Clinical And Experimental Studies Of Hypoalbumineamia In Advanced Colorectal Cancer: Molecular Mechanisms And Treatment

Chapter 1 Clinical studies on the mechanism of hypoalbumineamia in advanced colorectal cancerObjective To explore the relationship between acute phase protein response induced proinflammatory cytokines(TNF-a and IL-6)and hypoalbuminemia in advanced colorectal cancer patients.Moreover,this study was alsoconducted to clarify the expression levels of IL-6 mRNA and PIF mRNA in tissue of advanced colorectal cancer and to further elucidate the relationship between the expression levels of IL-6 mRNA,PIF mRNA and hypoalbumineamia in patients with advanced colorectal cancer.Methods According to the serum albumin concentration(detected by BCG method at the second day in hospital),63 patients with advanced colorectal cancer were divided into 2 groups:hypoalbumineamia group with concentration of serum albumin＜35g/L(38 patients)and normal group with concentration of serum albumin≥35g/L(25 patients).Serum IL-6 and TNF-a concentrations were determined by enzyme-linked immunosorbent assay(Elisa testing).Serum CRP concertration was measured by an immunoturbinometric method. Immunohistochemistry testing(Supervision^TM)was used to detect the expression of TNF-a and IL-6 in cancer tissues.RT-PCR semi-quantity method was used to detect the expression of IL-6 mRNA and PIF mRNA in the two groups.Results Compared with normal group,hypoalbumineamia group showed significantly higher serum concentration of CRP and serum concentration of FIB, while this group showed significantly lower serum concentration of total protein and prealbumin.The level of serum TNF-a and IL-6 in hypoalbumineamia group was significantly higher than that in normal group(P=0.000,P=0.003).Significantly,the concentration of serum IL-6 and TNF-a was negatively correlateed with serum albumin concentration and was positively correlated with serum CRP concentration.Furthermore,high IL-6 and high CRP levels were associated with reduced serum albumin concentration.In the normal tissues,expression of IL-6 and TNF-a were not showed by immunohistochemistry in two groups.There was no significant difference between normal group and hypoalbumineamia group(P=0.567)of TNF-a immunohistochemistry,while IL-6 immunohistochemistry were significantly different(P=0.005),the expression of IL-6 in hypoalbumineamia group was higher than that in normal group(x²=2.82 P=0.005).Compared with normal group,hypoalbumineamia group showed higher expression levels of IL-6 mRNA(1.39±0.49VS0.62±0.40)in colorectal cancer tissue(t=6.5,P=0.000).Expression levels of IL-6 mRNA in colorectal cancer tissue were negatively correlated with serum albumin concentration,and positively correlated with serum IL-6 concentration.PIFmRNA in tissue of advanced colorectal cancer were not expressed.Conclusion There is a acute-phase protein response in patiens with advanced colorectal cancer complicating hypoalbumineamia,which is characterized by elevated serum CRP concentration and reduced serum total protein,prealbumin,albumin concentration.There is high expression of IL-6 mRNA and no expression of PIF mRNA in advanced colorectal cancer tissue. IL-6 autocrined of colorectal cancer tissue prossibly play an important role in inducing acute-phase protein response in patiens with advanced colorectal cancer complicating hypoalbumineamia.Hypoalbumineamia in advanced colorectal cancer is associated with acute-phase protein response with serum IL-6 participated.Chapter 2Effect of exogenous recombinant growth hormone on the growth and proliferation of thansplanted colon adenocarcinoma carcinoma and serum protein metabolism in tumor-bearing BLBA/c miceObjective To investigate the effect of exogenous growth hormone on growth of transplanted tumor,proliferation of cancer cell and serum protein metabolism of tumor-bearing mice.In order to explore the molecular mechanisms of exogenous growth hormone enhancing serum protein synthesis on tumor-inducing mice.Methods Thirty male BALB/c mice were randomized into three groups:normal control group(A group)and tumor group(B group)and tumor group+GH treatment group(C,D,E group).In tumor group and tumor group+GH treatment,a suspension of 10⁶ murine colon 26 adnocarcinoma cells was inoculated s.c into each mouse.The model of thansplanted murine colon 26 adnocarcinoma cells in BALB/c was set up.Saline or GH were respectively administered S.C.daily from day 0 for 28 days for B or E group,Whereas GH were respectively administered s.c.daily from day 14 for 28 days for C and D group.Body weight and tumour volume were measured daily after inoculation.Serum glucose,total protein,albumin,triglyceride and IL-6 concentrations were determined at the day 28 following the inoculation.SOCS-3 mRNA expression levels of tumor-bearing mice's live tissue were observed by Real-time PCR.PCNA expression levels of transplanted tumor were observed by immunohistochemistry also.Results Compared with group B,the weight and serum albumin concentration of tumor-bearing mice in group C,D and E were increased significantly at the end of experiment.however there was no difference in tumor weight and volmue among B,C,D,E groups(p＞0.05).Whereas,the concentrations of glucose,total protein,albumin and IL-6 level showed significant difference between the three groups(p＜0.05).The serum IL-6 concentration in treatment group was lower than that in the tumour group(B group),but higher than the normal control group(A group).PCNA expression was always positive in transplantation tumor (F=3.14 v=3 P=0.048),The percentage of positive cells in each group was different,of which group E the highest,and group B the lowest.There was significant differences of the relative expression of SOCS-3 mRNA in mice liver tissue in each groups(F=7.88 P=0.00).Group E has the significance difference with group B(P=0.003).The express of SOCS-3 mRNA in group C,D and E were increased.Conclusion Exogenous growth hormone can amelioration hypoalbumineamia of tumor-bearing mice.The use of short-term,low dose exogenous growth hormone is safe and useful for the cancer-caused hypoalbumineamia,but using growth hormone in long-term and large dose will increase a possibility of cancer cell proliferation.The molecular mechanism of exogenous growth hormone regulating acute-phase protein response induced by IL-6 is possibly associated with the up-regulation of SOCS-3 mRNA expression in liver tissue of tumor-bearing mice.