Inter-cellular signaling network reveals a mechanistic transition in tumor microenvironment.

We conducted inter-cellular cytokine correlation and network analysis based upon a stochastic population dynamics model that comprises five cell types and fifteen signaling molecules inter-connected through a large number of cell-cell communication pathways. We observed that the signaling molecules are tightly correlated even at very early stages (e.g. the first month) of human glioma, but such correlation rapidly diminishes when tumor grows to a size that can be clinically detected. Further analysis suggests that paracrine is shown to be the dominant force during tumor initiation and priming, while autocrine supersedes it and supports a robust tumor expansion. In correspondence, the cytokine correlation network evolves through an increasing to decreasing complexity. This study indicates a possible mechanistic transition from the microenvironment-controlled, paracrine-based regulatory mechanism to self-sustained rapid progression to fetal malignancy. It also reveals key nodes that are responsible for such transition and can be potentially harnessed for the design of new anti-cancer therapies.