Authors' Affiliations: Department of Microbiology and Immunology, I3 Research Group, Life Sciences Institute, University of British Columbia, Vancouver; Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada; and Department of Pathology, University of Michigan, Ann Arbor, Michigan.
Cancer Res. 2013 Oct 1;73(19):5892-904. doi: 10.1158/0008-5472.CAN-13-0842. Epub 2013 Aug 1.
Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem/progenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis. We established an in vitro model to dissect interactions between mammary cancers and the hematopoietic system. Investigations in this model revealed that granulocyte colony-stimulating factor (G-CSF) produced by mammary tumors can synergize with FLT3L and granulocyte macrophage CSF (GM-CSF) to expand myeloid progenitors and their progeny in culture. Mammary tumor growth was associated with histone methylation changes within lineage-negative c-Kit-positive hematopoietic cells within the bone marrow of tumor-bearing mice. Similarly, parallel histone methylation patterns occurred in cultured bone marrow cells exposed to mammary tumor-conditioned cell culture media. Notably, changes in histone methylation in these cell populations correlated with dysregulated expression of genes controlling hematopoietic lineage commitment and differentiation, including Hox family genes and members of the Polycomb repressive complex 2 (PRC2) chromatin-remodeling complex. Together, our results show that mammary tumor-secreted factors induce profound perturbations in hematopoiesis and expression of key hematopoietic regulatory genes.
癌症与免疫功能障碍有关，其特征是存在促炎和免疫抑制细胞和因子，这些细胞和因子有助于肿瘤生长和进展。在这里，我们表明，乳腺肿瘤的生长与造血缺陷有关，导致骨髓增生性样疾病（类白血病反应）、贫血和骨髓干细胞/祖细胞区室的破坏。我们所描述的缺陷包括红细胞生成受损、白细胞增多、骨髓中早期祖细胞丢失以及脾脏髓外造血。我们建立了一个体外模型来剖析乳腺癌与造血系统之间的相互作用。在该模型中的研究表明，乳腺肿瘤产生的粒细胞集落刺激因子 (G-CSF) 可以与 FLT3L 和粒细胞巨噬细胞 CSF (GM-CSF) 协同作用，在体外培养中扩增髓系祖细胞及其后代。乳腺肿瘤的生长与荷瘤小鼠骨髓中谱系阴性 c-Kit 阳性造血细胞内的组蛋白甲基化变化有关。同样，在暴露于乳腺肿瘤条件培养基的培养骨髓细胞中也出现了平行的组蛋白甲基化模式。值得注意的是，这些细胞群中的组蛋白甲基化变化与控制造血谱系定向和分化的基因的失调表达相关，包括 Hox 家族基因和 Polycomb 抑制复合物 2 (PRC2) 染色质重塑复合物的成员。总之，我们的结果表明，乳腺肿瘤分泌的因子诱导造血和关键造血调节基因表达的深刻紊乱。
