Ma Ning, Liu Qilin, Hou Lin, Wang Yalin, Liu Ziling
1 Department of Rheumatology, First Affiliated Hospital, Jilin University, Changchun, P.R. China.
2 Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, P.R. China.
Int J Immunopathol Pharmacol. 2017 Jun;30(2):152-162. doi: 10.1177/0394632017711055. Epub 2017 May 23.
Chronic inflammation is thought to be a major driving force for the development of colitis-associated colorectal cancer (CAC). As one member of proinflammatory cytokine family, granulocyte macrophage colony-stimulating factor (GM-CSF) has been identified to play a key role in CAC pathogenesis recently. The underlying mechanisms, however, remain largely unknown. In this study, we found that myeloid-derived suppressor cells (MDSCs) accumulated increasingly in the lesions during the progression from colitis to cancer, which was critical for CAC formation. Importantly, this MDSC accumulation was controlled by GM-CSF. MDSC number decreased significantly in GM-CSF-deficient mice suffering from CAC induction, and transfusion of MDSCs from wild-type CAC-bearing mice into GM-CSF-deficient counterparts led to recurrence of CAC. Furthermore, the supernatants of CAC lesions or GM-CSF alone was sufficient to differentiate hematopoietic precursors into MDSCs. Addition of neutralizing anti-GM-CSF antibody impaired the MDSC-differentiating effects of the supernatants of CAC lesions. Overall, these findings shed new insights into the mechanisms of GM-CSF underlying CAC development, by inducing/recruiting CAC-promoting MDSCs. Blocking GM-CSF activity or MDSC function may represent new therapeutic strategies for CAC in clinic.
慢性炎症被认为是结肠炎相关结直肠癌（CAC）发生发展的主要驱动力。作为促炎细胞因子家族的一员，粒细胞巨噬细胞集落刺激因子（GM-CSF）最近被确定在CAC发病机制中起关键作用。然而，其潜在机制在很大程度上仍不清楚。在本研究中，我们发现从结肠炎发展到癌症的过程中，髓系来源的抑制细胞（MDSCs）在病变部位逐渐积累，这对CAC的形成至关重要。重要的是，这种MDSC的积累受GM-CSF控制。在诱导CAC的GM-CSF缺陷小鼠中，MDSC数量显著减少，将野生型荷CAC小鼠的MDSCs输注到GM-CSF缺陷小鼠体内会导致CAC复发。此外，CAC病变的上清液或单独的GM-CSF足以将造血前体细胞分化为MDSCs。添加中和抗GM-CSF抗体可削弱CAC病变上清液的MDSC分化作用。总体而言，这些发现通过诱导/招募促进CAC的MDSCs，为GM-CSF在CAC发生发展中的机制提供了新的见解。阻断GM-CSF活性或MDSC功能可能代表临床上治疗CAC的新策略。
