Nemosis (from Nemesis, Goddess in Greek mythology who brought justified revenge or compensation) is a newly discovered type of fibroblast activation which is thought to operate in inflammation and cancer. Experimentally, nemosis is induced when normal fibroblasts are not allowed to adhere and spread on a solid substratum but are instead forming spheroids and making cell–cell contacts. This may be achieved by placing fibroblasts for example, on top of agarose-coated culture wells or growing them in hanging drops.
Nemosis is characterized by a massive induction of Cyclooxygenase-2 (COX-2 producing prostanoids), growth factors and especially hepatocyte growth factor/scatter factor (HGF/SF), proteolytic enzymes (plasminogen activation, matrix metalloproteinases MMP-1, MMP-10, and MT1-MMP), and proinflammatory chemokines (e.g., MIP-1α, RANTES, and IL-8) promoting leukocyte migration. In cell culture conditions, the fibroblast spheroids terminate in programmed necrosis with typical ultrastructural changes in electron microscopy but no induction of apoptosis-related markers. Under the same conditions malignant cells grow to enlarging spheroids, used as a model of primary avascular tumors without any early signs of necrosis.
The massive amounts of HGF/SH domain (SH2/SH3 domain) produced by the fibroblast spheroids (>200-fold in monolayer cultures of fibroblasts) promote human carcinoma cell spreading and invasion to collagen provided a functional, properly processed c-Met receptor is present on the tumor cells which was then rapidly phosphorylated. Interestingly, not only function-blocking antibodies to HGF/SF inhibited the tumor cell invasion, but also nonsteroidal anti-inflammatory drugs (COX-2 inhibitors) which have been shown to be protective against a variety of cancers in vivo. Nemosis is initiated by fibronectin–integrin interaction which leads to over 100-fold induction of 30 genes and 10–100-fold upregulation of over 300 genes.
Possible significance of nemosis
While activation of fibroblasts in spheroids thus far only represents primarily an in vitro model, it is of interest that fibroblasts activated to myofibroblasts form direct cell–cell contacts in wound healing and that such myofibroblasts are found in association with cancer cells (cancer-associated fibroblasts, CAFs). CAFs are considered a prerequisite for effective tumor progression. Similarly, in chronic inflammation, which is often associated with tumor progression, sustained fibroblast activation seems to play a crucial role. The results on nemosis present a novel role for fibronectin as the mediator of fibroblast clustering and as the initiator of a massive induction of inflammatory genes and growth factors suggesting that this kind of fibroblast activation may be involved in pathological conditions and specifically in chronic inflammation and cancer.