IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma.
IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma.
复制标题
DOI：
10.1158/1078-0432.ccr-10-3445
复制
发表时间：
2011-05-01
期刊：
影响因子：
--
通讯作者：
Keller C
中科院分区：
文献类型：
--
作者：
Hosoyama T;Aslam MI;Abraham J;Prajapati SI;Nishijo K;Michalek JE;Zarzabal LA;Nelon LD;Guttridge DC;Rubin BP;Keller C
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. The alveolar subtype of rhabdomyosarcoma (ARMS) is a paradigm for refractory and incurable solid tumors because more than half of the children at diagnosis have either regional lymph node or distant metastases. These studies follow our previous observation that Interleukin-4 receptor α (IL-4R) is upregulated in both human and murine ARMS, and that the IL-4R signaling pathway may be a target for abrogating tumor progression. By in vitro biochemical and cell biology studies as well as preclinical studies using a genetically-engineered mouse model, we evaluated the role of IL-4 and IL-13 in IL-4R mediated mitogenesis, myodifferentiation and tumor progression. IL-4 and IL-13 ligands accelerated tumor cell growth and activated STAT6, Akt or MAPK signaling pathways in the human RMS cell lines, RD and Rh30, as well as in mouse primary ARMS cell cultures. IL-4 and IL-13 treatment also decreased protein expression of myogenic differentiation factors MyoD and Myogenin, indicating a loss of muscle differentiation. Using a genetically-engineered mouse model of ARMS, we have demonstrated that inhibition of IL-4R signaling pathway with a neutralizing antibody has a profound effect on the frequency of lymph node and pulmonary metastases, resulting insignificant survival extension in vivo. Our results indicate that an IL-4R-dependent signaling pathway regulates tumor cell progression in RMS, and inhibition of this pathway could be a promising adjuvant therapeutic approach.
