The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6-8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 10(5)) and randomly assigned to exercise (n = 28) or a non-intervention control (n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with "productive" tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer.
Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin–cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow (15O–water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P < 0.001 and P = 0.07, respectively). These changes were accompanied by significant time × group interactions in CEPs and select CAFs [placenta growth factor, interleukin (IL)-1β, and IL-2], also favoring the AC+AET group (P < 0.05). 15O–water positron emission tomography (PET) imaging revealed a 38%decrease in tumor blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined.
Specific inhibitors of COX-2 have been associated with increased risk for cardiovascular complications. These agents reduce prostacyclin (PGI2) without affecting production of thromboxane (Tx) A2. While this abnormal pattern of eicosanoid generation has been implicated in the development of vascular disease associated with COX-2 inhibition, its role in the development of hypertension, the most common cardiovascular complication associated with COX-2 inhibition, is not known. We report here that mice lacking the receptor for PGI2 (IPKOs) develop salt-sensitive hypertension, cardiac hypertrophy, and severe cardiac fibrosis. Coincidental deletion of the TxA2 (TP) receptor does not prevent the development of hypertension, but cardiac hypertrophy is ameliorated and fibrosis is prevented in IPTP double knockouts (DKOs). Thus, deletion of the IP receptor removes a constraint revealing adverse cardiovascular consequences of TxA2. Our data suggest that adjuvant therapy that blocks unrestrained Tx actions might protect against end-organ damage without affecting blood pressure in patients taking COX-2 inhibitors.
One thousand consecutive cases of surgically proven endometriosis were reviewed to evaluate the frequency and types of pelvic cancers that were associated with ovarian and extraovarian endometriosis. The frequency and types of histologic abnormalities present in the eutopic endometrium when cancers were noted in endometriosis were also evaluated. In the large subset of cases for which the authors were the primary pathologists and all foci of endometriosis were recorded, the frequency of malignancy was 10.8%. In contrast, the frequency was only 3.2% in cases diagnosed by others previously in our institution. Cancers were more commonly found in ovaries when endometriosis was present in that ovary (5%) compared to when endometriosis was present at other sites (1%). Clear cell and endometrioid carcinomas were the malignancies most commonly seen in ovaries containing endometriosis, while clear cell adenocarcinoma and adenosarcoma were most commonly seen in conjunction with extraovarian endometriosis. The association of endometriosis with endometrioid and clear cell carcinoma was much stronger than that of serous and mucinous tumors (p < .01). Concurrent endometrial pathology was commonly seen in cases of malignant transformation of endometriosis (32% of cases).
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