Study Of Risk Factors Of Adult Leukemia And The Mechanism Of The VEGF-DLL4/Notch Signaling Pathway Feedback On The Tumor Angiogenesis

Background:Leukemia is a common hematologic malignancy worldwide, which originate from hematopoietic stem cell clones, characterized by abnormal differentiation or proliferation of functionally incompetent leukemic cells. Benzene and ionizing radiation have been well-documented as the risk factors of adult leukemia, and others include pesticides, cigarette smoking, family history of cancers, and electromagnetic fields. Previous studies have also showed that allergy history was correlated with leukemia, but until now this relationship has not been determined. Little information was available whether there are interactions between allergy history and other risk factors. This study may provide clues to the etiology of adult leukemia.Objective:To investigate the roles of allergy history and family history of cancers and their interaction in the etiology of adult leukemia.Marterials and methods:This case-control study based on hospital group was conducted at Dept. of Hematology, Qilu Hospital, Shandong University. Eligible cases were volunteers of leukemia patients aged18years and above, with histologically confirmed leukemia diagnosed (according to FAB diagnosis and typing standard). The leukemia patients who were pregnant or lactating women, comorbid other serious diseases (Cardiorespiratory failure, cachexia in late stage of carcinoma etc), or refused to be interviewed were ruled out of this study.Controls were selected from volunteers of patients aged18years and above who were admitted to the same hospital during the same period with cases other than any type of cancers or any diagnosed diseases associated with hematological system. The patients who were pregnant or lactating women, comorbid any type of cancers or any diagnosed diseases associated with hematological system, or refused to be interviewed were ruled out of the control group.During the study period, a total of143leukemia cases and243controls were enrolled in this study. The socio-demographic factors included sex, age, ethnicity, education level, smoking status, drinking status, allergy history, and family cancer history and toxic exposure history. All data analyses were performed using SPSS18.0, Single factor analysis was used to analyze the variables (α=0.10), then the significant variables were put into the stepwise regression analysis model for multivariate analyses (α=0.05). To clarify the interaction between allergy history and family history of cancers for the risk of leukemia, the unconditional logistic regression analysis was employed to establish regression model and interaction of these factors was analyzed.Results:1. Single factor analysis:The cumulative exposures of living locations, toxic exposure history, allergy history, and family cancer history could be significant factors in the causes of most cases of leukemia.2. Results from multivariate analyses showed that there are positive associations between allergy history, toxic exposure history, family cancer history and the risk of adult leukemia(OR=1.94,95%CI:1.15-3.28for prior allergies, OR=2.16,95%CI:1.06-4.42for family history of cancer, OR=1.85,95%CI:1.16-2.94for toxic exposure). 3. The results showed that there was an synergistic effect of the allergy history and family cancer history(RERI=13.01, AP (AB)=81.90%,S=7.96).ConclusionThe present study suggested that allergy history, family cancer history and toxic exposure history may be risk factors for adult leukemia; and the interaction between allergy history and family cancer history was likely to be synergistic rather than additive for the risk of leukemia. Objective:To investigate the correlations between hypoxia of ovarian tissues and the expression level of VEGF and DLL4/Notch signaling pathway molecules, as well as clinical features of ovarian cancer, and explore the effects of DLL4/Notch signaling pathway on the angiogenesis of ovarian cancer and related mechanisms involved in the VEGF feedback, trying to find the best treatment which can inhibit the angiogenesis effectively, and finally inhibit the growth of ovarian tumor.Methods:We collected tissues from patients with ovarian cancer and benign ovarian tumor which are diagnosed by certified pathologists, as well as tissues from normal ovaries. Immunohistochemistry was used to detect the expression of VEGF/VEGFR and DLL4/Notch signaling pathway markers.Results:Expression levels of VEGF/VEGFR and DLL4/Notch signaling pathway molecules in ovarian tumor tissues were significantly higher than those in normal ovary tissues and benign ovarian tumor tissues (P<0.05, except VEGFR2). There are significant correlations between CD34and VEGFR2, CD34and Notch1, VEGFR1and DLL4, as well as between VEGFR2and Notch1in ovarian tumor tissues (P<0.05).Conclusion:VEGF and DLL4/Notch signaling pathways promote vascularization in ovarian tumors, which maybe the valuable targets for the treatment of this disease. Activated DLL4/Notch signaling pathway is another key regulator in the process of vascularization of ovarian tumor, indicating that there might be a negative feedback between VEGF and DLL4/Notch signaling pathways.