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Researchers have identified macrophage pathway for the development of glioblastoma

11 June 2019 13:20

As the researchers report in the Cancer Center of the University of Texas, a common genetic deficiency allows glioblastoma molecular transmit a message to the wrong type of immune cells, activating macrophages that protect the brain tumor rather than attack it.

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team work on a mouse model of glioblastoma, which lacks a functional suppressor gene PTEN cancer, indicating a potential new target for the treatment of the most common brain tumor. About a third of all glioblastomas are PTEN deficiency. Median survival with glioblastoma is 12 to 15 months, and only 5 percent of patients survive for five years.

"We have identified a symbiotic chain that is activated when the glioblastoma-deficient PTEN It affects the relationship between cancer cells and macrophages, which are part of the tumor microenvironment and provide for its growth." - the researchers say.

Macrophages engulf and digest bacteria and release cytokines which affect other cells. In the form of the M1, they actively help the immune response and inhibit tumor growth. The M2 they are in the recovery mode, which can promote the growth and progression of cancer.

The researchers decided to find common mutations in glioblastoma associated with immune changes in the tumor microenvironment.

They not only identified the way in which macrophages are transformed into glioblastoma, but also identified a growth factor secreted by macrophages, which in turn protects cancer cells from programmed cell death and stimulates the growth of new blood vessels.

In a series of experiments, the researchers showed that:

  • When activated YAP1 off PTEN gene, a transcription factor that increases expression of LOX gene that attracts macrophages;
  • LOX connected to macrophages by stimulating their migration to the tumor microenvironment;
  • Macrophages direct help glioma cells secreting SPP1 growth factor that enhances survival of cancer cells and the formation of blood vessels to tumors protection.

The team developed a mouse model of glioblastoma that had high expression of LOX markers, YAP1 and macrophages. The inhibition of LOX in four PTEN-deficient mouse models of glioblastoma with increased survival in all models.

Blocking LOX no effect on the proliferation of glioma cells, but increased the programmed death of cancer cells and reduces the formation of blood vessels supporting tumor.

As a first test the possible impact of the results of research on humans, the team analyzed 489 samples of human glioblastoma cancer genome atlas.

By grouping cases in groups with a high content of macrophages (201), middle-macrophage (153) and low-macrophage (135) and analysis related to macrophage tumor compared to monocytes obtained from blood in a mouse model, and patients with glioblastoma they have identified genes associated with macrophages of patients. Among them was SPP1 gene with the largest increase in expression.

In the group with high levels of macrophages were observed more frequently PTEN mutations, higher expression YAP1 and LOX and lower survival rates than patients in the cluster with low levels of macrophages. The researchers plan to develop drugs to destroy LOX and SPP1.

The results in mice are quite convincing, and relevant research in human glioblastoma give additional confidence to continue testing this approach in a clinical setting.



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