently related to reducing risk [16,[61][62][63]. This finding is mostly concluded from the results of case-control studies, which have used exercise questionnaires that decrease the validity and reliability of related studies. Although it is clear and mostly accepted that 30-50 years is the age period, in which exercise may optimally decrease CRC risk, it is also possible that people can recall the amount of physical activity they performed in this age period more reliably than in other age periods [54]. For example, in a study consisted of 3,240 men and 1,482 women with CRC and healthy controls, the association between physical activity during different ages (15-18 years, 19-29 years, and in the past 10 years) and reduced CRC risk was evaluated and it was found that total physical activity at ages 15-18 and ages 19-29 years was not associated with colon cancer, whereas a decrease in colon cancer risk was observed with increasing levels of total physical activity at ages 35-39 years and increasing levels of total lifetime physical activity [64]. On the other hand, decreased CRC risk is also associated with long-term or lifetime physical activity. This is based on the finding of case-control and cohort studies, which reported the reduced risk for individuals performing consistently high levels of physical activity [54].

Intensity of exercise
According to the metabolic-equivalent (MET) value of different physical activities, they are classified into three distinct categories, including light (a MET value between 1.6 and 2.9), moderate (a MET value between 3.0 and 5.9) and vigorous (a MET value equal to or greater than 6.0). Activities such as standing and most household chores are considered as light-intensity activities [65]. Walking for exercise, golf, and gardening are moderate-intensity activities and running, swimming, and squash are placed in the vigorous category. The number of epidemiologic studies investigated the physical activity in association with CRC risk, have compared the most active individuals with the least active ones [66]. However, it is suggested that physical activity may result in a 24% risk reduction in men and 23% risk reduction in women. The reason why the findings are less consistent for women is unclear. Because hormone therapy is associated with reduced risk of colon cancer among postmenopausal women, it may mask any beneficial effects of physical activity on colon cancer risk among women with a history of hormone use. In the case of comparing vigorous-intensity activity with moderate-intensity activity, it is found that vigorousintensity activity confers a greater risk reduction (26%). This conclusion is based on three case-control studies. There is not any cohort study for approving this finding. An increase in insulin sensitivity, downregulation of IGF signaling, decrease in obesity are among the most important and accepted biological mechanisms for preventive effects of vigorous-intensity physical activities [67]. Another possible explanation is that vigorous-intensity physical activity is recalled more reliably than moderateintensity meaning that vigorous activity is better able to distinguish between highly active and inactive participants [68][69][70].

Sedentary behavior
Any activity needing low energy expenditure such as prolonged sitting or watching television or working at a desk is considered sedentary behavior, which is confirmed by an increasing number of studies as an independent risk factor for multiple chronic diseases. In addition, sedentary behaviors have also a close association with an increased incidence of CRC (30%). However, these findings and suggestions are made based on hospital-based case-control studies evaluated occupational activity [71,72], which have major limitations. In other words, light-intensity activity has also demonstrated to have health benefits such as decreasing CRC incidence [73]. The effect of too much sitting on adiposity, metabolic dysfunction, inflammation, and vitamin D has been proposed to be the pathways through, which sedentary behavior may influence colon cancer risk [71]. In addition, Whitemore et al. reported that saturated fat intakes exceeding 10 g/day, particularly in combination with physical inactivity, could account for 60% of colorectal cancer incidence among Chinese-American men and 40% among Chinese-American women [74].

Exercise in colorectal cancer survivals
Due to the high importance of post-treatment for cancer survivors, sufficient post-treatment management is considered as one of the most important issues for improving the health and quality of life of survivors [75]. As mentioned before, great advances in the detection and therapeutic strategies for CRC, the number of CRC survivors is sharply increasing, which needs an effective post-treatment management program. Despite the existing multiple post-treatment management programs, there are not sufficiently effective universal guidelines [76]. Major changes in lifestyle such as physical activity and proper dietary habits are two key elements of these programs. Especially, studies have shown reduced physical activity in CRC survivors in comparison to other cancer survivors [77]. Lynch et al. reported that 68% of CRC survivors have physical inactivity after the treatment period [78]. Furthermore, in spite of approved beneficial effects of exercise and physical training, it has been demonstrated that only 23.5% of CRC survivors followed the exercise guidelines [79]. The majority of the barriers to sports participation reported by CRC survivors are similar to those identified for healthy populations (e.g., time, age/agility, distance to travel, cost); however, some of the barriers identified are unique to CRC survivors (e.g., poor bladder control, having an ostomy) [77]. Physical activity and exercise are considered as one of the most important and effective post-treatment managements for CRC survivors, which have been reported to enhance patients' fitness and improve their quality of life [80]. In addition, exercise also decreases the risk of tumor recurrence and developing chronic diseases, including cardiovascular disease and diabetes, hence all-cause mortality in CRC survivors [81,82]. Improving cardiorespiratory fitness and body composition, are other promising positive effects of exercise for CRC survivors [83]. Moreover, exercise and an appropriate lifestyle alleviate the treatment-induced long-term and severe side effects [84,85]. For example, Grimmett et al. demonstrated that increase physical activity along with fruit and vegetable intake, and reduce consumption of red/processed meat and alcohol in CRC survivors who had recently completed treatment resulted in the significant improvement in patients quality of life [86]. Other important beneficial impacts of exercise and physical activity in CRC survivors include improving quality of life, lymphedema, functional status, weakness, and muscle strength [87][88][89]. Table 2 has shown a comprehensive list of researches about outcomes of exercise in CRC survivors, who competed all surgery, chemotherapy and/or radiation.

Exercise during treatment
Surgical process and chemotherapy are two main therapeutic strategies in treating CRC patients. Various studies have shown that exercise and physical activity are effective in increasing patients' tolerance and decreasing the side effects of these modalities [85]. In the case of the effects of an exercise intervention on patients' quality of life before or after surgery, there is a limited number of completed studies and ongoing clinical trials. In a randomized controlled trial study by Ahh et al., it was reported that post-operative exercise consisted mostly of stretching and very-low-intensity resistance exercises effectively decreased length of hospital stay and improve bowel motility after a surgical procedure in patients with stages I-III CRC [104]. A clinical trial aimed to  In response to short-term training, HIE is a safe, feasible and efficacious intervention that offers clinically meaningful improvements in cardiorespiratory fitness and body composition for colorectal cancer survivors [83,103] investigate the effects of a training program with intensified physical activity before and after a surgical procedure on surgical-related postoperative recovery time, hospital stay, sick leave, and complication rate, is ongoing [105]. In patients undergoing chemotherapy, an 18-week supervised exercise program in 33 CRC patients, was shown to be safe and feasible. The intervention significantly reduced physical fatigue at 18 weeks and general fatigue at 36 weeks [106]. In addition, an aerobic exercise program for 150 min or more per week for 6-8 weeks during and after neoadjuvant chemo-radiotherapy (NACRT) is also safe in CRC patients [107]. Similar results were reported for the training performed three times per week for 1 year in 30 CRC patients [108]. A combined aerobic and resistance exercise program was shown to improve muscle strength, cardiorespiratory fitness, emotional distress, physical activity, fatigue, and sleep quality in patients with stage II-III CRC patients undergoing chemotherapy [109]. Chemotherapy-induced side effects such as peripheral neuropathy, fatigue, muscle weakness, pain, cardiovascular and pulmonary complications, immune dysfunction, anemia, anxiety, depression, sleep disorders, and endocrine changes are also alleviated by exercised training in CRC patients [57,110,111].

Molecular mechanisms
Recent years have witnessed a huge increase in the number of clinical trials focusing on the efficacy of various types of exercise programs in the treatment of CRC. Table 3 shows a long list of clinical trials extracted from clinicaltrials.gov. However, there is a limited number of studies investigated the mechanisms underlying the positive effects of physical activity in CRC. Previous reviews have focused on the beneficial therapeutic and preventive effects of exercise in CRC, however, there is not a comprehensive review focusing on the molecular mechanisms. Therefore, these mechanisms are not still fully understood and need more basic and deep investigations.
In the next section of the present review, we will discuss some important and well-studied mechanisms, which are suggested to be the lost pieces in the puzzle of physical activity and CRC (Fig. 2).

Inflammation
An accumulating number of evidence demonstrates that inflammation has a broader range of effects on CRC pathogenesis, from supporting primary tumor growth by promoting tumor cell proliferation to helping angiogenesis by increasing the availability of pro-angiogenic molecules, to suppressing anti-tumor immunity by recruiting anti-inflammatory cell types, and to shaping pre-metastatic niches to promote subsequent metastasis. In addition to the critical role of inflammation and inflammatory mediators in the initiation/ progression of CRC, it is suggested that this process has also been involved in the preventive effects of exercise on CRC [112]. Physical activity is demonstrated to have an inhibitory effect on systemic inflammation by decreasing various proinflammatory cytokines such as interleukins, C-reactive protein, and tumor necrosis factor (TNF)-α [113]. In animal models of CRC, numerous studies have evaluated the roles of exercise in the suppression of inflammatory events. For example, Mehl et al. [114] reported that treadmill running significantly decreased plasma IL-6 levels in APC min/+ male mice, hence inhibit CRC progression, as was shown by the decreased number of polyps. In a study by Frajacomo et al. [115] it was demonstrated that interleukin (IL)-10 was a vital element for anti-preneoplastic effects of aerobic training on the colon. They showed that aerobic training mice developed 36% less colon preneoplastic lesions than their controls. However, Knocking IL-10 out mice abrogated the anti-preneoplastic effects of aerobic training on the colon tissue [115]. Darband et al. [116] showed that exercise on a treadmill 5 days/week for 8 weeks reduced ACF. They reported that suppressing inflammation was a major underlying mechanism since serum levels of IL-6 and TNF-α, and expression levels of cyclooxygenase (COX)-1 in colon tissue were significantly elevated in the rats receiving 1, 2-dimethylhydrazine (DMH) and downregulated after performing the exercise program. COX enzymes (COX-1 and -2), which have key functions in intestinal tumor formation, are also indicated to be mediators of exercise beneficial effects on CRC [116]. Demarzo et al. [117] reported that swimming training resulted in the decreasing number of ACF in rats with DMH-induced CRC through the downregulation of COX-2. Exercise also resulted in decreasing local inflammation by decreasing inducible nitric oxide synthase (iNOS) expression in the colon mucosa in azoxymethane (AOM)-induced CRC in mice [117]. In a study by Baltgalvis et al. the effects of regular moderate-intensity treadmill exercise training in attenuating polyp formation in Apc (Min/+) mice fed the Western-style die were investigated. The authors found that exercise reduced total intestinal polyp number by 50% and the number of large polyps by improving the markers of systemic inflammation and immune system function. The Western-style diet increased polyp number by 75% when compared with control mice, but exercise did not decrease polyp number or alter polyp size in mice fed the Western-style diet. These data suggest that the induction of adiposity, inflammation, and immunosuppression by the Westernstyle diet may compromise the beneficial effect of moderate-intensity exercise on the intestinal polyp burden in Apc (Min/+) mice [118].

Insulin-like growth factor axis
The insulin-like growth factor (IGF) system plays a pivotal role in the pathogenesis, progression, and prognosis of CRC. Previous evidence indicates that hyperactivation of the IGF pathway represents an early step in colon cancerogenesis, establishing both mitogenic and pro-angiogenic signals that favor neoplastic transformation of normal colorectal epithelial cells [119]. The IGF axis is one of the most substantial mechanisms with well-defined roles in exercise activity and CRC [120]. Due to the main functions of IGF in the regulation of key cellular processes such as proliferation, differentiation, and apoptosis, these proteins and their binding proteins (IGFBPs) are a hot point in researching about CRC pathogenesis [120]. IGF-1 upregulation is reported to be linked to CRC risk [121]. The importance of the IGF axis in CRC incidence, initiation, and progression is strongly supported by observational and preclinical studies [122][123][124][125][126][127]. As a result, exercise-mediated manipulation of the IGF axis is considered as a preventive therapy for CRC, which may be effective in decreasing CRC-specific mortality.
In general, there is an inconsistency in the physiological response of IGFs to physical activity [128][129][130][131][132][133]. In other words, different studies have reported different responses of the IGF axis to exercise, which is proposed that relates to negative energy balance, physical, conditioning and energy flux [128,129]. The six-week voluntary exercise was shown to decrease the ratio of serum IGF-1 to IGFBP-3 levels, hence inhibit intestinal tumorgenesis in Apc Min/+ mice. It was suggested that the inhibitory role of exercise on colon carcinogenesis is related to decreased IGF-1/IGFBP-3 ratio [134]. In addition, 8-week resistance training was also demonstrated to reduce serum IGF-1 level and IGF-1/IGFBP-3 ratio in rats, which is considered as a link between resistance training and lower risk of CRC [135]. Investigating 526 CRC survivors have demonstrated that for the physically active patients, increasing IGFBP-3 by 26.2 nmol/l was associated with a 48% reduction in CRC specific deaths [136]. In an interventional study by Lee et al. it was reported that a 12-week home-based exercise program resulted in a significant reduction in insulin and IGF-1 levels, as well as an increase in IGFBP-3 levels in 70 patients with stage II-III CRC survivors [137]. Therefore, heterogeneous results decreased IGF-1 levels, and increased IGFBP-3 levels may be a reasonable mechanism underlying the inverse correlation between CRC and physical activity [120]. The association between exercise and CRC cannot be explained by using a single mechanism because exercise and interrelated factors exert varying effects.

Immunity
Exercise is shown to be a major modulator of the immune system. However, the exact role of this interaction is not yet completely understood. On the other hand, the key players of the immune system, including T cells and macrophages have also been demonstrated to play a critical function in CRC pathogenesis, such that an increased number of these immune cells is associated with poor prognosis in CRC patients [138,139]. In a study by McClellan et al. [140] it was reported that treadmill running for 1 h/day and 6 days a week at 15 m/min resulted in the decreased expression levels of specific markers for macrophage (IL-12, IL-23 and Nos2, CD206, IL-10, IL-4, CCL17, CCL22, and Arg-1) and T-cells (CD8 and Foxp3), hence led to reduced CRC progression. Other studies also confirmed the modulatory effects of exercise and physical training on the immune system in animal models [141,142].

Epigenetics and miRNA
The interaction between physical activity and epigenetics is based on the evaluation of variation in patterns of DNA methylation at CpG sites within specific genes with particular biological roles [143][144][145]. Molecular epidemiology has identified various target genes including adenomatous polyposis coli (APC), MutL homologue 1 (MLH1), tumor growth factor beta (TGF-β), the cyclindependent kinase inhibitor p16, K-Ras (KRAS), and B-Raf (BRAF), that are differentially methylated in normal versus neoplastic colonic epithelium [146,147]. In other words, increased methylation in mentioned genes are frequently observed in CRC tissues, which suggests the critical function of these genes and their functional proteins in the pathogenesis of CRC. With regard to CRC, a limited number of studies have evaluated the interaction between physical activity and DNA methylation. In spite of the informative nature of these studies, due to some limitations, all studies did not find a significant association between exercise and DNA methylation at promoters of IGFBP, MLH1, BRAF genes, and p15 tumor suppressor gene [148][149][150][151]. In addition to DNA methylation, the effects of exercise on the expression levels of microRNAs (miRNAs) were also investigated in some recent studies. In a study by Tonevitsky et al. it was reported that a 30 min of exercise had a direct effect on the expression levels of miR-21, miR-27a, and miR-18a eight adult males, all of which are involved in CRC pathogenesis [152]. In another study, it was found that exercise resulted in the decreased expression levels of miR-342, which targeted the DNA methyltransferase gene (DNMT1) [153]. In rats with Azoxymethane-induced CRC, Kriska et al. [154] showed that the colon, muscle, and serum expressed miR-378 inversely proportional to CRC progression; and treatment with a 24-week progressive treadmill-training program (1 h/d, 3 d/wk) resulted in suppression of cancer progression and increase in miR-378 expression.

Leptin and ghrelin
Leptin and ghrelin are two regulators of energy balance and weight control. Physical activity is also contributed to the regulation of the expression levels of these two hormones. Exercise increases ghrelin levels and decreases leptin levels [155,156]. On the other hand, CRC cells exposure to adipocytes and pre-adipocytes has been found to increase cellular proliferation [157,158]. In a study by Nuri et al. [159] the exercise program consisted of 8 weeks walking and three 45 min sessions in each week with 50-60% of the target heart rate in 30 men with CRC resulted in increased ghrelin levels; however, plasma leptin and insulin resistance were not affected by this protocol in male patients with CRC. In another study by Piringer et al. [108] exercise 3 times per week for 1 year resulted in significant increases in adiponectin and leptin levels in 30 CRC patients.

Oxidative stress
Perturbance in the oxidative balances is suggested as one the main mechanisms involved in the development of colorectal cancer [6]. Exercise-mediated suppression of oxidative stress, though, is a considered as a therapeutic mechanism in CRC. For example, Perse et al. demonstrated that exercise exerted protective effects on developing CRC is induction of oxidative stress. However, in terms of the combined effects of dietary fat and exercise, they indicated that the protective role of exercise was significantly depressed by a high fat mixed lipid (HFML) diet. An HFML diet significantly reduced the protective influence of exercise on colon carcinogenesis in rats and affected the degree of peroxidation in the large bowel during exercise, as well as concentrations of serum enzymes (LDH, α-HBDH, CK, ALT and AST) [160]. The authors, in another study, reported that endurance swimming prevented lipid peroxidation in the soleus muscle of HFML diet rats due to elevated activities of antioxidant enzymes. On the other hand, increased lipid peroxidation in the hearts of all cancer groups indicated that DMH-induced colon carcinoma impaired the antioxidant status of the heart. This failure in heart tissue indicated that enhanced anti-oxidant capacity after regular physical activity is not sufficient to offset oxidative stress caused by DMH-induced colon carcinoma [160]. Therefore, exercise exerted a protective effect in developing CRC via increasing the antioxidant capacity.

Apoptosis
It is now well-established that dysfunction in apoptotic pathways, which plays a pivotal function in maintaining tissue homeostasis, is one of the main contributors to tumorigenesis [161]. However, there is very little data on the benefits of exercise on apoptosis in the settings of CRC. Darband et al. [116] reported that an 8-week moderate-intensity exercise program resulted in the decreased number of aberrant crypt foci (ACF) and improvement in colon architecture in rats with DMHinduced CRC. They found that exercise upregulated apoptosis, which was evident from the increased Bax/ Bcl2 ratio, and enhanced the expression levels of activated caspase-3 as compared to the DMH group [116]. In another study, it was shown that moderate-intensity exercise also modulated apoptosis in Apc Min/+ mice, hence led to a 35% decreased in colon polyp formation and growth. In addition, exercise downregulated the expression levels of Bax in the colon tissue of Apc Min/+ mice [162]. Therefore, exercise is a major regulator of apoptosis and its components. However, research in this area is in its infancy and needs more investigations.

Signaling pathways
The Wnt/β-catenin signaling pathways are one the most important signaling involved in the initiation/ progression of CRC, with major roles in cellular proliferation, apoptosis, angiogenesis, and metastasis [31,163,164]. Loss of APC and its major mediator CTNNB1 (β-catenin), which is a common event in the early stages of CRC, leads to an increase in cellular proliferation independent of the energy balance [165]. There is a mutual interaction between exercise and Wnt/β-catenin signaling, such that exercise changes the WNT-CTNNB1 signal in colonic mucosa and the WNT-CTNNB1 pathway modulates the cellular sensitivity to exercise [134]. In animal models, exercise resulted in an increase in the phosphorylation of β-catenin in the colon tissue of mice with CRC [162]. Morikawa et al. demonstrated that in the active early-stage CTNNB1 negative CRC patients, who performed ≥ 18 MET hour/week of exercise after CRC diagnosis, the incidence rate of CRC-specific mortality decreased by 67%, in comparison to inactive patients [166]. In another study, it was found that patients with weak staining for β-catenin in the exercise program had a lower mortality rate [167]. Therefore, CTNNB1 status can be used as a predictive biomarker in response to exercise applications [168].

Future directions
There are several gaps in evidence identified in this review that deserve attention. First, few studies have been designed with the goal of investigating the therapeutic efficacy of exercise in CRC, as well as improving treatment efficacy. Second, very few studies included radiotherapy, immunotherapy, or other more recently developed anticancer therapies, which may also interact with exercise. Third, the number of studies investigating the mechanisms underlying exercise mediated protective effects, particularly downstream signaling pathways is very low. Despite the inherent limitations of the reviewed studies, the evidence presented here is promising. In the past four decades, over 700 exercise trials in the oncology setting and more than 30 trials in colorectal cancer have been conducted to establish evidence for safety and feasibility, and whether exercise can improve physical function and quality of life outcomes among cancer survivors.
Clinical studies with treatment efficacy as the primary outcome have been far fewer, probably because of the necessity of longer follow-up larg, er sample sizes, and limited funding opportunities. Nevertheless, treatment efficacy is the most important issue for CRC patient, and we need to pay more attention to this area. Existing and future cohort studies that collect physical activity information before or during cancer treatment should consider the feasibility of data linkage in their design to examine the associations between physical activity and cancer treatment outcomes. These studies may also begin to examine the biological mechanisms underlying the relationship between physical activity and cancer treatment efficacy by including biological samples (i.e., markers of angiogenesis, immune function, inflammation, metabolism). Alternatively, ongoing efficacy trials of new cancer treatments may collect physical activity information to examine their influence on treatment efficacy outcomes.

Conclusion
The health beneficial effects of exercise and physical activity have been proven and considered for many years and recent decades are witnessed with an increased number of studies investigating the effects of exercise and physical activity in preventing and treating various human malignancies, including CRC. In this regard, an accumulating number of observational and experimental studies have shown the modulatory function of exercise on CRC initiation/progression. Based on these studies, physical activity and avoiding a sedentary lifestyle have major positive effects in decreasing CRC incidence and mortality. In addition, applying exercise is also effective in improving the quality of life in CRC survivors and the severe side effects of various therapeutic strategies in CRC patients. Furthermore, various studies have introduced different underlying mechanisms for the beneficial effects of the exercise and physical activity in CRC, some important of them, which was discussed in this review, include suppression of inflammation, modulation signaling pathways such as IGF axis and β-catenin, and regulation of apoptosis and immunity. Investigating exercise targeting mechanisms is CRC is still in its infancy and needs further studies for better understanding the nature of exercise in CRC and identifying appropriate biomarkers for CRC.