Malignant gliomas, like other incurable gliomas, are characterized by high morbidity and mortality due to their aggressive growth and drug resistance.
Recently it was discovered that glioma cells extend ultralong membrane tube protrusions called tumor microtubules, which connect individual tumor cells through gap junctions to functional and communicating multicellular networks. They are consistently found in advanced animal models of incurable glioma and in human samples. Notably, these tumor cell networks enable multicellular communication through frequent intercellular Ca2+ signaling, which is partially influenced by neuronal input.
Furthermore, these communication networks can repair themselves after surgery, leading to local tumor recurrence, and network integration makes tumor cells better resistant to temozolomide chemotherapy and radiation therapy.
Based on these findings, the researchers conducted in-depth biological and mathematical studies of Ca2+ communication patterns in these tumor cell networks to better understand their basic structure and function and identify potential vulnerabilities. Relevant research was published in "Nature" with the title: "Autonomous rhythmic activity in glioma networks drives brain tumor growth".
researchers describe how the glioblastoma cell network includes a small, plastic population of highly active glioblastoma cells that display rhythmic Ca2+ signaling oscillations and specifically connect to other cells .
Their autonomous periodic Ca2+ transients precede those of other network-connected cells, activating frequency-dependent MAPK and NF-κB pathways.
Mathematical network analysis shows that the glioblastoma network topology follows scale-free properties, and periodic tumor cells are often located at network hubs. This network design is resistant to random disruptions, but can easily lose key hubs. Targeting autonomic rhythmic activity through selective physical ablation of periodic tumor cells or through genetic or pharmacological interference with the potassium channel KCa3.1 (also known as IK1, SK4, or KCNN4) severely impairs signaling communications throughout the body.
Summary: This resulted in a significant reduction in the viability of tumor cells throughout the network, reducing tumor growth in mice and extending the survival of the animals. Researchers found that there is a small group of highly plastic and active cells in gliomas, which display autonomous rhythmic Ca2+ oscillations and connect with other cells to activate the cycle-dependent MAPK and NF-κB pathways. In addition, the authors genetically manipulated the potassium channel KCa3.1 to interfere with the autonomous rhythmic activity of this cell group and inhibit tumor growth, becoming a new possible therapeutic target.
The dependence of the glioblastoma network on cyclic Ca2+ activity creates a vulnerability that could be exploited to develop new treatments such as Kca3.1 inhibitory drugs.
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-