Scientific evolution has resulted in the holistic treatment of the oncology patient through rehabilitation programs. However, the implementation of therapeutic exercise is not widely established in a daily clinical practice. Although randomized clinical trials have significantly demonstrated the anti-cancer protection of exercise, deepening scientific knowledge, the results are sometimes contradictory. The heterogeneity of tumor malignancies and the individualized characteristics of each population or even the personalized features of each patient are usually the cause of this inconsistency [1].

Cancer is one of the main causes of mortality in 57 countries worldwide and is characterized by a quick and uncontrolled proliferation of cells that do not follow the control mechanisms of cell division and may be sited on an organ or be metastatic [2]. Characteristically, in 2012, 14,106 new cancer cases and 82,106 deaths were diagnosed in the United States of America, while in the next two decades, the rate of new cases is expected to highly increase by 70% [3]. The latest global estimations have revealed that 1.4 billion adults (one third of the world’s adult population) do not meet the recommended level of physical activity to improve and protect their health. Alarmingly enough, this issue has remained highly unchanged, and it has further been adopted during the pandemic period due to the COVID-19 pandemic ^[4][5][4,5]. The distribution of cancer types shows an increasing trend over the last few years. According to World Health Organization (WHO) statistics, the most common new cases of cancer in 2020 were breast, lung, colon, prostate, cervical, skin, and stomach cancer ^[2][3][4][2,3,4].

Levels of physical inactivity in high-income countries (36.8%) were more than two-fold higher compared to low-income countries (16.2%) among adults in 2016. In most countries women still are more inactive than men, particularly in the Eastern Mediterranean and the United States of America regions [6]. On the other hand, cancer disease has been attributed to the interactions of genetic and environmental factors. Data from both laboratory and observational research have suggested that modifiable risk factors, such as physical inactivity, smoking, dietary habits, and alcohol consumption, can influence the risk of cancer recurrence and overall survival after diagnosis [7].

Globally, one third of adults are not physically active. Data from WHO surveys have revealed that 64% of adults are sedentary for more than four hours a day. Sedentary behavior has been considered as a major factor in the burden of non-communicable diseases, including cancer. A burden of 10% for breast cancer and 10% for colon cancer has been reported to be related with sedentary behavior ^[7][8][7,8].

A plethora of epidemiological, retrospective, prospective, and case control studies has described the potential benefits of physical activity/exercise in relation to cancer risk [8], revealing that regular exercise may promote protection against specific types of cancer, such as breast cancer in menopausal women, bowel (colon), and possibly prostate, endometrial, lung, and perhaps pancreatic cancer [9], reducing the overall incidence of these cancer types by a percentage of 40% [10]. Some evidence has also shown that the relative risk is increased in colon (RR = 2.0) and breast cancer (RR = 1.5) in people with sedentary lifestyles, whereas a 75% risk reduction for breast cancer and 22% for colorectal cancer in people with increased physical activity levels has been reported ^[2][11][2,11]. The Center for Disease Control and Prevention (CDC) reports also that physically active individuals have a lower risk of developing breast, colon, lung, and endometrial cancer [12].

Most studies support that exercise is generally safe for people being treated for cancer and has a positive effect on reducing the risk of cancer development and progression in specific organs ^[11][12][11,12]. The way in which exercise may prevent the development of cancer is still under investigation. Physical activity seems to considerably improve physical performance and muscle strength, also promoting several aspects of patients’ mental health. Exercise can reduce tumor development through multiple mechanisms such as the following: (a) vascularization and perfusion, (b) immune function, (c) tumor metabolism, and (d) muscle–cancer interaction [13]. Evidence of these mechanisms is currently emerging, but more intervention studies are still recommended to establish the cause–effect relationship between these mechanisms and the control of tumor genesis and growth [13].

2. Exercise and Colon Cancer

The most widely studied cancer in relation to the effect of exercise is colorectal cancer, particularly that located in the colon ^[10][14][15][10,77,78]. Almost 14% of colorectal tumor malignancies in the population are ascribed to a physically inactive lifestyle [16]. Most studies have observed a 70% reduction in the risk of colon cancer in individuals with higher levels of physical activity. The protective role of physical activity may be related to the incidence of colorectal precancerous polyps. Epidemiological studies have documented that there may be an association of exercise with the risk of developing colonic polyps. In fact, it was observed that those who exercised ≥ 1 h weekly exhibited a lower incidence of colorectal polyps and adenomas compared to those who exercised for <1 h. Moreover, exercise decreased the likelihood of developing polyps in the entire colon, independently of any specific colon location. Additionally, exercise has been found to decrease the whole number of intestinal polyps by 50% and the number of large polyps by 67% ^[17][73]. Both occupational and leisure time physical activities have significantly been associated with a reduction in colon cancer risk. The relative risk in cohort studies has been found to be higher compared to case control studies (RR = 0.85 vs. RR= 0.73) ^[18][31]. The mean risk factor reduction was found to be 40% to 50%, while the association dose–response was shown to be strong, being increased when exercise was combined with diet and BMI reduction ^[15][78]. The potential effects of exercise have been found to include increasing intestinal motility, reducing transit time, reducing fecal bile acids, and improving the immune system (up to two-fold elevation in macrophage activity immediately after high-intensity exercise). Additionally, high physical activity increases the levels of prostaglandins in particular PGF2a, which is inversely related to the prostaglandin PGE2 of the mucosa (having an “oncogenic behavior”) of the colon. The outbreaks of adenomatous polyposis have been associated with Program Cell Death (PD). Exercise may also be associated with Ki-ras oncogene mutations. Individuals with increased PD were less likely to have these mutations compared to non-active individuals ^[18][19][20][30,31,32]. Long-duration aerobic exercise has also been shown to exert a protective effect against colon cancer, whereas non-association was found between exercise and rectal cancer risk [9].

3. Exercise and Breast Cancer

Exercise has been shown to reduce the risk of breast cancer by 30–40% in women with increased physical activity and even a dose–response relationship has been found in menopausal women ^[15][21][22][65,78,79]. The dose–response relationship of exercise has not been found to be linear. In other words, as the dose of exercise increases, the risk factor does not decrease proportionally ^[22][79]. No relations have been observed for premenopausal women, while for all women a modest risk reduction from 10% to 20% percent has been reported. Notably, females who met at least five of the World Cancer Research Fund and American Institute for Cancer Research recommendations had a 60% lower risk of breast cancer ^[23][80]. Remarkably, for each additional hour of exercise per week, there has been a 6% risk reduction ^[22][79]. Moderate aerobic exercise five times a week combined with daily physical activity has reduced risk by 50–75% in postmenopausal women ^[24][81]. Aerobic exercise can also be beneficial for both the prevention and therapy of the cardiotoxicity impacts of doxorubicin and trastuzumab, promoting cardiorespiratory capability. In this aspect, the beneficial impact of upper extremity exercise on the controlling of lymphedema in breast carcinoma has been well established, bringing down the myth of restricting the usage of the influenced hand. Sixty percent of breast cancer patients experience body weight increase through simultaneous chemotherapy, which additionally elevates the probability of relapse. Exercise seems to decrease this probability and, specifically, aerobic exercise both during and next to therapy can improve quality of life, decreasing fatigue in breast carcinoma patients ^[25][82]. On a molecular basis, exercise stops the metabolic cascade of chronic inflammation by reducing the levels of IL-6 and CRP and inhibiting inflammation progress. Exercising muscles lead to the deceasing of TNFα and α amyloid ^{[26][27][28][29][30][31][32][33][34][35]}[51,52,53,54,55,56,57,58,60,61]. Moreover, serum under exercising conditions has been demonstrated to switch off Hippo/Yes-Associated Protein (YAP) signals in breast cancer cells by a mechanism regulated by epinephrine while the blockade of adrenergic signals mitigates the depressant role of exercise serum on both tumor development and cell survival ^[34][35][36][60,61,63].

4. Exercise and Endometrial Cancer

Exercise has been related with reduced risk of endometrial cancer incidence. Increased leisure time physical activity has been demonstrated to reduce by about 80% the risk of endometrial cancer. On the contrary, occupational physical activity has been found to exert a non-effect on the decline of endometrial cancer risk ^[15][22][37][28,78,79]. Exercise can help reduce the risk of death from endometrial cancer by reducing the rates of obesity and by regulating lipoproteins, insulin resistance, and endogenous sex hormone concentrations ^[38][46]. It is worth noting that moderate-intensity exercise may have a remarkably positive-association with increasing survival rates, while high-intensity exercise has not ^[39][83]. Moreover, exercise has been shown to improve cardiorespiratory fitness, quality of life, and mental health in obese and non-obese women who have experienced endometrial cancer stage I-IIIa ^[40][84].

5. Exercise and Ovarian Cancer

Ovarian cancer is the most common leading cause of death compared to other gynecological cancers. However, women both during and after treatment for ovarian cancer in stages I-IV of the disease are not willing to engage in exercise and do not follow the suggested exercise recommendations ^[41][85]. No significant relationship has been observed between the risk of this type of cancer and the effect of exercise or physical activity. The results of the currently available studies are contradictory with some of them supporting a moderate and inverse relation between physical activity and cancer risk, reporting a reduction in the risk of developing invasive ovarian endothelial cancer in women with intense physical activity ^[21][42][65,66]. Exercise has been associated with reduced ovarian cancer risk and improved clinical outcomes. However, the underlying molecular mechanisms remain unknown. Low levels of physical activity have been associated with all histopathological types of epithelial ovarian cancer and higher levels of physical activity seem to reduce the adverse effects of ovarian cancer treatments. Notably, exercise intervention (even at home) has improved quality of life, cardiorespiratory function, and muscle strength, reducing disease and/or disease treatment-related fatigue in women with ovarian cancer. Despite these clinical findings, there is limited research on the molecular mechanisms mediating the effect of exercise on improving ovarian cancer outcomes. Thus, it remains unclear whether physical activity directly or indirectly could affect ovarian cancer incidence and mortality due to the lack of research studying these mechanisms ^[43][47].

6. Exercise and Prostate Cancer

Multiple potential molecular pathways have been suggested to connect exercise and prostate carcinogenesis through mediating the circulating levels of IGF-1, oxidative stress, systemic inflammation, sex hormones, and myokines ^[44][48]. Studies investigating the relationship between physical activity and prostate cancer risk have demonstrated controversial results and presented unclear outcomes ^[19][30]. However, an overall prostate cancer risk reduction ranging from 5% to 65% has been associated with leisure time physical activity from 10% to 56%, which has been correlated to occupational physical activity. Interestingly, a large Scandinavian study including over one million male participants (73.2% between 60 and 80 years of age, 18.3% > 80 years) has reported an overall reduction in prostate cancer rates of 7–12% for those with a high workload. These results were confirmed by Benke et al. who reported a 17% reduction in prostate cancer risk in men over 60 years of age with long-term occupational physical activity ^[3][4][3,4]. The large main differences in prostate cancer mortality worldwide may be partly ascribed to differences in physical activity evaluation patterns ^[19][30]. The association of cancer risk reduction with exercise has not been found to be as strong as it was expected. However, a 54% reduction in metastatic cancer risk has been reported in the high physical activity category of men, with most studies reporting a reduction of about 10–30% ^[20][32]. The above findings contradict the conclusion of other studies, where the relative risk was found to be independent of exercise intensity, while in others studies the duration and frequency of exercise has been associated with cancer incidence. One possible molecular mechanism of exercise involved in risk reduction appears to be the increased testosterone binding by the musculoskeletal system because of chronic and high-intensity exercise. Resistance exercise has also led to a rise in testosterone that was offset by an increase in androgen receptors in exercising muscles ^[9][19][20][9,30,32]. In prostate cancer, 3 h per week of vigorous activity (jogging, cycling, swimming, tennis, and weight training) has led to a 70% reduction in the risk of high-grade, progressive, or fatal prostate cancer [13]. The magnitude of the effect of exercise on a wide variety of bodily functions appears to be extensive. Some of the beneficial metabolic effects may be influenced by the anti-inflammatory response, immune system, cognitive function, hematopoietic system, estrogen production, IGF-1, apoptosis, deoxyribonucleic acid damage, and genome diversion (gene expression and mutation) ^[45][86].

7. Exercise and Pancreatic Cancer

Pancreatic cancer is one of the most aggressive and early metastatic tumor malignancies with poor prognosis worldwide. It is expected to have a double incidence in 2030. Physical inactivity appears to increase the risk of pancreatic cancer. Total physical activity in subjects with BMI < 25 kg/m² has not been related with the risk factor. In contrast, exercise training, through improvement of glucose tolerance and weight loss in overweight and obese people, has been found to reduce pancreatic cancer risk. Vigorous physical activity has not been associated with cancer risk, while moderate physical activity has inversely been associated with cancer risk. Individuals, both male and female, who walked more than four hours per week have showed a 54% lower risk of pancreatic cancer compared to those who spent less than 20 min walking weekly, with a significant reduction in relative risk (RR = 0.45) ^[46][41]. Investigations of the exercise mechanisms leading to pancreatic cancer risk induction and tumor suppression have also been limited. Scientific evidence has revealed contradictory results and particularly few studies have supported that exercise can reduce tumor growth when chemotherapy agents have not been delivered. Recent research has highlighted that not only the absence of chemotherapy medicine but the volume and intensity of exercise training may be associated with tumor growth, while others have provided positive response to cancer suppression and growth reduction during chemotherapy implementation ^[47][67]. Both the endurance and resistance exercise of moderate intensity seem to enhance the psychological status and improve the functional capacity of the affected people. High-intensity interval training has also showed a negative correlation with pancreatic tumor growth in patients who underwent medical treatment ^[48][87]. Aerobic exercise combined with chemotherapy has exhibited a greater effect on tumor growth reduction through the activation of calcineurin-NFAT-TSP1 signaling in endothelial cells, exerting a key role in exercise-induced shear stress mediated tumor vessel remodeling ^[47][67].

8. Exercise and Lung Cancer

Lung cancer is the underlying cause of almost all cancer-related deaths worldwide and non-small-cell lung cancer (NSCLC) represents 85% of all lung tumor malignancies, presenting survival rates less than 5 years. Three main histological forms of NSCLC have been described as large-cell carcinoma (10–15%), adenocarcinoma (40%), and squamous cell carcinoma (25–30%). Adenocarcinomas represent the majority of non-small lung cancer cases and there is evidence that its incidence rates are increasing worldwide compared to other lung carcinomas ^[49][88]. Elevated cell proliferation, decreased apoptosis, and prolonged survival have been considered as the main features of cancer cells, which are induced by the modulation of key signaling molecules/single pathways and thus may activate a cascade of biological reactions. The above cellular mechanisms are induced or regulated by the anti-cancer molecular mechanisms of exercise. Physical activity has positive effects not only in the prevention of lung cancer, but also in the treatment and prognosis. Exercise has been shown to reduce chronic inflammation and oxidative stress in both normal and pathophysiological lung conditions, like lung carcinoma and/or cystic fibrosis, promoting molecular mechanisms that can activate anti-inflammatory mediators. Moreover, exercise has been shown to influence lung functionality and decrease the probability of infections and pulmonary disorders. There is currently considerable evidence that diverse mechanisms may be involved in the relationship between cancer and physical activity through the regulation of chronic inflammation and the regulation of different substances that can act as part of metabolic dysregulation such as insulin, glucose, and sex hormones. In addition, physical activity seems to exert an impact on oxidative stress and immune function by modifying some critical molecular mechanisms related to the tumor microenvironment such as angiogenesis, cell proliferation, and apoptosis ^[50][89]. Elevated cell proliferation, decreased apoptosis, and prolonged survival are the main features of cancer cells, which are induced by the modulation of key signaling molecules/single pathways and by activating a cascade of reactions. Phosphatidylinositol-3- kinase (PI3K)-Akt and the kinase that is regulated by the Ras-extracellular signaling (Erk1/2) have been stimulated by attaching growth factor to cell surface receptors, resulting in elevated cell proliferation and surveillance ^[51][68]. The activated Akt has triggered the following mechanisms of rapamycin (mTOR), which in response can activate ribosomal kinase S6 (p70 S6K), leading to the augmentation of cell proliferation and protein synthesis ^[52][69]. Akt has also induced phosphorylation and degeneration of the pro-apoptotic Bad protein, which has resulted in both suppression of apoptosis and increased survival, being involved in cancer cell therapy resistance ^[53][70]. On the other hand, the Ras signaling molecule has been shown to be mutated/activated in cancer, including NSCLC, leading to the subsequent activation of Erk1/2 and resulting in cell proliferation and resistance to chemotherapy and radiation ^[54][71]. Therefore, identifying strategies that can restrict the Akt and Ras-Erk1/2 signaling cascades may be an effective therapeutic approach for the treatment of lung cancer. Regular exercise is generally related to overall health benefits and a decreased risk of many types of cancer. Although the relation between lung cancer and exercise has not comprehensively been investigated, exercise at a moderate intensity (>4.5 METs) and a frequency of more than four times a week has been found to be effective in lung cancer risk reduction compared to people following exercise training at lower intensity and frequency ^[21][65]. Hence, adaption of exercise over a long period of life may exert a positive effect on reducing the risk of lung cancer. The reduction differs between genders, with women being at a greater advantage than men, and it is greater for people with high physical activity ^[42][66]. Interestingly, an inverse association of vigorous leisure time physical activity and lung cancer risk has been found, while strenuous severe occupational physical activity has been shown to exert a larger effect on the reduction of lung cancer risk ^[37][28]. Thus, lung cancer cases in men and women with sedentary lifestyles could have been prevented by including regular exercise in their daily lives ^[42][66].

9. Exercise and Gastric Cancer

Nowadays, the incidence rates of gastric cancers tend to decline. However, it remains the most common cause of death among men compared to women. More than one million new cases of stomach cancer are detected worldwide every year. Stomach cancer is also one of the most behaviorally influenced cancers and is therefore preventable ^[55][90]. Regular exercise training has possibly affected health-related quality of life, contributing to gastric cancer risk reduction. Nevertheless, research findings are scarce and contradictory. Studies have reported exercise side effects in this subgroup of oncological patients such as nausea, vomiting, gastrointestinal breeding, reflux, depression, fatigue, and lack of motivation. On the other hand, the indirect outcomes of sustained regular aerobic exercise have been demonstrated ^[56][91], which may result in muscle mass and strength elevation, as well as the improvement of functional capacity and psychological status with a regular individualized exercise program adapted to patients’ needs and clinical conditions ^[54][71]. However, it has been elucidated that an aerobic and resistance exercise program of 30 min twice a week has resulted in the reduction of plasma 3-hydroxy-kynurenine (HK), a major compound that relates to depression, and of the neurotoxic metabolites of gastric cancer patients ^[57][92]. Nevertheless, most of the published studies which have investigated the effect of exercise on gastric cancer have been focused on the pre- and/or post-operative period of the affected patients. Adoption of an exercise program based on Frequency–Intensity–Time–Type (FITT) principles and the objective perception of exercise fatigue has improved the functional capacity and cardiorespiratory function of esophageal and gastric cancer patients who underwent neoadjuvant treatment preoperatively ^[57][92]. Extensive investigation is further required in order to detect the exact dominating molecular mechanisms through which exercise may elicit benefits in gastric cancer patients.

10. Exercise and Skin Cancer

The main types of skin cancer include melanoma, basal cell carcinoma, cutaneous squamous cell carcinoma, and Merkel cell carcinoma. There is limited literature on the examination of the association between exercise and skin cancer. The association of exercise with the likelihood of cutaneous squamous cell carcinoma (SCC) remains still unknown and is problematic to examine because of the confounding exposure to sunlight ^[58][74]. There is no considerable association of recreational activity tools with SCC next to adjusting for possible confounding factors, containing sun exposure indices. In men, the observed risk motif has proposed an enhanced risk with elevating total hours of leisure-time activity. Concerning women, the higher amount of occupational activity (standing and manual work vs. sedentary work) has been associated with a decreased prevalence of developing SCC tumors (p = 0.03) ^[58][74]. However, exercise appears to have an important role for confronting melanoma by modifying energy imbalance and by promoting and upregulating ceramides. Ceramides are bioactive molecules, which can promote the proliferation and apoptosis in cancer cells. It has been highlighted that aerobic exercise may activate and also increase ceramides, which in turn could act as apoptotic agents of tumor cells ^[59][93]. Few studies have also examined genes induced by exercise and the prognosis of skin melanoma and particularly by providing the expression of tumor suppression genes ^[58][74].

11. Exercise and Liver Cancer

Exercise seems to have a protective role against liver cancer risk and disease progression. However, this relationship has not been defined because of the lack of interventional studies in humans. Notably, lower rates of mortality between active and less active liver cancer patients have been observed ^[60][94]. Particularly, regular exercise has been shown to reduce the risk of hepatocellular cancer. Exercise seems to activate adenosine monophosphate protein kinase (AMPK), phosphorylating the regulatory protein related to the mammalian target of rapamycin (raptor), which in turn may lead to the inhibition of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). The mTOR has been considered to act as a crucial regulator of cell proliferation, tumor growth, and survival in response to molecular growth factors and nutritional status. AMPK has been shown to function as an energy sensor in cells, exerting a dominant impact in connecting metabolism and cancer ^[61][75]. Nonetheless, molecular mechanisms by which exercise can inhibit cancer cell growth and metastasis are still unclear. Substantial research has also demonstrated that regular exercise may improve the quality of life of liver cancer inpatients after diagnosis without deteriorating liver function ^[62][95] and has also reduced the extent of the tumor ^[63][96]. Moreover, regular physical activity has been shown to exert a profound effect on the prognostic transcriptional signature by downregulating most of the genes involved in poor survival and upregulating the most genes related to optimal prognosis ^[64][76].