巨噬细胞,胶质母细胞瘤 z-bo 2020-10-08 314

　　A new study published in Cancer Cells by researchers at the University of Texas MD Anderson Cancer Center found that due to widespread genetic defects, glioblastoma transmits molecular information to the wrong type of immune cells, resulting in Macrophages. Called to protect and nurture brain tumors instead of attacking them.

　　Senior author Ronald DePinho, MD, discovered a study on a mouse model of glioblastoma, which lacks the functional tumor suppressor PTEN and has new potential for the treatment of the most common and fatal brain tumors. Indicates that good goals are provided.

　　About one-third of glioblastomas lack PTEN. The median survival time of patients with glioblastoma is about 12 to 15 months, and only 5% of patients can survive for 5 years.

　　DePinho said: "We have identified the symbiotic circuit activated in PTEN-deficient gliomas. This circuit establishes a mutually supportive relationship between cancer cells and macrophages that enter the tumor microenvironment. Tumors are growth. Factors. Macrophages swallow and digest microorganisms, cell debris and tumor cells. As part of the immune response, it secretes cytokines that affect other cells. It actively supports the immune response and inhibits tumor growth in the form of M1. M2 also enters repair Models to help recover from immunity, and can also promote the growth and development of cancer. As many as half of the living cells of glioblastoma are macrophages. Researchers pointed out that they are the main components of the tumor microenvironment. Cancer. Peiwen Chen, DePinho and his colleagues have begun to search for common mutations in glioblastoma that are associated with immune changes in the tumor microenvironment. They have not only determined how macrophages enter glioblastoma, but also The growth factors secreted by macrophages are determined. This protects cancer cells from programmed cell death. And it promotes the growth of new blood vessels. "We first discovered that only PTEN is lacking, and there are no other common genetic changes, unlike macrophages. Infiltrating into glioblastoma is related," Chen said. It is. Researchers conducted experiments with PTEN knockout cell lines and glioblastoma mouse models, and after PTEN was down-regulated, a gene called YAP1 When activated, this gene can increase LOX. When expressed, LOX is a powerful attractant for new types of macrophages, which have been transformed. LOX is linked to the β1 integrin-PYK2 pathway of macrophages, It also stimulates migration to the tumor microenvironment. Macrophages directly help glioma cells by secreting the growth factor SPP1. Researchers have found that SPP1 can increase the survival rate and angiogenesis of cancer cells, thereby protecting tumors. Inhibiting LOX can shrink tumors and shrink tumors. Preventing macrophage infiltration team has developed a human glioma xenograft mouse model that highly expresses LOX, YAP1 and macrophage markers. In these models, shRNA, the small LOX inhibitor BAPN or anti- LOX antibody can be used to destroy LOX, prevent tumor growth and significantly reduce macrophage infiltration. In four PTEN-deficient glioblastoma mouse models, researchers found that LOX inhibition can prolong the survival of all animals. LOX The block does not affect the growth of glioma cells, but it increases the death of programmed cancer cells and reduces the formation of blood vessels that support the tumor.

　　As the first test to discover the potential impact on humans, the research team performed macrophage marker clustering on 489 human glioblastoma samples from Cancer Genome Atlas. Macrophages (201), medium macrophages (153), and low macrophages (135) were collected from 3 groups of cases. This model combines tumor-associated macrophages and glioblastoma mice and a patient’s The blood source list compares and analyzes the spheroids to determine eight genes related to the infiltration of macrophages in the patient. Among them, SPP1 is the most expressed gene.

　　The mutation or deletion of PTEN in the high macrophage group is more frequent than that in the low macrophage group, the expression of YAP1 and LOX is high and the survival rate is low.

　　LOX and SPP1 are new targets for PTEN-deficient neuroblastoma

　　DePinho pointed out that the most targeted components in this pathway are LOX and SPP1, and drugs for these two genes are currently being developed.

　　DePinho said: "The results of the research conducted in mice are convincing, and related studies on human glioblastoma provide a way to test this method in clinical practice in patients with recurrent glioblastoma. Further confidence."

　　He said that it is very important to recruit only patients with PTEN-deficient tumors because their research shows that LOX inhibition is not effective in PTEN wild-type tumors.