Differentiation of the tumor microenvironment: are CAFs the Organizer?

Cancers contain a suite of genetically stable cells within an extracellular matrix, collectively termed the tumor microenvironment (TME). The TME strongly influences disease outcome for patients. Gleaning clues from the literature, we propose that the TME should be viewed not as disparate populations of cells constituting a pathological lesion, but as a cohesive tissue constituting a novel pathological organ, arising from the coordinated differentiation of its constituent cell types - a process we have termed tumor-associated neodifferentiation (TAND). We also discuss why cancer-associated fibroblasts (CAFs) may assume the role of Organizer of this organ, directing the recruitment and differentiation of cells within the TME. Viewing the microenvironment in this way will reveal new cancer vulnerabilities that may be exploited for therapy.