Hepatocyte growth factor͞scatter factor (HGF͞SF), acting through the Met receptor, plays an important role in most human solid tumors, and inappropriate expression of this ligand-receptor pair is often associated with poor prognosis. The molecular basis for the malignant potential of the HGF͞SF-Met signal in cancer cells has mostly been attributed to its mitogenic and invasive properties. However, HGF͞SF also induces angiogenesis, but the signaling mechanism has not been fully explained, nor has this activity been directly associated with HGF͞SF-Met-mediated tumorigenesis. It is known that HGF͞SF induces in vitro expression of vascular endothelial growth factor (VEGF), a key agonist of tumor angiogenesis; by contrast, thrombospondin 1 (TSP-1) is a negative regulator of angiogenesis. Here, we show that, in the very same tumor cells, in addition to inducing VEGF expression, HGF͞SF dramatically downregulates TSP-1 expression. We show that TSP-1 shut-off plays an important, extrinsic role in HGF͞SF-mediated tumor development, because ectopic expression of TSP-1 markedly inhibits tumor formation through the suppression of angiogenesis. Interestingly, although VEGF-induced expression is sensitive to inhibitors of several pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase, and signal transducer and activator of transcription 3, TSP-1 shut-off by HGF͞SF is prevented solely by inhibiting mitogen-activated protein kinase activation. These studies identify HGF͞SF as a key switch for turning on angiogenesis. They suggest that TSP-1 is a useful antagonist to tumor angiogenesis and that it may have therapeutic value when used in conjunction with inhibitors of VEGF.

Stress is an out of the norm state caused by emotional or physical insults. While chronic stress is considered harmful, acute stress is thought to cause transient and reversible changes essential for fight or flight. Stress has been anecdotally associated with hair greying, but scientific evidence linking the two is scant. Here, using mouse stress models, we found that acute stress leads to hair greying through rapid depletion of melanocyte stem cells (MeSCs). Combining adrenalectomy, denervation, chemogenetics, cell ablation, and MeSC-specific adrenergic receptor knockout, we found that stress-induced MeSC loss is independent of the immune attack or adrenal hormones. Instead, hair greying results from activation of the sympathetic nervous system that innervates the MeSC niche. Upon stress, sympathetic nerve activation leads to burst release of the neurotransmitter norepinephrine, which acts directly on MeSCs. Norepinephrine drives quiescent MeSCs to proliferate rapidly, followed by migration and differentiation, leading to their permanent depletion from the niche. Transient suppression of MeSC proliferation with topical application of cell cycle inhibitors rescues stress-induced hair greying. Our studies demonstrate that stress-induced neuronal activity can be an upstream trigger that forces stem cells out of quiescence, and suggest that acute stress stimuli can be more detrimental than anticipated by causing rapid and irreversible loss of somatic stem cells.