Control of Ocular Tumor Growth and Metastatic Spread by Soluble and Membrane Fas Ligand

Abstract

Fas ligand (FasL) can be either membrane bound, or cleaved by metalloproteinases (MMP) to produce a soluble protein.The two different forms of FasL are reported to have opposite functions-membrane-bound FasL (mFasL) is proinflammatory and soluble FasL (sFasL) is antiinflammatory. We previously showed that, within the immune-privileged eye, tumors expressing high levels of mFasL overcame the suppressive ocular environment, triggered an inflammatory response, and were subsequently rejected. By contrast, eye tumors expressing low levels of mFasL grew progressively. To evaluate the effect of sFasL on the tumor growth and metastatic potential of ocular FasL-expressing tumors, we compared tumor cell clones that expressed equal amounts of (low) mFasL in the presence or absence of sFasL. Tumor cells transfected with a modified FasL gene expressed only mFasL (noncleavable), grew progressively within the eye, and induced systemic protective immunity that prevented metastatic spread of tumor cells to the liver. Unexpectedly, tumors transfected with wild-type FasL (wtFasL; cleavable), which could produce both sFasL and mFasL, elicited considerably more inflammation and grew more slowly within the eye. However, the cleavable wtFasL eye tumors failed to trigger protective immunity and gave rise to liver metastases. Interestingly, exposure to the ocular environment was required for the wtFasL tumors to gain metastatic potential. We conclude that the fate of FasL-expressing tumors is determined by a combination of the following: (a) the relative proportion of membrane and sFasL, and (b) the local environment that determines the extent of FasL cleavage.

Tumor necrosis factor-related apoptosis-inducing ligand induces apoptotic cell death through c-Jun NH2-terminal kinase activation in squamous cell carcinoma cells

“…The molecular mechanisms of metastasis remain incompletely understood. TNF superfamily proteins, including TRAIL, have been proposed to be involved in the metastases of some tumors (17,18,25,26). Our present study demonstrates that MIL6 cells derived from a metastatic lesion were markedly resistant to TRAIL exposure, while MIT6 cells from the primary tissues were considerably sensitive (Fig.…”

Fas/FasL Complex Promotes Proliferation and Migration of Brain Endothelial Cells Via FADD–FLIP–TRAF–NF-κB Pathway

“…Interestingly, studies show that membrane-bound and soluble (as a result of cleavage by metalloproteinases) FasL have the opposing effects. While membrane FasL is pro-inflammatory, soluble FasL is antiinflammatory [17,18]. We showed here that soluble FasL was a positive regulator of angiogenesis in a dose-dependent manner.…”

“…Thus, there is a Previous studies reported that Fas, commonly regarded as an inducer of cell apoptosis, may induce inflammatory angiogenesis [6,16,17]. In murine model where Matrigel was used as a vehicle for the delivery of agonistic anti-Fas antibody Jo2, there were no apoptotic cells detected in the process of angiogenesis, suggesting it may be mediated by stimulatory signal through Fas-engagement [6].…”

Increased Resistance to Staphylococcus aureus Endophthalmitis in BALB/c Mice: Fas Ligand Is Required for Resolution of Inflammation but Not for Bacterial Clearance

“…We demonstrated that FasL engagement of Fas ϩ macrophages not only induces apoptosis but also induces the production of neutrophil chemotactic factors (14). Moreover, using an ocular tumor model, we demonstrated that overexpression of the membrane form of FasL within the immune-privileged eye induced a potent neutrophil-mediated inflammatory response, leading to the termination of ocular immune privilege (15,16). Together, these studies suggest that a more efficient and/or rapid engagement of the Fas receptor on cells resident within the eye will trigger a quicker innate-mediated inflammatory response, accelerate pathogen clearance, and ultimately increase resistance to bacterial endophthalmitis.…”