Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression.
Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression.
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DOI：
10.1016/j.ccell.2017.03.006
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发表时间：
2017-04-10
期刊：
影响因子：
50.3
通讯作者：
Ernst M
中科院分区：
文献类型：
--
作者：
Poh AR;Love CG;Masson F;Preaudet A;Tsui C;Whitehead L;Monard S;Khakham Y;Burstroem L;Lessene G;Sieber O;Lowell C;Putoczki TL;O'Donoghue RJJ;Ernst M
SRC家族激酶造血细胞激酶（HCK）的异常激活作为肿瘤细胞内在癌基因触发血液恶性肿瘤。在这里，我们发现高水平的HCK与结直肠癌患者的生存率降低相关。同样，小鼠中Hck活性的增加促进内源性结肠恶性肿瘤和人结肠直肠癌细胞异种移植物的生长。此外，相应肿瘤的肿瘤相关巨噬细胞显示出明显的交替激活的内型，其独立于成熟淋巴细胞或Stat6依赖性Th2细胞因子信号传导而发生。因此，Hck活性的药理学抑制或遗传降低抑制肿瘤相关巨噬细胞的交替活化和结肠癌异种移植物的生长。因此，Hck可能作为一个有前途的治疗靶点的实体恶性肿瘤。
Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies.