Tumor Microenvironment: Unleashing Metalloproteinases to Induce a CAF Phenotype

Pathologically activated fibroblasts have been shown to play a role in fibrotic disorders and cancer, but the molecular mechanisms regulating their emergence are still poorly characterized. A recent study demonstrates that unleashing metalloproteinase activity in fibroblasts is sufficient for the acquisition of an activated pro-tumorigenic phenotype. Stromal cells and extracellular matrix (ECM) molecules within the tumor — collectively defined as the tumor microenvironment [1] — participate in many of the hallmarks of cancer [2]. Cancer-associated fibroblasts (CAFs) are non-malignant cells found in many solid tumors that provide a chemical and physical microenvironment that can favor tumor aggressiveness and dissemination [3,4]. Unlike normal fibroblasts, CAFs present a pathologically activated phenotype that is responsible for their pro-tumorigenic activities. This phenotype is also found in fibroblasts in fibrotic disorders and is reminiscent of the activated status observed in fibroblasts during wound healing. Despite the major role of CAFs in tumor progression and their influence in overall patient survival [3,5], the molecular rearrangements leading to the altered CAF state are not well understood. A new study by Shimoda et al. [6] now demonstrates that deletion of a family of metalloproteinase inhibitors is sufficient for the acquisition of an activated fibroblast phenotype that promotes cancer progression through the production of exosomes. The metzincin superfamily of proteases comprises several families of endopeptidases that include matrix metalloproteinases (MMPs) and adamalysins (ADAM), among others. By influencing the ECM, cell–adhesion molecules and soluble factors, proteinases participate in many physiological and pathological processes [7]. Due to their potent activity on signaling and ECM remodeling, proteinases are tightly regulated at the transcriptional and post-translational levels. Tissue inhibitors of metalloproteinases (TIMPs) are one of the main regulators of metzincin proteases [8]. The roles of TIMPs in both normal development and pathological processes have been investigated by gene deletion studies in mice, revealing some functional redundancy between different TIMPs [9]. To identify new fundamental functions mediated by TIMPs and to avoid any compensatory effects between different isoforms, Shimoda et al. [6] generated a mouse lacking all four Timp genes [6]. These quadruple Timp-deficient (TIMPless) mice showed widespread developmental problems that hindered any cancer study but that underline an essential role for TIMPs in normal development that will need to be explored in the future. Due to the early lethality of TIMPless mice, primary dermal fibroblasts were derived and used throughout the study as a model to investigate the impact of TIMPs on fibroblast …