title: Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise.
abstract: Exercise has been shown to improve postischemia perfusion of normal tissues; we investigated whether these effects extend to solid tumors. Estrogen receptor-negative (ER-, 4T1) and ER+ (E0771) tumor cells were implanted orthotopically into syngeneic mice (BALB/c, N = 11-12 per group) randomly assigned to exercise or sedentary control. Tumor growth, perfusion, hypoxia, and components of the angiogenic and apoptotic cascades were assessed by MRI, immunohistochemistry, western blotting, and quantitative polymerase chain reaction and analyzed with one-way and repeated measures analysis of variance and linear regression. All statistical tests were two-sided. Exercise statistically significantly reduced tumor growth and was associated with a 1.4-fold increase in apoptosis (sedentary vs exercise: 1544 cells/mm(2), 95% CI = 1223 to 1865 vs 2168 cells/mm(2), 95% CI = 1620 to 2717; P = .048), increased microvessel density (P = .004), vessel maturity (P = .006) and perfusion, and reduced intratumoral hypoxia (P = .012), compared with sedentary controls. We also tested whether exercise could improve chemotherapy (cyclophosphamide) efficacy. Exercise plus chemotherapy prolonged growth delay compared with chemotherapy alone (P < .001) in the orthotopic 4T1 model (n = 17 per group). Exercise is a potential novel adjuvant treatment of breast cancer.
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC (ASB, CDL, DW, CL, PMS, GRD, GP, MWD); Department of Internal Medicine, Massachusetts General Hospital, Boston, MA (ASB); Memorial Sloan Kettering Cancer Center, New York, NY (LWJ).
authors.forename: Allison S
authors.initials: AS
authors.lastname: Betof
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC (ASB, CDL, DW, CL, PMS, GRD, GP, MWD); Department of Internal Medicine, Massachusetts General Hospital, Boston, MA (ASB); Memorial Sloan Kettering Cancer Center, New York, NY (LWJ).
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lascola
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC (ASB, CDL, DW, CL, PMS, GRD, GP, MWD); Department of Internal Medicine, Massachusetts General Hospital, Boston, MA (ASB); Memorial Sloan Kettering Cancer Center, New York, NY (LWJ).
authors.forename: Douglas
authors.initials: D
authors.lastname: Weitzel
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC (ASB, CDL, DW, CL, PMS, GRD, GP, MWD); Department of Internal Medicine, Massachusetts General Hospital, Boston, MA (ASB); Memorial Sloan Kettering Cancer Center, New York, NY (LWJ).
authors.forename: Chelsea
authors.initials: C
authors.lastname: Landon
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC (ASB, CDL, DW, CL, PMS, GRD, GP, MWD); Department of Internal Medicine, Massachusetts General Hospital, Boston, MA (ASB); Memorial Sloan Kettering Cancer Center, New York, NY (LWJ).
authors.forename: Peter M
authors.initials: PM
authors.lastname: Scarbrough
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC (ASB, CDL, DW, CL, PMS, GRD, GP, MWD); Department of Internal Medicine, Massachusetts General Hospital, Boston, MA (ASB); Memorial Sloan Kettering Cancer Center, New York, NY (LWJ).
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC (ASB, CDL, DW, CL, PMS, GRD, GP, MWD); Department of Internal Medicine, Massachusetts General Hospital, Boston, MA (ASB); Memorial Sloan Kettering Cancer Center, New York, NY (LWJ).
authors.forename: Gregory
authors.initials: G
authors.lastname: Palmer
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC (ASB, CDL, DW, CL, PMS, GRD, GP, MWD); Department of Internal Medicine, Massachusetts General Hospital, Boston, MA (ASB); Memorial Sloan Kettering Cancer Center, New York, NY (LWJ).
authors.forename: Lee W
authors.initials: LW
authors.lastname: Jones
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC (ASB, CDL, DW, CL, PMS, GRD, GP, MWD); Department of Internal Medicine, Massachusetts General Hospital, Boston, MA (ASB); Memorial Sloan Kettering Cancer Center, New York, NY (LWJ).
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology; D015444:Exercise; D005260:Female; D006801:Humans; D016014:Linear Models; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000737:chemistry / Q000188:drug therapy* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation / Q000187:drug effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011897:Random Allocation; D011960:Receptors, Estrogen / Q000032:analysis; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011960:Receptors, Estrogen; D003520:Cyclophosphamide