Autocrine Production of Interleukin-4 and Interleukin-10 Is Required for Survival and Growth of Thyroid Cancer Cells

Abstract

Although CD95 and its ligand are expressed in thyroid cancer, the tumor cell mass does not seem to be affected by such expression. We have recently shown that thyroid carcinomas produce interleukin (IL)-4 and IL-10, which promote resistance to chemotherapy through the up-regulation of Bcl-xL. Here, we show that freshly purified thyroid cancer cells were completely refractory to CD95-induced apoptosis despite the consistent expression of Fas-associated death domain and caspase-8. The analysis of potential molecules able to prevent caspase-8 activation in thyroid cancer cells revealed a remarkable up-regulation of cellular FLIP L (cFLIP L ) and PED/PEA-15, two antiapoptotic proteins whose exogenous expression in normal thyrocytes inhibited the death-inducing signaling complex of CD95. Additionally, small interfering RNA FLIP and PED antisense sensitized thyroid cancer cells to CD95-mediated apoptosis. Exposure of normal thyrocytes to IL-4 and IL-10 potently up-regulated cFLIP and PED/PEA-15, suggesting that these cytokines are responsible for thyroid cancer cell resistance to CD95 stimulation. Moreover, treatment with neutralizing antibodies against IL-4 and IL-10 or exogenous expression of suppressor of cytokine signaling-1 of thyroid cancer cells resulted in cFLIP and PED/PEA-15 downregulation and CD95 sensitization. More importantly, prolonged IL-4 and IL-10 neutralization induced cancer cell growth inhibition and apoptosis, which were prevented by blocking antibodies against CD95 ligand. Altogether, autocrine production of IL-4 and IL-10 neutralizes CD95-generated signals and allows survival and growth of thyroid cancer cells. Thus, IL-4 and IL-10 may represent key targets for the treatment of thyroid cancer. (Cancer Res 2006; 66(3): 1491-9)

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

“…21,22 Particularly, IL-4 plays a major role in inducing T H 2 responses acting through IL-4Ra and activating the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade. 17,23 Recently, IL-4 has been shown to induce apoptosis in hepatocarcinoma cells 24 and a similar finding has been reported in renal cell carcinoma (RCC), where in vitro treatment of tumor cells with IL-4 and tumor necrosis factor-a is shown to increase RCC apoptosis. 25 However, this point remains controversial since several clinical trials of IL-4 therapy for the treatment of both hematologic and nonhematologic cancers have been disappointing, with little antitumor effects or even with an increase in the number of malignant cells.…”

“…29 Moreover, we have previously shown that refractoriness of thyroid cancer cells to chemotherapy and death receptors is due to the concomitant production of IL-4 and IL-10. 16,17 In the present study, we provide evidence that other epithelial tumors, including tumors of the colon, breast and lung, produce IL-4 in an autocrine manner. This cytokine is likely to be associated with the high proliferation rate of tumor cells and with the inhibition of tumor cell apoptosis through upregulation of proteins that block the extrinsic as well as the intrinsic apoptotic pathway.…”

“…Interestingly, only the concomitant inhibition of IL-4 and IL-10 resulted in sensitization to apoptosis by chemotherapy and death ligands. 16,17 Here, we studied whether the production of IL-4 and/or IL-10 and the consequent modulation of apoptosis-related proteins, conferring refractoriness to death ligand-and drug-induced apoptosis, may be a mechanism involved in cell survival, tumor progression and therapy resistance in other epithelial cancer cells.…”

Paradoxical Roles of IL-4 in Tumor Immunity

“…Stassi et al demonstrated thyroid cancer cells showed refractoriness to chemotherapeutic agents including cisplatin, doxorubicin and taxol treatment (70). Todaro found cancer cells from papillary, follicular or undifferentiated anaplastic thyroid carcinoma were resistant to CD95-induced apoptosis (71). All these effects were IL-4-dependent (70,71).…”

“…Todaro found cancer cells from papillary, follicular or undifferentiated anaplastic thyroid carcinoma were resistant to CD95-induced apoptosis (71). All these effects were IL-4-dependent (70,71). Other cancer cells, such as human bladder cancer cell RT112, prostate cancer cell LNCap and breast cancer cell MDA-MB-231 also exhibited IL-4-dependent apoptosis resistance (72).…”