Role of the microenvironment and feedback signaling loops in stabilizing disease states

In this paper, we identify several of the feedback loops that we posit play key roles in establishing and maintaining states of disease in the human body. These routes are established through signaling between the affected cells and cells in their local microenvironment. Signals sent and received by these cells underlie the pathogenesis of diseases ranging from type 2 diabetes and atherosclerosis to cancers to various neurodegenerative disorders. In the tumor stroma, the focus in this paper, signaling loops are established between cancer cells, macrophages, fibroblasts, and others. In the disease state, these loops and the cell populations that sustain them are hypothesized to counter beneficial actions of drugs and eventually render them ineffective. A major challenge for systems medicine is to understand how the cellular microenvironment and its signaling routes stabilize disease states and how these impediments may be overcome.