Research progress on the relationship between exercise and tumor

Xuan-Ying Wang,Ning Lu

1The Second Clinical College of Zhejiang Chinese Medical University,Hangzhou,310000,China.

2Department of oncology,Ningbo Municipal Hospital of Traditional Chinese Medicine,Ningbo,315010,China.

Abstract Tumor is a major threat of the health of Chinese people at present.Exercise has a certain relationship with tumor and is one of the hot topics in the research of tumor.In this paper,it made a review of the researches on the occurrence and development of tumor,therapeutic effect and prognosis,rehabilitation of tumor patients,and the effect of tumor on exercise in recent years.It indicates that the interaction between exercise and tumor is one of the best prevention methods for tumor and has a positive impact on the prognosis and rehabilitation of tumor patients.

Keywords:Malignancies,Exercise,Review

Background

Well known,the World Health Organization(WHO)has defined malignancies as a chronic disease.Malignancy is a serious threat to the health of our residents a major disease at present.With the gradual aging of our population,the acceleration of industrialization and urbanization,and the accumulation of risk factors such as chronic infection,unhealthy lifestyle,and the environment,the morbidity and mortality rates have increased year by year[1].Due to the 3-year lag of data,the latest data released by the National Cancer Institute in 2019 show that in 2015,the number of patients with new malignant tumors in China was about 3.929 million,and the national incidence rate of malignancies was 285.83/100,000(305.47/100,000 for males and 265.21/100,000 for females)[2].

Three centuries ago,Rammazzini proposed that there is a certain relationship between exercise and the occurrence of human tumors[3].With the in-depth research in recent years,the development of tumors and exercise,treatment effect,rehabilitation,and tumor on the effect of exercise have gradually attracted attention.The article reviews the current research on the relationship between the two.

The Development of The Tumors and Exercise

Exercise is one of the three effective malignancy prevention measures recommended by the World Public Health Recommendations and Health Promotion Activities to the world[4].Research shows[5]that exercise can prevent various common malignant tumors(Figure 1).

Figure 1 Relationship between maximum and minimum physical activity and decreased tumor risk(Cited from Reference 5).RR,relative risk;CI,confidence intervals

The American Cancer Society(ACS)publishes guidelines on nutrition and exercise to prevent cancer every five years,which are the basis to formulate health policies and community behaviors,and are expected to eventually affect the diet and exercise patterns of Americans[6].The guidelines states that about one-third of patients with malignancies in the United States are attributable to dietary and exercise habits.Maintaining good diet and exercise habits can reduce the incidence of many malignancies,especially breast cancer,colorectal cancer,prostate cancer and pancreatic cancer[7].The latest meta-analysis shows that exercise also has a significant reduction in the risk of esophageal cancer and gastric cancer(OR=0.71;95%CI=0.57-0.89)[8,9].

Cai Bin[10]summarized various domestic studies and found that regular exercise has preventive effect on a variety of malignancies such as breast cancer,endometrial carcinoma,ovarian cancer,prostate cancer,colorectal cancer,and lung cancer of Chinese people.And there is a certain dose-response relationship.Moderate exercise can reduce the occurrence of malignancies,while excessive exercise will increase the risk of malignancies.

Exercise has an impact on the risk of cancer in a variety of ways.Regular exercise helps maintain healthy weight by balancing energy intake and consumption,and may also help prevent certain cancers directly or indirectly,such as improving metabolism,oxidative stress,and regulation sex hormones,insulin,and prostaglandins exert a variety of beneficial effects on the immune system[11].Its core mechanism is to control weight and reduce central fat.Down-regulation of PI3K-Akt and[12]RAS-MAPK pathway signaling is a key target.

The impact of aerobic exercise on tumor microenvironment is the focus of current research on the development of tumorigenesis and exercise,mainly including three directions[13]:1.Aerobic exercise and tumor hypoxia microenvironment;2.Aerobic exercise and tumor-related macrophages;3.Aerobic exercise and chronic inflammatory response.

Hypoxia plays an important role in the occurrence and development of tumors.Hypoxia can induce malignant transformation of tumor cells[14],promote tumor neovascularization,increase glycolysis,inhibit apoptosis,and promote tumor cell metastasis.Research shows that aerobic exercise can improve tissue hypoxia microenvironment[15],thereby inhibiting the development of tumors.

Tumor-associated macrophages are one of the important components of tumor microenvironment.They are divided into two types of polarization,M1 and M2.M2 antigens can stimulate tumor cell proliferation and angiogenesis by secreting a series of cytokines,such as EGF,VEGF,PDGF,TGF-β,which are closely related to tumor invasion and metastasis[16],while long-term regular aerobic exercise can reduce tumor-associated macrophages in tumor microenvironment[17].

As early as 1863,Rudolf Virchow hypothesized that inflammation can promote the occurrence and development of tumors.Various cancers can be caused by infection and chronic inflammatory diseases.The effect of inflammatory response on tumor occurrence is mainly related to the release of cytokines such as TNF-α and IL-6 by inflammatory cells.Regular aerobic exercise can inhibit chronic inflammatory reactions and block the occurrence and development of tumor.The mechanism may be related to the reduction of adipose tissue,and the subsequent reduction of the pro-inflammatory factors(TNF-α,IL-6)secreted by adipose tissue[18].In addition,it is known that the expression of inducible nitric oxide synthase(iNOS)and cyclooxygenase-2(COX-2)will increase and promote the occurrence of colorectal cancer at the initial stage of tumor occurrence.Exercise can reduce the levels of iNOS,nitrotyrosine AOM,and tumor necrosis factor α[19],suggesting that exercise can prevent the occurrence of malignancy by inhibiting the expression of iNOS related to anti-inflammation.

In addition,research also shown that oxidative stress is an important reason for the occurrence of tumors.Cancer patients often show imbalances of antioxidant system,resulting in reactive oxygen species(ROS)[20],which can cause cell damage,oxidative damage of protein and DNA[21].If the body cannot repair these damages,it is likely to lead to the occurrence of tumors.ROS can also inhibit hydroxylase,and further inhibit the degradation of hypoxia-inducible factor(HIF-1).The increased expression of HIF-1 is associated with the occurrence of tumors and is an important growth regulator for many malignancies[22].Aerobic exercise can increase the oxygen level of tissues and accelerate the degradation of HIF,thus preventing the occurrence of tumors.

In addition to ROS,hydrogen peroxide(H2O2),an intermediate product of oxidative stress,is also closely related to tumor formation and growth[23].The antioxidant system of human body is divided into antioxidant enzymes and antioxidants(Non-enzymes).Antioxidant enzymes cannot be ingested from external sources,mainly including superoxide dismutase(SOD),catalase(CAT),peroxidase(POD),glutathione Peroxidase(GSH-Px),etc.Exercise can improve the activity of antioxidant enzymes,Li Feng[24]concluded that:different exercise modes have different effects on the antioxidant effect of the body.Long term aerobic exercise with moderate and small intensity can improve the body’s antioxidant enzyme activity and keep it at a higher level,so as to protect the body from oxidative stress damage and prevent the occurrence of tumors.But high frequency and high intensity exercise will increase the generation of ROS and damage by oxidative stress(Figure 2).Pedersen[25]and others carried out animal experiments and found that exercise reduced the occurrence and development rate of different tumors(including melanoma,liver tumors,lung tumors,etc.)by 60%,and its mechanism is related to the up-regulation of immune-related functions in mice induced by aerobic exercise.

Figure 2 The molecular mechanism of physical activity to prevent and treat tumor cachexia(Cited from Reference 4)

Treatment Effect and Prognosis of Tumor and Exercise

Exercise has a direct impact on the efficacy and prognosis of various malignancies.The mechanisms may include 1.Improving the nutritional status of patients,preventing and relieving cachexia,and improving immunity;2.Alleviating the side effects of treatment and improving the tolerance of patient.

Judging from the big data,Mok Y et al.[26]found that absolute value of death risk of colorectal cancer patients who often take physical exercise is reduced by 9% within 5 years.The survey shows that exercise is beneficial to improve and prolong the prognosis and survival time of patients with colorectal cancer.

20. White: White symbolizes light, innocence78 and purity (Matthews 1986). White is also associated with faith and peace. It is a recurring79 color in this version of the tale and is frequently mentioned. With the exception of the witch s red eyes, it is the only color mentioned.Return to place in story.

The final death of a cancer patient is often not caused by the tumor itself,but by the loss of skeletal muscle and weight due to treatment and cancer fatigue,cachexia-induced organ failure and various infections and complications caused by immunocompromise.Exercise can prevent or delay the occurrence of these complications.Basic research has found that exercise can release autophagy flux in skeletal muscle to maintain muscle homeostasis and alleviate the occurrence of tumor cachexia[27].Brown JC[5]and other research have found exercise can even reduce the death risk of colorectal cancer by 30-50%,surpassing the therapeutic effect of most drugs.Exercise can reduce weight loss in cancer patients during chemotherapy and has a positive effect on skeletal muscle atrophy[28].After a systematic review,KruijsenJaarsma M et al.[29]have found that the immune system of tumor patients who exercise regularly is more healthy and the incidence rate of infectious diseases is lower than those who do not exercise.Domestic scholar Li Ling et al.[30]found that exercise together with nutritional support can effectively improve the nutritional status of patients with advanced tumors,the symptoms of fatigue in a short period of time,the depressive symptoms of cachexia,and the life quality of patients.Nutrition support together with exercise is obviously better than simple nutritional support.

Tumors,especially gastrointestinal tumors,are often accompanied by fatigue[31],decreased appetite,abdominal distension,constipation and other symptoms,which are also the most common adverse reactions of patients.Studies of Lee JE[32]have found that exercise is the best over-the-counter method to alleviate the above symptoms.A meta-analysis involving 113 RCTs shows that exercise reduces cancer-related fatigue more obviously than drug therapy,nutrition therapy and psychological intervention[33].

Witlox,Freitag[34,35]and others have found that exercise is still a good auxiliary measure during chemotherapy,which can reduce the side effects caused by chemotherapy.Wu Aiping et al.[36]found that the sports can improve the QLQ-C30 score of tumor patients during chemotherapy,especially the sleep quality measured by Pittsburgh Sleep Quality Index(PSQI),and the symptoms of pain,fatigue,nausea,vomiting,anorexia,abdominal distension and constipation during chemotherapy are obviously improved.Exercise can relieve discomfort caused by various tumors and is partially effective even for tumor patients at the end stage.At present,the Oncology Nursing Society(ONS)recommends exercise as a routine clinical method to relieve the above symptoms.

In short,the benefits of more physical activity in cancer patients include almost all aspects:improving physical and mental health,increasing the treatment tolerance,shortening the recovery time of traumatic therapy,improving the quality of life,improving appetite,preventing weight loss and cachexia,and obtaining a longer survival time[37].

Exercise and Tumor Rehabilitation

The concept of tumor rehabilitation was first proposed by Americans in 1971.The rehabilitation of tumor patients covers many subjects and contains a wide range of contents,but physiological and psychological rehabilitation are the main contents[38].The exercises of physiological rehabilitation also focus on functional exercises that promote functional recovery and prevent complications.

It is well known that edema of the affected upper limb of breast cancer patients is a common postoperative complication,Lack of effective treatment drugs seriously affects the limb function and social ability of patients.Reasonable limb movement in the early postoperative period is very important for the recovery of upper limb function and can significantly improve the life quality of patients[39].The main movements include flexion and extension,lifting activities from 24h to 15 days after surgery,and 6-8 weeks of restorative muscle movement training[40].The key time for recovery of upper limb function is 3 months after operation,and the affected limb's functions of flexion,extension,abduction and pronation can be restored to the maximum extent at this stage.Domestic scholars,Wang Guofei et al.[41]have found that yoga can accelerate the rehabilitation of breast cancer patients,including the rehabilitation of limb function.Huang Yanling[42]have found that Tai Chi aerobic combined exercise can also effectively improve the shoulder joint function and muscle strength of the affected limbs.

Osteoarticular tumor also affects the motor ability of patients seriously,which is often accompanied by the reduction or loss of motor ability of relevant parts after the operation.Wang Gang et al.[43]found that patients with malignant bone tumor around the knee joint can better improve the flexion and extension activity of the affected knee joint and promote the functional recovery of affected limb by starting anti-blocking exercise as soon as possible after prosthesis replacement.The exercise included isometric contraction of quadriceps femoris and active activity of ankle joint and toe joint 48 hours after the operation.After the drainage tube was removed,the knee joint continued passive movements,and cold therapy was carried out after the exercise therapy.On the 28th day,walking training of crutches was started,with double crutches first,then a single crutch was used for the healthy side,and walking was gradually abandoned after the 42nd day.

Head and neck tumors often require radiotherapy and chemotherapy,which severely affects patients'quality of life and physiological functions.Complications such as swallowing distress,pain,increased secretions,dry mouth,fatigue,local infection and other complications occur.Samuel et al.[44]found that compared with ordinary care,exercise intervention can significantly improve the above symptoms and the tolerance and life quality of patients undergoing radiotherapy and chemotherapy.

Li Haidong et al.[46]observed that the functional rehabilitation of affected limbs such as joint movement,limb aerobic weight-bearing exercise,walking and ball flexibility exercise was significantly better than those of the control group who do not exercise.

In addition,ankle movement[47],limb and somatic movement can significantly reduce the risk of thrombosis after operations,promote the recovery of intestinal function,reduce complications,and accelerate the recovery of patients.

Clinically,more attention is paid to patients'physiological rehabilitation and less to the psychological rehabilitation.Statistics show that most patients with malignant tumor have psychological problems,mainly anxiety[48]and depression[49].Vallance et al.[50]found that tumor survivors who often doing exercise have significantly lower probability of depression and anxiety than those who do not.Moderate vigorous physical activity(MVPA)is the best type of physical exercise.Active participation in MVPA by tumor patients can accelerate recovery,reduce psychological pressure,maintain mental health and improve quality of life.Domestic scholars Han Wenfeng et al.[51]carried out meta-analysis and found that tumor patients who kept exercising(such as fast walking,riding,swimming and mountaineering)had the effects of anti-anxiety and anti-depression,which can reduce the incidence of social fear,and their role emotional adaptability was significantly stronger than that of tumor patients without physical exercise.

The Effect of Tumor on Exercise

Exercise has its effect on the tumor,on the contrary,the tumor will also affect the patient's exercise ability and willingness.

The effect of exercise capacity is the most direct.Tumors of the central nervous system often affect the motor center,resulting in the reduction or even loss of motor function of patients,which prevents patients from normal exercise,such as glioma,meningioma,lymphoma,pituitary tumor,various intraspinal tumors,etc.In addition,various types of tumors involving the motor system,such as osteosarcoma,osteochondroma,bone metastatic tumors,various soft tissue sarcomas,etc.,may result in patients with limited movement.What’s more,operation,radiotherapy and local lesion treatment of tumor may lead to the decline and loss of motor ability of patients.For example,with the advancement of treatment concepts and technologies,effective reconstruction of bone and soft tissue defects,amputation surgery and limb salvage surgery for 5 years The survival rate is basically similar,so there are more and more patients with limb salvage surgery[52]The patient's affected limb is severely impaired due to the tumor and its treatment,which affect exercise ability,and it needs to be gradually improved through long-term rehabilitation treatment.

In addition to the influence of exercise ability,the influence of the tumor on the willingness to exercise of the patient is also very obvious.Tan Qiqiong et al.[53]found that cancer patients generally do not understand that exercise can reduce fatigue caused by tumors,fearing that exercise will have a negative impact on disease and treatment.It is these common misconceptions that have affected cancer patients to actively participate in sports,and tumor patients also lack medical staff to continue to exercise.Humpel N et al.[54]reported that after breast cancer and prostate cancer patients were diagnosed,the exercise time decreased by an average of 72 minutes/week compared with that before the diagnosis.Only a few patients increased their average exercise time after diagnosis.

In 2017,Vallerand et al.[55]from Canada conducted a survey on patients with hematological tumors.Only 22% of patients exercised and 46% did not exercise at all.

After studying 72 patients with digestive tract tumors and 58 patients with lung cancer,Ying Hongyan et al.[56,57]found that the proportion of elderly patients with digestive tract tumors and lung cancer who continued to do physical exercise was significantly lower than that before tumor diagnosis,reaching the lowest level at 3 months after diagnosis,but the proportion of patients who gradually started exercising increased,and they basically returned to the pre-diagnosis level after 1 year.The main reasons for patients to reduce exercise were fatigue,discomfort,lack of motivation and laziness,fear of injury and disease recurrence,and numbness of hands and feet after treatment.The main motivation to exercise again was to hope for physical recovery,fear of disease recurrence,and recognition that exercise can improve physical fitness and enhance immunity.

Summary

Exercise and tumor affect each other."Life lies in exercise".Regular exercise is one of the important means to maintain health.For people who do not suffer from malignant tumors,regular and reasonable exercise can effectively prevent the occurrence of malignant tumors,which is one of the best preventive methods.For patients who have unfortunately suffered from malignant tumors,the American College of Sports Medicine recommends to exercise at least 5 times a week with moderate intensity or more for 30-60 minutes each time according to the physical strength and illness of the patients.The minimum requirement is at least once a week for more than 30 minutes of moderate exercise.The National Comprehensive Cancer Network(NCCN)guidelines also recommend that the cancer patients can exercise gradually and can adjust reasonably according to the condition of patients[4].

Of note,the ordinary daily activities do not belong to moderate vigorous exercises.The moderate vigorous exercises suitable for Chinese people include fast walking,jogging,cycling,swimming,Taijiquan,square dancing,yoga,ball games and other activities that make the heart rate and breathing faster.Regular and reasonable exercises can delay the progress of tumors,promote rehabilitation,reduce the occurrence of complications,enhance the body's tolerance to tumor treatment,improve anxiety and depression,overcome the decline in exercise willingness and exercise ability caused by tumors,improve the life quality and prolong the survival time.