PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
IUBMB Life. Author manuscript; available in PMC 2014 July 1.
Published in final edited form as:
Published online 2013 June 12. doi:  10.1002/iub.1169
PMCID: PMC3691305
NIHMSID: NIHMS457563

TARGETING THE THERAPEUTIC EFFECTS OF EXERCISE ON REDOX-SENSITIVE MECHANISMS IN THE VASCULAR ENDOTHELIUM DURING TUMOR PROGRESSION

I. SUMMARY

The American Cancer Society estimated 1.5 million new cancer cases in the US in 2012. Although the exact number is not known, it is estimated that brain metastases occur in 20–40% of cancer patients (NCI). Due to the complexity of development and the variation in tumor etiology, therapy options have been limited for a number of cancers while progressive treatments have been successful for some malignancies. Combining treatment strategies has shown potential to increase positive outcomes, however cancer remains a formidable diagnosis with no true cure. Many researchers have focused on alternative forms of cancer prevention or treatment to slow cancer progression. Studies have shown that with moderate, regular exercise signaling pathways associated with increased antioxidant activity and cellular repair are upregulated in vascular tissue, however the physiological mechanisms are poorly understood. The purpose of this review is to examine the current literature in order to better understand the impact of exercise on cancer progression and tumor metastasis and discuss potential redox related signaling in the vasculature that may be involved.

Keywords: Cancer, exercise, reactive oxygen species, brain microvasculature, metastasis, tight junction

II. INTRODUCTION

Cancer is a multidimensional disease that can arise from a variety of factors including age, genetic predisposition, environmental, and lifestyle choices. With a growing number of associations between daily activities and cancer development and progression, recent research has focused on understanding the contribution of lifestyle choices such as exercise. Several groups have demonstrated that exercise can have positive outcomes on activity, strength, aerobic capacity and emotional factors in humans (1). In rodents, exercise has been shown to alter primary tumor size and regulate factors involved tumor cell survival and growth (2). The types of exercise, intensity of training and cancer type are key factors that vary greatly between studies (3). Less is known about the effect of exercise on tumor progression and metastasis. Key steps in metastatic initiation and growth are determined by the tumor cells’ ability to transverse the vascular membrane, enter the blood stream and penetrate the endothelium in a new site. In addition to metastasis, tumor development and maintenance require adequate blood supply and nutrients to grow. The role of the vasculature and vascular endothelial environment is critical in understanding how these metastatic events unfold. Tumor cells can disrupt tight junction (TJ) protein expression (4). TJs are the main structural components that determine paracellular integrity in brain endothelium, and tumor cells extravasate and disseminate into the brain between disrupted TJs. It is known that exercise alters the gene expression of factors involved in angiogenesis as well as components associated with permeability of the vascular endothelium (5, 6). These processes are of particular consequence in the brain endothelium where tight junction protein complexes form an additional barrier that limits passage into the cerebrospinal environment. Activation of redox-sensitive small GTPases can lead to the disruption of TJs and promote tumor cell extravasation (7). There is evidence that exercise can alter the oxidation status of the microvasculature and thereby may offer protection against tumor cell invasion into the brain (8).

III. TUMOR DEVELOPMENT AND VASCULAR SIGNALING

Risk Factors

Cancer can arise from a variety of sources including genetic mutations or predisposition, environmental factors or toxins, as a result of lifestyle and behavioral choices, and as a consequence of the natural progression of aging. Mutations in tumor suppressor genes such as p53, BRCA1/2, PER2 and others involved in cell growth and turnover can be inherited however familial predisposition does not guarantee cancer development (911). Industrial workers or those persons working shift-work or in transcontinental travel industries are also at a higher risk for cancer (12, 13). Diet and lifestyle choices also have strong connections to cancer development (14). Obesity and metabolic syndromes have been linked to increased incidence of cancer and challenges when managing tumor progression.

Progression

Three fundamental steps have been described in the process of tumor development and malignant progression (15). Initiation of cancer development begins at the cellular level where individual cells acquire the capacity to form malignant growth. Initiation can be triggered by the factors mentioned previously or can arise spontaneously during normal cell division. At this phase pathways that deter tumor initiation such as those that enhance DNA repair, promote detoxification or reduce reactive oxygen species (ROS) can slow or prevent tumorigenesis. Studies have shown that exercise is associated with an increase in antioxidant vitamins as well as enzymes glutathione peroxidase, catalase and superoxide dismutase (SOD) (16, 17). Once cells have gained the capacity for unabated growth a “promoting” stimulus is needed to maintain the cells and promote further development. Promotion involves the colonization of tumor cells and is often involved with environmental factors that promote development, such as circulating hormones (18). Some studies have also shown a relationship between exercise and reduced levels of circulating hormones, which may have anti-promotional/progressive effects on tumor growth (19, 20). The final fundamental step is progression (21). Progression involves the accumulation of more malignant cells and the development of a pro-growth environment within which the tumor can be self-sustained. Once the tumor has been established, progression can be characterized by the development of the primary tumor, metastatic growth, or both. Progression requires adaptation and compliance of the surrounding tissues including, very importantly, the vasculature (22). The effects of exercise with respect to vascularization and tumor maturation have been mixed. Studies have shown that exercise decreases angiogenesis in the tumor environment, decreases vascular endothelial growth factor (VEGF) and increases oxygen content (23) while others have reported that exercise increases tumor vascularization and lowers oxygen levels within the tumor mass (24). The following section will discuss contributions of specific signaling molecules in the context of vascularization and tumor development.

Cancer and vascular endothelium

The vascular system plays a critical role in the development and progression of cancer (25). By providing a “highway” for growing tumors to receive nutrients and travel to other sites in the body, the signaling and regulatory pathways in the vasculature are essential to understanding cancer progression (26). Several factors have been determined to be important for tumor vascularization and development of a pro-growth environment. VEGF signaling promotes angiogenesis and vascularization of the tumor environment (27). Multiple studies have shown that ROS may be involved in VEGF signaling and angiogenesis (28, 29). ROS are generated as result of normal physiological function (30). Increased ROS are associated with cell proliferation and migration (31, 32), increased VEGF (33), angiogenesis (34), and other signaling pathways (35, 36). Indeed ROS are also involved directly in cell signaling events including alteration of redox-sensitive modifiers such as phosphatases. The activation of these pathways in vascular endothelial cells leads to mobilization, rearrangement of the cytoskeleton, and tubular formation (31, 37). In addition to vascularization, ROS can stimulate small GTPase signaling pathways leading to cellular rearrangement and alterations in the vascular endothelial cells which may can promote tumor cell invasion (36, 38, 7).

IV. METASTASIS

Tumor metastasis is a complicated event that involves many variables and depends on both the tumor cells and the host. Normal healthy cells do not live long when detached from the connective tissues of the extracellular matrix, however tumorigenic cells must gain the ability to survive and translocate in order to recognize another location in the body. Metastatic growth is more common within the visceral cavity i.e. lungs, liver, or bone (NCI). Tumor cells can travel through lymphatic or blood vessels to gain access to these regions of the body. Brain metastases occur about ten times more frequently than primary brain tumors, and they manifest in approximately 30% of all other cancer types (NCI) (39). Because the central nervous system does not have any lymphatic vessels the only method of entry for tumor cells is the blood stream. Once inside the brain microvasculature tumor cells must cross the blood-brain barrier (BBB), which is reinforced with tight junctions (7). The mechanism of tumor cell extravasation into the brain is not well understood, however one hypothesis involves the activation of redox-sensitive pathways, which compromise tight junction protein integrity leading to tumor cell invasion (40). ROS are generated during tumor progression and metastasis within the tumor and surrounding tissue (41, 42). Tumor cells promote ROS generation which can lead to further DNA damage by increasing NADPH oxidase (NOX) activity and promoting redox-sensitive pro-growth pathways (43) Studies have also demonstrated that tumor cells often have a reduced sensitivity to ROS or may “hijack” ROS-mediated signaling in order to progress (41). Studies have shown that exercise has different effects on redox status depending on several variables (discussed below). Increased antioxidant activity can counterbalance heightened ROS levels in surrounding tissue (44). In the context of the vasculature and infiltration through the BBB, damage to the vessels and the TJs directly contribute to tumor cell invasion (Figure 1).

Figure 1
Balancing redox status. Tumor cells promote increased oxidation, tissue and DNA damage, and angiogenesis. Exercise can modulate some of these effects in specific tumor types. Tumorigenesis and tumor cell proliferation (black arrows) generate ROS, which ...

V. EXERCISE AND CANCER PROGRESSION

Exercise can be divided into two major categories, aerobic and anaerobic. Aerobic exercise occurs when oxygen is in ready supply and has the potential to generate more superoxides and hydrogen peroxide, which can cause harm to the organism (2). Anaerobic exercise or strength training can take place under low oxygen conditions or when ATP demand has exceeded oxygen availability. Anaerobic exercise is not as likely to generate free radicals but can lead to more cellular damage if performed incorrectly (45). Short-term, intense bouts of exercise also have the potential to generate more ROS however adaptive responses are also upregulated to counteract the increase in ROS (21). In addition to ROS generation, studies have shown that exercise is associated with the upregulation of SOD (Figure 1), which are responsible for the dismutation of free radicals and the generation of hydrogen peroxide. Hydrogen peroxide can increase the activity of endothelial nitric oxide synthase (eNOS) (38). Indeed, vascular expression of eNOS is associated with increased vasodilatation, improved blood flow and vascular endothelial function (46).

Exercise Models

There are several key variables to keep in mind when evaluating the protective effects of exercise on cancer development. The type of exercise and duration are important. Studies have shown that anaerobic exercise can be protective for some types of lung cancer while aerobic activity (even 1 hour/week) could be beneficial to reduce the risk for colon cancer (47, 2). Intense physical activity has been associated with decreased risk for breast cancer and others have shown that regular moderate exercise, which is also connected with decreased levels of ROS, can exert positive effects for several types of cancers (48). Another factor to be aware of in several exercise and cancer studies is diet. While diet is not the topic of this review, it is important to note animals feed a high-fat or western diet showed less benefit (sometimes no benefit) with exercise when compared with animals on standard chow diet (2). Lastly, a potentially important distinction when evaluating the therapeutic benefit of exercise is “primary vs. secondary” effects of exercise treatment. Many cancer studies have reported positive outcomes with exercise based on the fact that regular activity improves muscle tone and mobility thereby increasing quality of life for some cancer patients. This is not surprising considering side effects of most cancer treatments include weakness and fatigue (49). The fact that regular activity can improve these secondary effects of cancer drug treatment are not surprising considering that skeletal muscle comprises approximately 40% of body mass in adults (50). The “primary” effects of exercise on cancer development and progression are less understood. These include biological changes in the tumor cells or the tumor environment that are a direct consequence of exercise, such as alterations in oxidative status, gene expression and signaling pathways that may influence tumor growth and/or survival. Several specific cancer types have been studied in the context of exercise. The most prevalent and well studied are discussed in the following sections.

Lung Cancer

Lung cancer has the highest mortality rate among all cancer types (69). In 2012 alone, there were an estimated 225,000 new cases of lung cancer in the United States (68). Primary lung tumors are also the most likely to form brain metastases (51). Several studies have focused on the effects of exercise and lung cancer development/progression. Paceli et al. demonstrated that anaerobic but not aerobic exercise decreased the number of tumor cell lesions in an experimental model of lung cancer development (52). Exercise was also associated with higher glutathione levels (53) and increased ROS scavengers (54, 55) in the lung. Interestingly each of these studies observed changes in oxidative measurements using methods of forced exercise rather than voluntary aerobic exercise suggesting that activity intensity somehow influences antioxidant mechanisms.

Hormone Sensitive Cancers

Prostate and breast cancer patients have been shown to gain significant benefit from regularly scheduled exercise. It has been shown that men had reduced risk for prostate cancer when they exercised at least 3 hours per week at a high intensity and women also had a protective benefit from regularly scheduled exercise (48). The incidence of brain metastases from primary breast tumors is second to lung cancer and studies show that BCRA1 mutations are associated with a greater risk for brain metastases (51). Indeed studies have suggested that exercise can modulate steroid hormone levels, estradiol, testosterone and androstenedione thereby reducing the risk or progression of hormone sensitive tumors (56, 57). In addition to hormone sensitive mechanisms some data have shown that redox-sensitive pathways including small GTPases (Ras, Rac1 and RhoA) are altered in a model of breast cancer metastasis (58) and conversely antioxidant mechanisms are enhanced with exercise (59).

Gastrointestinal Cancer

Thus far, the neoplasm that appears to be the most influenced by exercise intervention is gastrointestinal cancer (47, 48, 2). Studies have shown that exercise can delay the onset of intestinal cancers and protect against the development of chemically induced carcinogenesis (60, 2). Increased levels of activity were associated with greater risk reduction (47) and also decreased tumorigenesis (61) or tumor progression (62). Several studies have shown a link between diet/exercise and metabolic and oxidative factors. Using a mouse model of “multiple intestinal neoplasia” ApcMin (63) mice were given either standard or high-fat chow and exposed to exercise (64). The exercised mice on standard chow had a reduction in the number of polyps but the high-fat mice did not. Furthermore the high-fat fed mice had increased inflammation and immunosuppression that was not altered by exercise. However in high-fat fed rats exercise completely prevented carcinoma development (65). Disruption of cell cycle control genes and oncogenic mutations, which promote uncontrolled growth and angiogenesis were observed in gastrointestinal carcinomas (66). Finally, mice showed decreased inducible nitric oxide synthase expression (decreased cell growth and angiogenesis) following exercise in a chemical model of carcinogenesis (61). Data from these studies and others have lead some researchers to hypothesize that the positive effects of exercise maybe be related to increased gut motility or clearance of irritants/inflammatory factors and an inhibition of cell proliferation (57).

VI. CONCLUSIONS

Although many associations have been made between exercise and cancer prevention and progression, the mechanisms that underlie tumor progression and metastasis are poorly understood. Of the most prevalent cancer types, gastrointestinal (colon) has shown the most promise with respect to exercise as a treatment. Several biochemical pathways are believed to be involved with exercise and tumor development (3, 21). Alterations in redox status can modulate many processes in normal physiology as well as pathophysiology. In the initial stages of cancer development an increase in ROS can promote tumorigenesis through DNA damage and increased inflammatory response (21). Once the tumor cells begin to multiply, angiogenesis and enhanced cellular proliferation are necessary for the tumor to grow and establish. Tumor metastasis is a complicated phenomenon that can arise if the circumstances are favorable (3). In the brain, metastasis formation becomes more arduous due to the fortification of microvessels with tight junctions (4). With respect to exercise a variety of outcomes have been described in various cancer models. It appears that duration, intensity, and metabolic type (aerobic vs. anaerobic) are all important as well as the cancer cell type in understanding the effect of exercise on tumorigenesis or tumor progression (48, 2). Because oxidative status appears to play a role in cancer development and exercise can modulate redox-related components such as antioxidant enzymes and DNA repair mechanisms (21), it seems crucial that more work be done to further elucidate the molecules and pathways involved.

VII. Future Directions

Exercise is a multifaceted intervention, which can promote a variety of outcomes in a host-specific manner. At the present time evidence suggests that exercise can have variety of effects on the development and progression of cancer. However, many pathways involved in cancer growth and metastasis can also be driven by exercise and may in fact be beneficial under normal physiological contexts such as aging (67). Therefore, more stringent research designs are advocated in order to better understand the protective effects of physical activity on tumor progression and metastasis development.

Acknowledgments

This work was supported by the NIH/NCI grant R0CA133257.

References

1. Adamsen L, Quist M, Andersen C, Moller T, Herrstedt J, Kronborg D, Baadsgaard MT, Vistisen K, Midtgaard J, Christiansen B, Stage M, Kronborg MT, Rorth M. Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial. BMJ (Clinical research ed) 2009;339:b3410. [PMC free article] [PubMed]
2. Na HK, Oliynyk S. Effects of physical activity on cancer prevention. Annals of the New York Academy of Sciences. 2011;1229:176–183. [PubMed]
3. Hoffman-Goetz L. Exercise, natural immunity, and tumor metastasis. Medicine and science in sports and exercise. 1994;26:157–163. [PubMed]
4. Feng SR, Chen ZX, Cen JN, Shen HJ, Wang YY, Yao L. Disruption of blood brain-barrier by leukemic cells in central nervous system leukemia. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2011;32:289–293. [PubMed]
5. Li J, Ding YH, Rafols JA, Lai Q, McAllister JP, 2nd, Ding Y. Increased astrocyte proliferation in rats after running exercise. Neuroscience letters. 2005;386:160–164. [PubMed]
6. Gielen S, Sandri M, Erbs S, Adams V. Exercise-induced modulation of endothelial nitric oxide production. Current pharmaceutical biotechnology. 2011;12:1375–1384. [PubMed]
7. Martin TA, Harrison GM, Mason MD, Jiang WG. HAVcR-1 reduces the integrity of human endothelial tight junctions. Anticancer research. 2011;31:467–473. [PubMed]
8. Cechetti F, Worm PV, Elsner VR, Bertoldi K, Sanches E, Ben J, Siqueira IR, Netto CA. Forced treadmill exercise prevents oxidative stress and memory deficits following chronic cerebral hypoperfusion in the rat. Neurobiology of learning and memory. 2012;97:90–96. [PubMed]
9. Runnebaum IB, Kreienberg R. p53 trans-dominantly suppresses tumor formation of human breast cancer cells mediated by retroviral bulk infection without marker gene selection: an expeditious in vitro protocol with implications towards gene therapy. Hybridoma. 1995;14:153–157. [PubMed]
10. Zieker D, Jenne I, Koenigsrainer I, Zdichavsky M, Nieselt K, Buck K, Zieker J, Beckert S, Glatzle J, Spanagel R, Koenigsrainer A, Northoff H, Loeffler M. Circadian expression of clock- and tumor suppressor genes in human oral mucosa. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2010;26:155–166. [PubMed]
11. Katapodi MC, Northouse LL, Milliron KJ, Liu G, Merajver SD. Individual and family characteristics associated with BRCA1/2 genetic testing in high-risk families. Psycho-oncology 2012 [PubMed]
12. Blask DE, Hill SM, Dauchy RT, Xiang S, Yuan L, Duplessis T, Mao L, Dauchy E, Sauer LA. Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night. Journal of pineal research. 2011;51:259–269. [PMC free article] [PubMed]
13. Wu M, Zeng J, Chen Y, Zeng Z, Zhang J, Cai Y, Ye Y, Fu L, Xian L, Chen Z. Experimental chronic jet lag promotes growth and lung metastasisof Lewis lung carcinoma in C57BL/6 mice. Oncology reports. 2012;27:1417–1428. [PubMed]
14. Pilie PG, Ibarra-Drendall C, Troch MM, Broadwater G, Barry WT, Petricoin EF, 3rd, Wulfkuhle JD, Liotta LA, Lem S, Baker JC, Jr, Stouder A, Ford AC, Wilke LG, Zalles CM, Mehta P, Williams J, Shivraj M, Su Z, Geradts J, Yu D, Seewaldt VL. Protein microarray analysis of mammary epithelial cells from obese and nonobese women at high risk for breast cancer: feasibility data. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2011;20:476–482. [PMC free article] [PubMed]
15. Foulds L. The natural history of cancer. Journal of chronic diseases. 1958;8:2–37. [PubMed]
16. Ji LL. Antioxidants and oxidative stress in exercise. Proc Soc Exp Biol Med. 1999;222:283–292. [PubMed]
17. McArdle A, Jackson MJ. Exercise, oxidative stress and ageing. Journal of anatomy. 2000;197(Pt 4):539–541. [PubMed]
18. Key TJ, Beral V. Sex hormones and cancer. IARC scientific publications. 1992:255–269. [PubMed]
19. McTiernan A, Tworoger SS, Ulrich CM, Yasui Y, Irwin ML, Rajan KB, Sorensen B, Rudolph RE, Bowen D, Stanczyk FZ, Potter JD, Schwartz RS. Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial. Cancer research. 2004;64:2923–2928. [PubMed]
20. Coyle YM. Physical activity as a negative modulator of estrogen-induced breast cancer. Cancer causes & control : CCC. 2008;19:1021–1029. [PubMed]
21. Rogers CJ, Colbert LH, Greiner JW, Perkins SN, Hursting SD. Physical activity and cancer prevention : pathways and targets for intervention. Sports medicine (Auckland, NZ) 2008;38:271–296. [PubMed]
22. Jiang BH, Agani F, Passaniti A, Semenza GL. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer research. 1997;57:5328–5335. [PubMed]
23. Verma VK, Singh V, Singh MP, Singh SM. Effect of physical exercise on tumor growth regulating factors of tumor microenvironment: implications in exercise-dependent tumor growth retardation. Immunopharmacology and immunotoxicology. 2009;31:274–282. [PubMed]
24. Jones LW, Viglianti BL, Tashjian JA, Kothadia SM, Keir ST, Freedland SJ, Potter MQ, Moon EJ, Schroeder T, Herndon JE, 2nd, Dewhirst MW. Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer. Journal of applied physiology (Bethesda, Md : 1985) 2010;108:343–348. [PubMed]
25. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature medicine. 1995;1:27–31. [PubMed]
26. Folkman J. Tumor angiogensis: role in regulation of tumor growth. The symposium / The Society for Developmental Biology Society for Developmental Biology Symposium. 1974;30:43–52. [PubMed]
27. Rosenthal RA, Megyesi JF, Henzel WJ, Ferrara N, Folkman J. Conditioned medium from mouse sarcoma 180 cells contains vascular endothelial growth factor. Growth Factors. 1990;4:53–59. [PubMed]
28. Ushio-Fukai M, Nakamura Y. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer letters. 2008;266:37–52. [PMC free article] [PubMed]
29. Jayaraman P, Parikh F, Lopez-Rivera E, Hailemichael Y, Clark A, Ma G, Cannan D, Ramacher M, Kato M, Overwijk WW, Chen SH, Umansky VY, Sikora AG. Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. J Immunol. 2012;188:5365–5376. [PMC free article] [PubMed]
30. Liu Y, Fiskum G, Schubert D. Generation of reactive oxygen species by the mitochondrial electron transport chain. Journal of neurochemistry. 2002;80:780–787. [PubMed]
31. Stone JR, Collins T. The role of hydrogen peroxide in endothelial proliferative responses. Endothelium : journal of endothelial cell research. 2002;9:231–238. [PubMed]
32. Yang J, Cheng Y, Ji R, Zhang C. Novel model of inflammatory neointima formation reveals a potential role of myeloperoxidase in neointimal hyperplasia. American journal of physiology Heart and circulatory physiology. 2006;291:H3087–3093. [PubMed]
33. Chua CC, Hamdy RC, Chua BH. Upregulation of vascular endothelial growthfactor by H2O2 in rat heart endothelial cells. Free radical biology & medicine. 1998;25:891–897. [PubMed]
34. Yasuda M, Ohzeki Y, Shimizu S, Naito S, Ohtsuru A, Yamamoto T, Kuroiwa Y. Stimulation of in vitro angiogenesis by hydrogen peroxide and the relation with ETS-1 in endothelial cells. Life sciences. 1999;64:249–258. [PubMed]
35. Yamaoka-Tojo M, Ushio-Fukai M, Hilenski L, Dikalov SI, Chen YE, Tojo T, Fukai T, Fujimoto M, Patrushev NA, Wang N, Kontos CD, Bloom GS, Alexander RW. IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species--dependent endothelial migration and proliferation. Circulation research. 2004;95:276–283. [PubMed]
36. Ikeda S, Ushio-Fukai M, Zuo L, Tojo T, Dikalov S, Patrushev NA, Alexander RW. Novel role of ARF6 in vascular endothelial growth factor-induced signaling and angiogenesis. Circulation research. 2005;96:467–475. [PubMed]
37. Luczak K, Balcerczyk A, Soszynski M, Bartosz G. Low concentration of oxidant and nitric oxide donors stimulate proliferation of human endothelial cells in vitro. Cell biology international. 2004;28:483–486. [PubMed]
38. Kojda G, Hambrecht R. Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy? Cardiovascular research. 2005;67:187–197. [PubMed]
39. Patchell RA. The management of brain metastases. Cancer treatment reviews. 2003;29:533–540. [PubMed]
40. Langer HF, Orlova VV, Xie C, Kaul S, Schneider D, Lonsdorf AS, Fahrleitner M, Choi EY, Dutoit V, Pellegrini M, Grossklaus S, Nawroth PP, Baretton G, Santoso S, Hwang ST, Arnold B, Chavakis T. A novel function of junctional adhesion molecule-C in mediating melanoma cell metastasis. Cancer research. 2011;71:4096–4105. [PMC free article] [PubMed]
41. Bauer G. Tumor cell-protective catalase as a novel target for rational therapeutic approaches based on specific intercellular ROS signaling. Anticancer research. 2012;32:2599–2624. [PubMed]
42. Vallejo CG, Cruz-Bermudez A, Clemente P, Hernandez-Sierra R, Garesse R, Quintanilla M. Evaluation of mitochondrial function and metabolic reprogramming during tumor progression in a cell model of skin carcinogenesis. Biochimie 2013 [PubMed]
43. Landry WD, Woolley JF, Cotter TG. Imatinib and Nilotinib inhibit Bcr-Abl-induced ROS through targeted degradation of the NADPH oxidase subunit p22phox. Leukemia research. 2013;37:183–189. [PubMed]
44. Frasier CR, Moukdar F, Patel HD, Sloan RC, Stewart LM, Alleman RJ, La Favor JD, Brown DA. Redox-dependent increases in glutathione reductase and exercise preconditioning: role of NADPH oxidase and mitochondria. Cardiovascular research 2013 [PubMed]
45. Magal M, Dumke CL, Urbiztondo ZG, Cavill MJ, Triplett NT, Quindry JC, McBride JM, Epstein Y. Relationship between serum creatine kinase activity following exercise-induced muscle damage and muscle fibre composition. Journal of sports sciences. 2010;28:257–266. [PubMed]
46. Hambrecht R, Adams V, Erbs S, Linke A, Krankel N, Shu Y, Baither Y, Gielen S, Thiele H, Gummert JF, Mohr FW, Schuler G. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation. 2003;107:3152–3158. [PubMed]
47. Friedenreich CM, Orenstein MR. Physical activity and cancer prevention: etiologic evidence and biological mechanisms. The Journal of nutrition. 2002;132:3456S–3464S. [PubMed]
48. Newton RU, Galvao DA. Exercise in prevention and management of cancer. Current treatment options in oncology. 2008;9:135–146. [PubMed]
49. Hoffman AJ, Brintnall RA, Brown JK, von Eye A, Jones LW, Alderink G, Ritz-Holland D, Enter M, Patzelt LH, Vanotteren GM. Too Sick Not to Exercise: Using a 6-Week, Home-Based Exercise Intervention for Cancer-Related Fatigue Self-management for Postsurgical Non-Small Cell Lung Cancer Patients. Cancer nursing 2012 [PubMed]
50. Kim J, Wang Z, Heymsfield SB, Baumgartner RN, Gallagher D. Total-body skeletal muscle mass: estimation by a new dual-energy X-ray absorptiometry method. The American journal of clinical nutrition. 2002;76:378–383. [PubMed]
51. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Current oncology reports. 2012;14:48–54. [PubMed]
52. Paceli RB, Cal RN, dos Santos CH, Cordeiro JA, Neiva CM, Nagamine KK, Cury PM. The influence of physical activity in the progression of experimental lung cancer in mice. Pathology, research and practice. 2012;208:377–381. [PubMed]
53. Rundle AG, Orjuela M, Mooney L, Tang D, Kim M, Calcagnotto A, Richie JP, Perera F. Preliminary studies on the effect of moderate physical activity on blood levels of glutathione. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals. 2005;10:390–400. [PubMed]
54. Duncan K, Harris S, Ardies CM. Running exercise may reduce risk for lung and liver cancer by inducing activity of antioxidant and phase II enzymes. Cancer letters. 1997;116:151–158. [PubMed]
55. Al-Obaidi S, Mathew TC, Dean E. Exercise may offset nicotine-induced injury in lung tissue: a preliminary histological study based on a rat model. Experimental lung research. 2011;38:211–221. [PubMed]
56. McTiernan A, Ulrich CM, Yancey D, Slate S, Nakamura H, Oestreicher N, Bowen D, Yasui Y, Potter J, Schwartz R. The Physical Activity for Total Health (PATH) Study: rationale and design. Medicineand science in sports and exercise. 1999;31:1307–1312. [PubMed]
57. Kruk J, Aboul-Enein HY. Physical activity in the prevention of cancer. Asian Pacific journal of cancer prevention : APJCP. 2006;7:11–21. [PubMed]
58. Rochlitz CF, Scott GK, Dodson JM, Liu E, Dollbaum C, Smith HS, Benz CC. Incidence of activating ras oncogene mutations associated with primary and metastatic human breast cancer. Cancer research. 1989;49:357–360. [PubMed]
59. Gago-Dominguez M, Jiang X, Esteban Castelao J. Lipid peroxidation and the protective effect of physical exercise on breast cancer. Medical hypotheses. 2007;68:1138–1143. [PubMed]
60. Lunz W, Peluzio MC, Dias CM, Moreira AP, Natali AJ. Long-term aerobic swimming training by rats reduces the number of aberrant crypt foci in 1,2-dimethylhydrazine-induced colon cancer. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica [etal] 2008;41:1000–1004. [PubMed]
61. Aoi W, Naito Y, Takagi T, Kokura S, Mizushima K, Takanami Y, Kawai Y, Tanimura Y, Hung LP, Koyama R, Ichikawa H, Yoshikawa T. Regular exercise reduces colon tumorigenesis associated with suppression of iNOS. Biochemical and biophysical research communications. 2010;399:14–19. [PubMed]
62. Demarzo MM, Martins LV, Fernandes CR, Herrero FA, Perez SE, Turatti A, Garcia SB. Exercise reduces inflammation and cell proliferation in rat colon carcinogenesis. Medicine and science in sports and exercise. 2008;40:618–621. [PubMed]
63. Moser AR, Pitot HC, Dove WF. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1990;247:322–324. [PubMed]
64. Baltgalvis KA, Berger FG, Pena MM, Davis JM, Carson JA. The interaction of a high-fat diet and regular moderate intensity exercise on intestinal polyp development in Apc Min/+ mice. Cancer Prev Res (Phila) 2009;2:641–649. [PMC free article] [PubMed]
65. Thorling EB, Jacobsen NO, Overvad K. The effect of treadmill exercise on azoxymethane-induced intestinal neoplasia in the male Fischer rat on two different high-fat diets. Nutrition and cancer. 1994;22:31–41. [PubMed]
66. Tahara E. Growth factors and oncogenes in human gastrointestinal carcinomas. Journal of cancer research and clinical oncology. 1990;116:121–131. [PubMed]
67. Iemitsu M, Maeda S, Jesmin S, Otsuki T, Miyauchi T. Exercise training improves aging-induced downregulation of VEGF angiogenic signaling cascade in hearts. American journal of physiology Heart and circulatory physiology. 2006;291:H1290–1298. [PubMed]