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Author | Xueyue Editor | Qi In advanced cancer patients, tumor-related anorexia (anorexia) can affect the success rate and survival rate of treatment.
It is closely related to cachexia caused by tumors and seriously affects the lives of patients.
Among them, more than 60% of patients have anorexia, and it also occurs in patients who have not received chemotherapy, which shows that the anorexia caused by tumor patients is independent of the treatment process.
However, the development mechanism of anorexia in cancer patients is still unclear.
In tumor anorexia cachexia syndrome, cytokines secreted by tumors play an important role in the mutual influence of organs.
Inflammatory factors entering the systemic circulation and tumor-derived hormones and growth factors can cause muscle loss in patients.
Recently, it has been reported that in chronic diseases, GDF15 (growth differentiation factor) is related to the amount of food consumed and weight loss.
ImpL2 is a gene homologous to mammalian insulin-like growth factor binding protein IGFBP in Drosophila.
It is secreted from tumor tissue into the circulatory system.
By inhibiting IGF signal, it can damage muscle function and loss.
On February 8, 2021, the Kweon Yu team from the Center for Disease Target Research, a researcher of the Korean Bioengineering, published an article titled Tumour-derived Dilp8/INSL3 induces cancer cc by regulating feeding neuropeptides via Lgr3/8 in the brain in Nature Cell Biology.
.In this paper, a Drosophila tumor-derived anorexia model was established, and it was found that Dilp8 derived from Drosophila tumors is regulated by Lgr3, and INSL3 derived from mammalian tumors is regulated by Lgr8, thereby inducing tumor-related anorexia.
The author first overexpressed yorkie (yki) (Hippo pathway transcriptional co-activator) in the eyes of Drosophila to establish a tumor model.
Analysis found that this tumor model caused a significant reduction in the life span of fruit flies.
Compared with the control group, the food intake of fruit flies was reduced by about 30%, indicating that this fruit fly tumor model can simulate the anorexia of human tumors.
Continuous observation revealed that food intake began to decrease after five days, and the triglyceride concentration in adipose tissue of the Drosophila tumor model decreased on the tenth day, severe weight loss phenotype appeared on 15-20 days, and abnormal mitochondrial structure of muscles appeared in flies on 15 days.
, Muscle loss occurs.
This shows that the appearance of anorexia precedes organ wasting.
The author used the transcriptome to detect the expression levels of the tumor secretion factors Dilp8, ImL2 and Upd2.
It was found that Dilp8 and Upd2 were highly expressed at five days, and ImpL2 expression reached a peak at 15 days.
Because anorexia precedes weight loss, the author believes that Dilp8 and Upd2 may be related to anorexia.
The authors found that Dilp8-RNAi can rescue the anorexia phenotype.
In addition, the authors used Dilp8 antibody to confirm that Dilp8 can be secreted from tumor tissues into the peripheral circulation.
Recent studies have shown that Lgr3 is the receptor of Dilp8 and plays an important role in the regulation of organ size.
The authors found that Lgr3 mutation can reverse tumor anorexia, and Dilp8 overexpression can lead to reduced food intake, indicating that Dilp8-Lgr3 signaling can regulate tumor anorexia behavior.
The two mutations will not reverse this tumor growth phenotype, indicating that Dilp8-Lgr3 is not involved in tumor growth regulation.
Transcriptome analysis of neuropeptide expression related to eating found that the anorectic neuropeptide NUCB1 increased, while the phagocytic neuropeptide sNPF and NPF decreased.
In the Drosophila tumor model with Dilp8 mutation, the expression of NUCB1 decreased, and increased when Dilp8 was overexpressed, while the expression changes of sNPF and NPF were opposite to that of NUCB1.
The author identified that the homologous gene of Dilp8 in mammals is INSL3, and Lgr8 is the homologous gene of Lgr3.
Tumor-derived INSL3 regulates the expression of anorexia regulator Nucb2 and feeding regulator Npy in mouse hypothalamic cells through INSL3-Lgr8 signals, and induces anorexia phenotype in mouse tumor models.
This mode of regulation is similar to Dilp8, which is derived from Drosophila tumors.
About 80% of patients with pancreatic ductal adenocarcinoma will develop tumor anorexia cachexia syndrome.
Human pancreatic cancer cell lines were used to construct pancreatic cancer anorexia models in mice.
Five weeks after tumor implantation, the mice showed reduced food intake.
The analysis found that the level of INSL3 secreted by the tumor was significantly increased.
These results indicate that INSL3 is evolutionarily conserved in inducing tumor anorexia.
The author finally compared the levels of INSL3 in the blood of patients with pancreatic cancer.
Compared with other non-tumor diseases, INSL3 in the serum of patients with pancreatic cancer was significantly increased, and its level was negatively correlated with the calorie intake of patients with pancreatic ductal adenocarcinoma.
And compared with patients with pancreatic ductal adenocarcinoma without anorexia, serum INSL3 levels in pancreatic ductal adenocarcinoma patients with anorexia increased significantly.
These results indicate that tumor-derived INSL3 is related to anorexia in human pancreatic cancer.
This study has discovered the molecular mechanism of tumor-related anorexia regulation.
The authors used fruit flies and mouse models to verify the findings of this study.
When INSL3 was injected into the mouse brain, the mice's food intake was significantly reduced. This also indicates that the Dilp8/INSL3-Lgr3/8 signal is a potential therapeutic target for the treatment of anorexia tumors.
Original link: https://doi.
org/10.
1038/s41556-020-00628-z
It is closely related to cachexia caused by tumors and seriously affects the lives of patients.
Among them, more than 60% of patients have anorexia, and it also occurs in patients who have not received chemotherapy, which shows that the anorexia caused by tumor patients is independent of the treatment process.
However, the development mechanism of anorexia in cancer patients is still unclear.
In tumor anorexia cachexia syndrome, cytokines secreted by tumors play an important role in the mutual influence of organs.
Inflammatory factors entering the systemic circulation and tumor-derived hormones and growth factors can cause muscle loss in patients.
Recently, it has been reported that in chronic diseases, GDF15 (growth differentiation factor) is related to the amount of food consumed and weight loss.
ImpL2 is a gene homologous to mammalian insulin-like growth factor binding protein IGFBP in Drosophila.
It is secreted from tumor tissue into the circulatory system.
By inhibiting IGF signal, it can damage muscle function and loss.
On February 8, 2021, the Kweon Yu team from the Center for Disease Target Research, a researcher of the Korean Bioengineering, published an article titled Tumour-derived Dilp8/INSL3 induces cancer cc by regulating feeding neuropeptides via Lgr3/8 in the brain in Nature Cell Biology.
.In this paper, a Drosophila tumor-derived anorexia model was established, and it was found that Dilp8 derived from Drosophila tumors is regulated by Lgr3, and INSL3 derived from mammalian tumors is regulated by Lgr8, thereby inducing tumor-related anorexia.
The author first overexpressed yorkie (yki) (Hippo pathway transcriptional co-activator) in the eyes of Drosophila to establish a tumor model.
Analysis found that this tumor model caused a significant reduction in the life span of fruit flies.
Compared with the control group, the food intake of fruit flies was reduced by about 30%, indicating that this fruit fly tumor model can simulate the anorexia of human tumors.
Continuous observation revealed that food intake began to decrease after five days, and the triglyceride concentration in adipose tissue of the Drosophila tumor model decreased on the tenth day, severe weight loss phenotype appeared on 15-20 days, and abnormal mitochondrial structure of muscles appeared in flies on 15 days.
, Muscle loss occurs.
This shows that the appearance of anorexia precedes organ wasting.
The author used the transcriptome to detect the expression levels of the tumor secretion factors Dilp8, ImL2 and Upd2.
It was found that Dilp8 and Upd2 were highly expressed at five days, and ImpL2 expression reached a peak at 15 days.
Because anorexia precedes weight loss, the author believes that Dilp8 and Upd2 may be related to anorexia.
The authors found that Dilp8-RNAi can rescue the anorexia phenotype.
In addition, the authors used Dilp8 antibody to confirm that Dilp8 can be secreted from tumor tissues into the peripheral circulation.
Recent studies have shown that Lgr3 is the receptor of Dilp8 and plays an important role in the regulation of organ size.
The authors found that Lgr3 mutation can reverse tumor anorexia, and Dilp8 overexpression can lead to reduced food intake, indicating that Dilp8-Lgr3 signaling can regulate tumor anorexia behavior.
The two mutations will not reverse this tumor growth phenotype, indicating that Dilp8-Lgr3 is not involved in tumor growth regulation.
Transcriptome analysis of neuropeptide expression related to eating found that the anorectic neuropeptide NUCB1 increased, while the phagocytic neuropeptide sNPF and NPF decreased.
In the Drosophila tumor model with Dilp8 mutation, the expression of NUCB1 decreased, and increased when Dilp8 was overexpressed, while the expression changes of sNPF and NPF were opposite to that of NUCB1.
The author identified that the homologous gene of Dilp8 in mammals is INSL3, and Lgr8 is the homologous gene of Lgr3.
Tumor-derived INSL3 regulates the expression of anorexia regulator Nucb2 and feeding regulator Npy in mouse hypothalamic cells through INSL3-Lgr8 signals, and induces anorexia phenotype in mouse tumor models.
This mode of regulation is similar to Dilp8, which is derived from Drosophila tumors.
About 80% of patients with pancreatic ductal adenocarcinoma will develop tumor anorexia cachexia syndrome.
Human pancreatic cancer cell lines were used to construct pancreatic cancer anorexia models in mice.
Five weeks after tumor implantation, the mice showed reduced food intake.
The analysis found that the level of INSL3 secreted by the tumor was significantly increased.
These results indicate that INSL3 is evolutionarily conserved in inducing tumor anorexia.
The author finally compared the levels of INSL3 in the blood of patients with pancreatic cancer.
Compared with other non-tumor diseases, INSL3 in the serum of patients with pancreatic cancer was significantly increased, and its level was negatively correlated with the calorie intake of patients with pancreatic ductal adenocarcinoma.
And compared with patients with pancreatic ductal adenocarcinoma without anorexia, serum INSL3 levels in pancreatic ductal adenocarcinoma patients with anorexia increased significantly.
These results indicate that tumor-derived INSL3 is related to anorexia in human pancreatic cancer.
This study has discovered the molecular mechanism of tumor-related anorexia regulation.
The authors used fruit flies and mouse models to verify the findings of this study.
When INSL3 was injected into the mouse brain, the mice's food intake was significantly reduced. This also indicates that the Dilp8/INSL3-Lgr3/8 signal is a potential therapeutic target for the treatment of anorexia tumors.
Original link: https://doi.
org/10.
1038/s41556-020-00628-z
