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

Abstract

We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED, cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis induction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2. Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptotic proteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 acts as an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a novel treatment for epithelial cancers.

Leukocytes in Mammary Development and Cancer

“…In some human breast carcinoma cell lines, particularly those that express the estrogen receptor a, IL-4, and IL-13 inhibit both basal and estrogeninduced cell proliferation in vitro and in xenograph tumor models in vivo (Toi et al 1992;Gingras et al 2000;Nagai and Toi 2000;Gooch et al 2002). However, in other breast carcinoma cell lines, IL-4 regulates tumor cell survival by conferring resistance to apoptosis (in vitro) that translates to resistance to chemotherapy in xenograph models (Todaro et al 2008). Palucka and colleagues reported that CD4 þ T cells directly enhance early breast tumor development in xenograph tumors using humanized NOD/SCID mice, and reported that the ability of CD4 þ T cells to produce T H 2 cytokines including IL-4 and IL-13 was key (Aspord et al 2007).…”

Cancer Stem Cells and Response to Therapy

“…Epithelial tumor cells secrete Interleukin-4 which contributes in an autocrine manner to apoptosis resistance (Todaro et al, 2008). Colon CSCs showing resistance to fluorouracil and oxaliplatin, were made responsive to these chemotherapy drugs with the use of antibodies against IL-4 ( Todaro et al, 2007).…”

Cross-Talk of Breast Cancer Cells with the Immune System

“…The contribution of Th2 CD4 cells has been recently demonstrated in an experimental study showing that interleukin (IL)-4 produced by Th2 CD4 T cells regulates the function of macrophages and promotes their pro-tumorigenic M2 phenotype in a mouse breast cancer model DeNardo et al, 2009). Interestingly, IL-4 has also been shown to be produced by primary epithelial breast cancer cells and to serve as an autocrine survival factor (Todaro et al, 2008). Another Th2 cytokine, IL-13, was shown to be involved in growth of human breast cancer cells (Aspord et al, 2007).…”

“…These intriguing observations emphasize the complexity of interactions between tumor cells and immune system. Breast cancer cells also produce IL-4 and use it as an autocrine survival factor (Todaro et al, 2008). The expression and production of IL-10 and IL-12 p40, but not of IL-12 p70, by human breast tumor cells was recently reported (Heckel et al, 2011).…”