Tumor Derived Factors In Animal Experimental Cancer Cachexia

Background & ObjectiveCachexia is a complex metabolic status with progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle.Cancer cachexia occurs most frequently in malignancy and is associated with more than 20% of cancer deaths. This study was to explore the effect of tumor derived VEGF in animal experimental cancer cachexia as well as observe the effect of Bevacizumab and Celecoxib on the cachectic mice.MethodsMurine fibrosarcoma T241-VEGF cells were s.c. implanted on the back of 6—8-week-old female C57BL/6 mice to construct the xenograft tumor model. Primary tumors were measured on alternate days following injection of tumour cells.The body weight,tumor volume and food intake were monitored three times a week.When tumors reached a mean volume of 0.1cm3,the therapy of the selective COX-2 inhibitor celecoxib in the diet was initiated and maintained for 3 weeks(250 mg/kg/day), while anti-VEGF neutralizing antibody bevacizumab (Roche) at the dose of 5mg/kg twice weekly was i.p. injected for 3 weeks.Tumor-bearing and control mice were killed when they were in the agonal state. The level of hemoglobin,the numbers of erythrocytes in peripheral blood were analyzed.Histological analysis of liver and lung were applied.Statistical analysis was performed using the student's t test.Results(1)The construction of cancer cachexia model:About 10 days after tumor implantation,VEGF tumor-bearing mice exhibited piloerection and asthenia followed by deteriorated physical conditions.Swelling abdomens and pale nose,oral lips and paws were increasingly evident accompanied by obvious increase in the tumor's size. When mice were killed at the end,significant reductions in body mass,gastrointestinal weight and carcass were observed in the VEGF group mice,accompanied by a severe decrease in food intake.Hematological analysis showing significant reduced levels of hemoglobin in peripheral blood, P<0.05. Histological examination showed significant congestion and edema of liver.The hepatic lobules were destructed and liver sinusoids were expanded.Pulmonary edema and alveolar wall thickening were seen in the lung tissues with a large number of inflammatory cells infiltration.(2)The effect of Anti-VEGF Agents:Bevacizumab significantly delayed tumor growth rate at 5mg/kg.VEGF induced anorexia,anemia,body weight loss and hepatosplenomegaly were significantly alleviated by bevacizumab.Histological analysis indicated that the dilated sinusoidal blood vessels in the liver appeared normal.(3)The Effect of celecoxib on tumor growth:There was a conspicuous reduction in tumor size between treated and non-treated group at the end of the experiment (p<0.05). The survival time was prolonged.ConclusionThe tumor derived VEGF can affect multiple tissues,organs and result in cancer cachexia in mice models,indicating that VEGF might be involved in the progression of cancer cachexia.Bevacizumab could inhibit tumor growth,improve the cachexia-related symptoms and reduce the pathological damages of tissues.Celecoxib could improve the general situation of cancer cachexia mice,increase terminal non-tumor weight.Thus bevacizumab and celecoxib could both play an anti-cancer cachexia role.