Granulocytes mediates the Fas-L-associated apoptosis during lung metastasis of melanoma that determines the metastatic behaviour

Abstract

The survival of tumour cells in a new tissue environment is crucial for tumour metastasis. Factors contributing to the death of tumour cells during metastasis are not completely understood. In murine melanoma model, activation of Fas (CD95, APO-1) signal in tumour cells reduces their lung metastasis potential, which may be associated with an induction of apoptosis in tumours. To elucidate the cellular mechanism, we used a Fas-ligand (Fas-L) specific ribozyme (Fas-L ribozyme ) to suppress the expression of Fas-L but not Fas or TNF-a in B16F10 melanoma cells. The Fas-L ribozyme -carrying cells grew slightly faster in vitro with better viability than controls. Suppression of Fas-L in B16F10 melanoma cells by Fas-L ribozyme enhanced lung metastasis of the cells in C57BL/6 mice, and that was correlated with reductions in both apoptotic tumour cells and granulocytic infiltration. Mice depleted of granulocytes, but not CD4 + and CD8 + cells, showed a greatly elevated susceptibility to lung metastasis. Moreover, apoptosis in tumour cells was significantly reduced in granulocyte-depleted mice during the course of tumour formation. Taken together, our findings indicate that Fas-L-associated apoptosis in tumour cells determines the metastasis behaviour of melanoma in the lung and this apoptosis is primarily mediated by the cytotoxicity of recruited granulocytes.

Overexpression of Pigment Epithelium-Derived Factor Decreases Angiogenesis and Inhibits the Growth of Human Malignant Melanoma Cells in Vivo

“…Recently, granulocytes have been shown to inhibit melanoma lung metastasis by inducing Fas ligand-associated apoptosis, further supporting this speculation. 24 Our present study has highlighted two beneficial aspects of the effects of PEDF on melanoma growth and expansion; one is the suppression of tumor angiogenesis, and the other is induction of Fas ligand-dependent apoptosis in tumor cells. PEDF is therefore a promising novel therapeutic agent for treatment of patients with certain types of cancer including melanoma.…”

It is possible that tumour-infiltrating granulocytes promote tumour progression

“…FasL expressed on gastric carcinoma cells can induce tumour infiltrating lymphocyte (TIL) apoptosis, thereby helping tumour cells to evade host immune defense (22)(23)(24)(25). Similarly, FasL expressed on gliomas or melanomas promoted an accumulation of granulocytes at tumour sites (14)(15)(16), and extensive granulocyte infiltration into tumour tissues are seen in glioma patients (17). Thus, we analyzed their correlation in this study, we detected TIGs and FasL-expression in the same specimens.…”

“…Therefore, the presence of tumour-infiltrating granulocytes (TIGs) might be indicative for a better or worse host antitumoural response. Recently, we found that the expression of Fas ligand (FasL) on gliomas or melanomas caused an accumulation of neutrophils in tumour sites, and this was associated with a reduction in tumourigenesis and metastasis (14)(15)(16)(17).…”

Fas Ligand on Tumor Cells Mediates Inactivation of Neutrophils

“…This argument is implied by the finding that some FasL-positive tumors do induce a mild degree of inflammation, but which, however, fails to cause tumor rejection (28). In this study, these questions were further addressed using a functional knockdown strategy with a hammerhead ribozyme to specifically suppress the FasL gene (27). The important role of neutrophils in antitumor immunity was demonstrated by depletion experiments using Abs for CD4 ϩ cells, CD8 ϩ T cells, and neutrophils.…”