Cancer cell: to reveal the mechanism of macrophages supporting PTEN deficient glioblastoma!

June 14, 2019 / Biovalley / a new study published in the journal Cancer Cell by researchers from MD Anderson Cancer Center of the University of Texas shows that a common genetic defect enables glioblastoma to transmit molecular information to wrong types of immune cells, thus calling on macrophages to protect and cultivate brain tumors, rather than attack it Senior author Ronald depinho, MD, said the team's work on a mouse model of glioblastoma lacking functional tumor suppressor gene PTEN provided a new potential target for the treatment of the most common and deadly brain tumors Photo source: about one third of glioblastomas in cancer cell lack PTEN The median survival time of glioblastoma patients is about 12 to 15 months, and only 5% of them can survive for 5 years "We have identified a symbiotic loop that is activated in PTEN deficient glioblastomas, which establishes a mutually supportive relationship between cancer cells and macrophages entering the tumor microenvironment and provides growth factor support for tumors," depinho said "Macrophages phagocytize and digest microorganisms, cell fragments and tumor cells, which secrete cytokines that affect other cells as part of the immune response It has two states -- in the form of M1, they actively assist the immune response and inhibit tumor growth; in M2, they are in the repair mode and help the immune recovery, which can also promote the growth and progress of cancer Up to half of the living cells in glioblastoma are macrophages The researchers point out that they are the main components of the tumor microenvironment Dr Peiwen Chen, depinho and his colleagues began to search for common mutations in glioblastoma related to immune changes in the tumor microenvironment They identified not only the pathway of macrophages entering glioblastoma, but also a growth factor secreted by macrophages, which in turn protects cancer cells from programmed cell death and promotes the growth of new blood vessels "We first found that only PTEN deficiency, rather than other common genetic changes, was associated with macrophage infiltration in glioblastoma," Chen said In PTEN knockout cell lines and glioblastoma mouse models, researchers found that after PTEN was down regulated, a gene named Yap1 was activated, which is a transcription factor that can increase the expression of LOX, LOX is a new strong attractor of macrophages; LOX connects to β 1 of macrophages Integrin Pyk2 pathway stimulates their migration to tumor microenvironment; macrophages directly help glioma cells by secreting growth factor SPP1 The research team found that SPP1 can increase the survival of cancer cells and the formation of blood vessels, thus protecting tumors Inhibition of LOX reduces tumor size and prevents macrophage infiltration the team developed a mouse model of human glioma xenotransplantation with high expression of LOX, Yap1 and macrophage markers In these models, the use of shRNA, small LOX inhibitor bapn or anti LOX antibody can destroy LOX, prevent tumor growth and significantly reduce macrophage infiltration In four PTEN deficient glioblastoma mouse models, the researchers found that LOX inhibition prolonged survival in all animals Blocking LOX had no effect on the proliferation of glioma cells, but it did increase the programmed death of cancer cells and reduce the formation of blood vessels supporting the tumor As the first test of the possible human impact of their findings, the team clustered 489 human glioblastoma samples from the cancer genome map with macrophage markers By clustering three groups of patients with high macrophage (201), medium macrophage (153) and low macrophage (135), and comparing tumor related macrophages with mouse models of glioblastoma and patients' blood mononuclear cells, eight genes related to patients' macrophage infiltration were identified SPP1 is the gene with the most increased expression PTEN mutation or deletion was more frequent in the high macrophage group than in the low macrophage group, Yap1 and LOX expression were higher, and survival period was worse LOX and SPP1 are new targets of PTEN deficient glioblastoma Depinho said that the most targeted components in this pathway are LOX and SPP1 Currently, drugs targeting these two genes are under development "The results in mice are convincing enough, and studies in human glioblastomas provide additional confidence in testing this approach in the clinical environment of patients with recurrent glioblastomas," depinho said "It's important to recruit only cancer patients with PTEN deficiency because their research shows that LOX inhibition has no effect on PTEN wild-type tumors," he said Reference: Peiwen Chen et al Symbolic macrophase glioma cell interactions reveal synthetic lethality in PTEN null glioma Cancer cell Doi: https://doi.org/10.1016/j.ccell.2019.05.003