The Inhibitory Effect Of Systemic Hypoxia On Tumorigenesis And Tumor Progression

Background and Objectives:Cancer is one of the first leading causes of deaths in China and it has been a serious threat to people’s health.In the past decades lots of research had shown that exercise can plays a positive role in tumor therapy,including inhibition of tumor recurrence,metastasis,reduce mortality.However,the method of exercise therapy has its limitations,cancer patients experience cachexia and tend to be fatigue,it is hard to perform strenuous exercise.So people are trying to find surrogates of exercise which has less physical burdens but the same effect on inhibition tumorigenesis.Previous studies have shown that exercise and hypoxia trigger a similar response to increase catecholamine,activate and mobilize NK cells.Almost all studies of local hypoxia in tumor microenvironment on the promotion of tumorigenesis,whereas the acute systemic effect of hypoxia has never been investigated.Therefore,in this study,a variety of animal tumor models were selected to observe,the effect of systemic hypoxia on tumorigenesis was observed.Many studies have demonstrated the promoting effect of local hypoxia in tumor microenvironment on cancer growth and metastasis.But it is worth noting that,systemic hypoxia was used in this study（animals were placed in a 10%O2 environment,so that animals appeared systemic hypoxia）,observed its effect on tumorigenesis.This study will provide a basis for systemic hypoxia treatment of tumors.Methods:1、Effect of systemic hypoxia on tumorigenesis of NEU transgene mice:4months female NEU transgene mice were randomly divided into two groups,10 mice of each group.Systemic hypoxia was subjected of low oxygen group mice for 1 h,10%O₂ every day.Normal oxygen group mice was not subjected to systemic hypoxia,other feeding conditions were the same.Weekly subcutaneous palpation was used to observe tumor formation in mice,tumor formation time was recorded.Tumor volume of mice was measured every three days after tumor formation in mice.2、Effect of systemic hypoxia on tumorigenesis of C57 xenograft mice:4 weeks female C57 mice were randomly divided into two groups,10 mice of each group.Pre-systemic hypoxia was subjected of low oxygen group mice for 2 weeks for 1 h,10%O₂ every day.Then low oxygen and normal oxygen group mice were injected subcutaneously with B16-F10 melanoma cells.Low oxygen group mice were continued to be subjected to systemic hypoxia for another two weeks.Normal oxygen group mice were not subjected to systemic hypoxia,other feeding conditions were the same.Tumor formation in mice was observed after injection of cells every day,tumor formation time was recorded.Tumor volume of mice was measured the every two days after tumor formation in mice.After 2 weeks,mice were sacrificed,tumors removed and weighed.3、Effect of systemic hypoxia on gene expression in tumor tissue:RNA Sequence technique was used to detect the expression of genes in tumor tissues collected from normal oxygen and low oxygen group.4、Effect of systemic hypoxia on tumorigenesis of nude mice:4 weeks female nude mice were randomly divided into two groups,10 mice of each group.Pre-systemic hypoxia was subjected of low oxygen group nude mice for 2 weeks for1 h,10%O₂ every day.Then low oxygen and normal oxygen group mice were injected subcutaneously with B16-F10 melanoma cells.Low oxygen group was continued to be subjected to systemic hypoxia for another two weeks,normal oxygen group was not subjected to systemic hypoxia,other feeding conditions were the same.Tumor formation in mice was observed after injection of cells every day,tumor formation time was recorded.Tumor volume of mice was measured the every two days after tumor formation in mice.After 2 weeks,mice were sacrificed,tumors were removed and weighed after Subcutaneously injected cells for 2 weeks.Results:1、Effect of systemic hypoxia on tumorigenesis of NEU transgene mice:The average time of tumor formation in low oxygen group mice was longer than in normal oxygen group.However,it had no significant difference between two groups（p>0.05）.The tumor growth rate of mice in low oxygen group was significantly slower than that in normal oxygen group（p<0.01）.The tumor-bearing number of mice in low oxygen group was significantly lower than that in normal group（p<0.01）.The results suggested that systemic hypoxia inhibits tumorigenesis.2、Effect of systemic hypoxia on tumorigenesis of C57 xenograft mice:The tumor growth rate of mice in low oxygen group was significantly lower than in normal oxygen group（p<0.01）.Moreover,the tumor weight of mice in low oxygen group was significantly lower than in normal group（p<0.01）.The results further confirmed that the inhibitory effect of systemic hypoxia on the tumorigenesis.3、Effect of systemic hypoxia on gene expression in tumor tissue:RNA sequence results showed that 44 gene expression about the immune system were changed,it was significantly higher than the number of other system gene changes in the body.T cell-associated chemokines such as CCL3,CCL4,CXCL12 and other genes were significantly increased in mRNA levels.T cell surface markers,such as CD4,CD28and other gene had also been upregulated in mRNA levels.The results suggested that the inhibitory effect of systemic hypoxia on tumorigenesis may relate to the immune system,moreover maybe it is associated with T cell immunity.4、Effect of systemic hypoxia on tumorigenesis of nude mice:The rate of tumor growth in normal oxygen mice was significantly lower than in low oxygen group（p<0.01）.And at the same time after tumor formation,the tumor weight of mice in normal oxygen group was significantly lower than in low oxygen group（p<0.05）.The results suggested that systemic hypoxia inhibition of the tumor maybe is associated with T cell immunity.Conclusion:Systemic hypoxia can inhibit tumorigenesis and tumor progression,the inhibitory effect of systemic hypoxia on tumor maybe is associated with T cell immunity.