CAF-secreted annexin A1 induces prostate cancer cells to gain stem cell-like features.
CAF-secreted annexin A1 induces prostate cancer cells to gain stem cell-like features.
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DOI：
10.1158/1541-7786.mcr-13-0469
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Roy-Burman P
中科院分区：
文献类型：
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作者：
Geary LA;Nash KA;Adisetiyo H;Liang M;Liao CP;Jeong JH;Zandi E;Roy-Burman P
膜联蛋白 A1 (AnxA1) 是一种磷脂结合蛋白，也是糖皮质激素诱导的炎症信号传导的调节剂，在癌症中具有重要意义。在这里，使用原代培养物和肿瘤细胞系 (cE1) 确定了 AnxA1 在前列腺腺癌中的作用，所有这些都源自前列腺癌的条件性 Pten 缺失小鼠模型。前列腺来源的癌症相关成纤维细胞 (CAF) 分泌的 AnxA1 显着高于正常前列腺成纤维细胞 (NPF)。根据非造血谱系、高 SCA-1 以及高或中等水平的 CD49f 对前列腺肿瘤细胞进行分类，以富集上皮亚群。与对照相比，AnxA1 增强了分选的 cE1 和原代细胞的高和中表达亚群中的干细胞样特性：在体外，通过形成更多数量且复杂性增加的球体；在体内，通过产生更多、更大且组织学上复杂的腺体结构，以及基础/祖细胞标记物 p63 的表达增加。来自 cE1 和原代细胞的分化中等表达亚群最容易获得干细胞样特性，如球体和腺体形成增加所示。 AnxA1 可调节 cE1 细胞中的上皮间质转化 (EMT)，进一步支持了这种可塑性的增加。这些结果表明，CAF 分泌的 AnxA1 通过两个独立但互补的途径促进肿瘤干细胞动力学：诱导去分化过程，导致癌症上皮细胞亚群产生干细胞样细胞，以及刺激癌症干细胞样细胞的增殖和分化。
Annexin A1 (AnxA1), a phospholipid-binding protein and regulator of glucocorticoid-induced inflammatory signaling, has implications in cancer. Here, a role for AnxA1 in prostate adenocarcinoma was determined using primary cultures and a tumor cell line (cE1), all derived from the conditional Pten deletion mouse model of prostate cancer. AnxA1 secretion by prostate-derived cancer-associated fibroblasts (CAFs) was significantly higher than by normal prostate fibroblasts (NPFs). Prostate tumor cells were sorted to enrich for epithelial subpopulations based on non-hematopoietic lineage, high SCA-1, and high or medium levels of CD49f. Compared to controls, AnxA1 enhanced stem cell-like properties in high- and medium-expression subpopulations of sorted cE1 and primary cells: in vitro, through formation of greater number of spheroids with increased complexity; and in vivo, through generation of more, larger and histologically complex glandular structures, along with increased expression of p63, a basal/progenitor marker. The differentiated medium-expression subpopulations from cE1 and primary cells were most susceptible to gain stem cell-like properties as shown by increased spheroid and glandular formation. Further supporting this increased plasticity, AnxA1 was shown to regulate epithelial-to-mesenchymal transition (EMT) in cE1 cells. These results suggest that CAF-secreted AnxA1 contributes to tumor stem cell dynamics via two separate but complementary pathways: induction of a de-differentiation process leading to generation of stem-like cells from a subpopulation of cancer epithelial cells, and stimulation of proliferation and differentiation of the cancer stem-like cells.