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Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF small interfering RNA (siRNA) treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia-resistant cancers.

Background Tumor-related leukocytosis (TRL) is occasionally found in patients with nonhematopoietic malignancies. We investigated the clinical implication of TRL and individualized treatment for TRL-positive cervical cancer, as well as the underlying biological mechanism. Methods Clinical data from 258 cervical cancer patients treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms responsible for TRL in cervical cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and myeloid-derived suppressor cells (MDSCs). All statistical tests were two-sided. Results TRL was statistically significantly associated with younger age (Wilcoxon rank sum test, P = .03), larger tumor size (Wilcoxon rank sum test, P= .006), advanced clinical stage (χ² test, P= .01 ), and shorter overall survival (Cox proportional hazard modeling and Wald tests, P< .001). Among cervical cancer patients, TRL was associated with upregulated tumor G-CSF expression (χ² test, P < .001), elevated serum G-CSF levels (Student f test, P= .03), larger spleens (Student f test, P = .045), and increased MDSC frequencies in the blood (Student f test, P< .001) compared with the TRL-negative patients. In vitro and in vivo experiments revealed that tumor-derived G-CSF was involved in the underlying causative mechanism of TRL and MDSCs induced by tumor-derived G-CSF are responsible for the rapidly progressive and radioresistant nature of TRL-positive cervical cancer. The administration of anti-Gr-1 neutralizing antibody or the depletion of MDSCs by splenectomy (n = 6 per group) inhibited tumor growth and enhanced radiosensitivity in TRL-positive cervical cancer xenografts (Wilcoxon rank sum test, P= .008 and P= .02, respectively). Conclusions TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients. [ABSTRACT FROM AUTHOR]

We investigated the effect of platelets on ovarian cancer and the role of adenosine diphosphate (ADP) receptors (P2Y12 and P2Y1) on platelets in the growth of primary ovarian cancer tumors. We showed that in murine models of ovarian cancer, a P2Y12 inhibitor (ticagrelor) reduced tumor growth by 60% compared with aspirin and by 75% compared with placebo. In P2Y122/2 mice, the growth of syngeneic ovarian cancer tumors was reduced by >85% compared with wild-type (WT) mice. In contrast, there was no difference in tumor growth between P2Y12/2 and WT mice. Reconstitution of hematopoiesis in irradiated P2Y122/2 mice by hematopoietic progenitor cells from WT mice (WT→P2Y122/2) restored tumor growth in P2Y122/2 mice. Finally, knockdown of ecto-apyrase (CD39) on ovarian cancer cells increased tumor growth in tumor-bearing mice. Although in the absence of platelets, ADP, the P2Y12 inhibitor, recombinant apyrase, or knockdown of CD39 did not affect cancer cell proliferation, in the presence of platelets, the P2Y12 inhibitor and recombinant apyrase reduced and knockdown of CD39 increased platelet-enhanced cancer cell proliferation. These results suggest that P2Y12 on platelets and ADP concentration at the interface between cancer cells and platelets affect the growth of primary ovarian cancer tumors in mice. If additional studies in mice and in pilot human trials confirm our results, inhibition of P2Y12 might be a new therapeutic option that can be used in adjuvant to the traditional surgery and chemotherapy in patients with ovarian cancer. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to investigate the prognostic significance of an elevated neutrophil count at the time of the initial diagnosis in patients with surgically treated endometrial cancer. Methods The baseline characteristics and outcome data of patients who were diagnosed with endometrial cancer between January 2000 and December 2010 were collected and retrospectively reviewed. The patients were separated into two groups according to their neutrophil counts. The clinicopathological characteristics and overall survival rates of the two groups were compared. A Cox proportional hazard regression model was used to investigate the prognostic significance of an elevated neutrophil count among patients with surgically treated endometrial cancer. Results An elevated neutrophil count was found to be associated with an advanced clinical stage (P < 0.0001), lymphovascular space involvement (P = 0.0003), cervical involvement (P = 0.0049), the proportion of patients that received adjuvant therapy (P = 0.0020), elevated NLR (P < 0.0001), and treatment failure (P < 0.0001). Multivariate analyses demonstrated that age (hazard ratio (HR) = 2.23, 95% confidence interval (95% CI) = 1.30 to 3.91; P = 0.0035), clinical stage (HR = 4.72, 95% CI = 2.61 to 8.90; P < 0.0001), lymphovascular space involvement (HR = 3.15, 95% CI = 1.60 to 6.68; P = 0.0007), an elevated neutrophil count (HR = 2.76, 95% CI = 1.43 to 5.03; P = 0.0033), and an elevated white blood cell count (HR = 2.79, 95% CI = 1.50 to 4.96; P = 0.0017) were significant predictors of survival. Conclusion The elevated neutrophil or leukocyte counts at the time of the initial diagnosis are independent prognostic factors in patients with surgically treated endometrial cancer. [ABSTRACT FROM AUTHOR]