Song Lanxi, Smith Matthew A, Doshi Parul, Sasser Kate, Fulp William, Altiok Soner, Haura Eric B
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Janssen R&D, Spring House, PA.
J Thorac Oncol. 2014 Jul;9(7):974-982. doi: 10.1097/JTO.0000000000000193.
Interleukin-6 (IL-6) can activate downstream signaling pathways in lung cancer cells, such as the STAT3 pathway, and is reported to be produced by tumor cells with activating EGFR mutations. We examined IL-6/STAT3 in lung cancer tumor tissues and the effects of siltuximab, a neutralizing antibody to human IL-6, in mouse models of lung cancer.
IL-6 and STAT3 activation levels were compared with tumor histology and presence of KRAS mutations in snap-frozen, non-small-cell lung cancer tumors. The effects of siltuximab alone or in combination with erlotinib were examined in mouse xenograft models constructed using three cell line xenograft models and one primary explant mouse model. We examined the influence of cancer-associated fibroblasts (CAFs) on tumor growth and siltuximab effects.
IL-6 levels were higher in tumors of squamous cell versus adenocarcinoma histology and were not associated with presence of KRAS mutations. Tyrosine phosphorylation status of STAT3 did not correlate with tumor IL-6 levels. Serine phosphorylation of STAT3 was correlated with KRAS mutation status. Both tumor and stromal cells contributed to total IL-6 within tumors. Siltuximab had minimal effect as a single agent in xenografts with tumor cells alone; however, in models coadministered with CAFs, siltuximab had more potent effects on tumor inhibition. We observed no effects of combined erlotinib and siltuximab.
IL-6 is elevated in subsets of human NSCLCs, especially with squamous cell histology. Tumors supported by stromal production of IL-6 seem to be the most vulnerable to tumor growth inhibition by siltuximab.
白细胞介素-6（IL-6）可激活肺癌细胞中的下游信号通路，如STAT3通路，据报道它由具有激活型表皮生长因子受体（EGFR）突变的肿瘤细胞产生。我们检测了肺癌肿瘤组织中的IL-6/STAT3以及抗人IL-6中和抗体西妥昔单抗在肺癌小鼠模型中的作用。
在速冻的非小细胞肺癌肿瘤中，将IL-6和STAT3的激活水平与肿瘤组织学及KRAS突变情况进行比较。在使用三种细胞系异种移植模型和一种原代外植体小鼠模型构建的小鼠异种移植模型中，检测了西妥昔单抗单独使用或与厄洛替尼联合使用的效果。我们研究了癌症相关成纤维细胞（CAF）对肿瘤生长及西妥昔单抗效果的影响。
鳞状细胞组织学肿瘤中的IL-6水平高于腺癌，且与KRAS突变的存在无关。STAT3的酪氨酸磷酸化状态与肿瘤IL-6水平不相关。STAT3的丝氨酸磷酸化与KRAS突变状态相关。肿瘤细胞和基质细胞均对肿瘤内的总IL-6有贡献。在仅含肿瘤细胞的异种移植模型中，西妥昔单抗作为单一药物效果甚微；然而，在与CAF共同给药的模型中，西妥昔单抗对肿瘤抑制作用更强。我们未观察到厄洛替尼与西妥昔单抗联合使用的效果。
IL-6在部分人类非小细胞肺癌中升高，尤其是鳞状细胞组织学类型。由基质产生IL-6支持的肿瘤似乎最易受到西妥昔单抗抑制肿瘤生长的影响。
