A Research Of Molecular Mechanism Of Adipose Tissue Wasting In Cancer Cachexia

Cancer cachexia is a devastating wasting syndrome which accompanied by muscle wasting and inflammation. This syndrome affects around 50–80% of cancer patients and may accounts for up to 20% of cancer deaths. To conquer this disaster, most researchers focus their attention on muscle wasting, but largely unsuccessfully. The research of adipose tissue wasting becom a point of focus among relevant academic circles. Our research team use two kinds of cancer cachexia mice models, at the early and advanced stage, explore the causes and mechanism of lipid lost in three different types of adipose tissue. Our research made by two parts:PART 1 The establishment of cancer cachexia model and the mechanism analysis of lipid loss.Objective: We aimed to establish a stable and reliable cancer cachexia model, record the weight change of adipose tissue, in addition, we aimed to explore the molecular mechanism of lipid lose in adipose tissue.Methods: We subcutaneously injects LLC tumor cells to male C57BL/6 mice, sacrifice the mice after 28 days, harvest inguinal white adipose tissue(i WAT), epididymis white adipose tissue(e WAT) and brown adipose tissue(BAT). Then, we purify the RNA in the adipose tissue, use q RT-PCR to detect the expression level of gene related to lipid metabolism. With HE staining, we comparise and analysis the change of e WAT, i WAT, BAT between tumor group and control group. More over, we analysis the browning of i WAT and e WAT with immunohistochemical staining.Result: Relative to the control group, mice of the tumor group have a lower tumor free body weight, and less lipid in adipose tissue. In two kinds of white adipose tissue, the expression of lipid synthesis related genes declined, the expression of heat production related gene(browning related gene) raise up, however, lipid degradation related gene have no obvious change. In brown adipose tissue of tumor group mice, relative to control group, the expression of lipid synthesis related genes declined, the expression of lipid degradation related gene raise up, however, the heat production related gene declined. Lastly, with Immunohistochemical staining technology, we prove that the browning of white adipose tissue happend not only in subcutaneous adipose tissue but also in visceral adipose tissue.Conclusion: We successfully build a mice cancer cachexia model, preliminary discover that lipid loss of white adipose tissue in cancer cachexia mice may caused by the reducing of lipid synthesis and browning. Lipid loss of brown adipose tissue in cancer cachexia mice may caused by reducing of lipid synthesis and increasing of lipid degradation. There is an obvious Inflammatory conditions in three kinds of adipose of cancer cachexia mice, this discover remind us that Inflammation plays an importent role in cancer cachexia.PART 2 The research of lipid loss in early and advanced cancer cachexia model.Objective: Build early and advanced cancer cachexia model, comparative observe the atrophy of adipose tissue, comparative analyze the difference mechanismof lipid lose between early stagecancer cachexia and advanced stagecancer cachexia.Methods: We subcutaneously injects LLC tumor cells to male C57BL/6 mice and injects C26 tumor cells to male CD2F1 mice, sacrifice the mice after 24 days or 36 days, harvest i WAT, e WATand BAT. Then, we analyze the difference mechanism of lipid lose in different stages of cancer cachexiawith HE staining, immunohistochemical staining or western blot.Result: Relative to control group, the mice of tumor group have lower tumor free body weight, less lipid in adipose tissue. More over, relative to early cancer cachexia group, the advanced stage group have a more serious situation. We found that, relative to control group, SREBP1 a and PPAR? down regulate in e WAT and BAT of cancer cachexia mice, PGC1?and UCP1 up regulated in e WAT of cancer cachexia mice, especially in the advanced stage group. It is strange that the expression of PGC1?and UCP1 are down regulate in BAT of cancer cachexia mice. Lastly, with Immunohistochemical staining, we found that UCP1 up regulate in i WAT of cancer cachexia C57BL/6 mice, and that PGC1? up regulate in e WAT of cancer cachexia CD2F1 mice, and that the advanced stage group have a more serious situation.Conclusion: Relative to the early stage cancer cachexia group, the mice of advanced stage cancer cachexia have less adipose tissue and more serious lipid lose. The reason under such phenomenon may come from less lipid synthesis and WAT browning. It is strange that the expression of heat production factors are down regulate in BAT of cancer cachexia mice. We hypothesis that there may be a kind of negative feedback mechanism under such situation.