Department of Dermatology, Faculty of Medicine, University of Tokyo, Japan.
Cancer Res. 2011 Mar 15;71(6):2056-65. doi: 10.1158/0008-5472.CAN-10-3764.
CCR3 is a specific marker of anaplastic large cell lymphoma (ALCL) cells. ALCL cells also express CCL11, a ligand for CCR3, leading to the hypothesis that CCL11 may play an autocrine role in ALCL progression. In this study, we investigated a role of CCL11 in cell survival and growth of human Ki-JK cells, established from an ALCL patient, and murine EL-4 lymphoma cells. Both Ki-JK and EL-4 cells expressed cell surface CCR3. CCL11 increased cell survival rates of Ki-JK cells in a dose-dependent manner, whereas it promoted EL-4 cell proliferation. Furthermore, CCL11 induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in both Ki-JK cells and EL-4 cells. Cell survival and tumor proliferation promoted by CCL11 was completely blocked by inhibition of ERK phosphorylation. CCL11 induced expression of antiapoptotic proteins, Bcl-xL and survivin, in Ki-JK cells. CCL11 also enhanced tumor growth of EL-4 and Ki-JK cells in vivo. Consistent with these results, tumor cells of cutaneous ALCL expressed CCR3 and increased levels of phosphorylated ERK1/2, Bcl-xL, and survivin in situ. Thus, our findings prompt a novel therapeutic approach to treat relapses of an aggressive form of lymphoma based on the discovery that a cell surface marker of disease functions as a critical autocrine growth receptor.
CCR3 是间变性大细胞淋巴瘤（ALCL）细胞的特异性标志物。ALCL 细胞还表达 CCL11，这是 CCR3 的配体，这导致了一个假设，即 CCL11 可能在 ALCL 进展中发挥自分泌作用。在这项研究中，我们研究了 CCL11 在人类 Ki-JK 细胞（源自 ALCL 患者）和鼠源性 EL-4 淋巴瘤细胞中的存活和生长中的作用。Ki-JK 和 EL-4 细胞均表达细胞表面 CCR3。CCL11 以剂量依赖性方式增加 Ki-JK 细胞的存活率，而促进 EL-4 细胞增殖。此外，CCL11 诱导 Ki-JK 细胞和 EL-4 细胞中细胞外信号调节激酶（ERK）1/2 的磷酸化。ERK 磷酸化的抑制完全阻断了 CCL11 诱导的细胞存活和肿瘤增殖。CCL11 诱导 Ki-JK 细胞中抗凋亡蛋白 Bcl-xL 和 survivin 的表达。CCL11 还增强了 Ki-JK 和 EL-4 细胞在体内的肿瘤生长。与这些结果一致，皮肤 ALCL 的肿瘤细胞表达 CCR3，并在原位增加磷酸化 ERK1/2、Bcl-xL 和 survivin 的水平。因此，我们的发现提示了一种新的治疗方法，基于疾病的细胞表面标志物作为关键的自分泌生长受体的发现，来治疗侵袭性淋巴瘤的复发。
