Identification of the niche cells interacting with cancer stem cells and elucidation of their functions in breast cancer

我们分析了CD44、CD133、EpCAM、CXCR4和c-Met等几种标记物在其他恶性肿瘤中的表达比例。结果发现，除EpCAM外，其余标记均存在阳性群体和阴性群体。此外，我们量化了Notch配体的表达水平，据报道，Notch配体与CSCs的细胞分化和肿瘤-间质相互作用有关。我们发现，乳腺癌细胞单独表达DLL1的水平高于其他癌细胞。我们还量化了Fas/FasL和LCP1的表达水平，据报道这两种基因与宿主的免疫反应有关。我们发现，与其他癌细胞相比，乳腺癌细胞中Fas/FasL的水平较低，这表明乳腺癌细胞倾向于避开宿主的免疫反应。由于LCP1高表达与乳腺癌预后不良有关，LCP1可作为乳腺癌耐药的新标记物。同时，我们对结肠癌、胰腺癌等肿瘤组织来源的原代培养成纤维细胞表达间充质/内皮干细胞(MSC/ESC)标记的亚群进行了分类，并对其生物学功能进行了分析。结果，我们发现CD10+肿瘤相关成纤维细胞显著增强了侵袭、转移和肿瘤形成。这些新的CSC/MSC特异性分子可能成为乳腺癌诊断和治疗的新靶点。

We analyzed the ratio of populations expressing several markers, including CD44, CD133, EpCAM, CXCR4 and c-MET, which reported as the cancer stem cell (CSC) markers in the other malignancies. As the result, we found the positive and negative populations in all markers except EpCAM. Additionally, we quantified the expression levels of Notch ligands, which reported to be associated with cellular differentiation of CSCs and cancer-stromal interactions. We found that breast cancer cells expressed higher levels of DLL1 alone than those in other cancer cells. We also quantified the expression levels of FAS/FasL and LCP1 which are reported to be associated with the host's immune responses. We found the lower levels of FAS/FasL in breast cancer cells compared with other cancer cells, indicating that breast cancer cells tend to avoid the host's immune responses. Because the cases with higher expression of LCP1 were reported to be associated with poor prognosis in breast cancer, LCP1 can be the novel marker of breast cancer cells resistant to anti-tumor therapies. Meanwhile, we sorted the subpopulations expressing mesenchymal/endothelial stem cell (MSC/ESC) markers from primary-cultured fibroblasts derived from cancer tissues including colonic/pancreatic cancers and analyzed their biological functions. As the result, we found that CD10+ cancer-associated fibroblasts markedly enhanced invasiveness, metastasis, and tumor formation. These novel CSC/MSC specific molecules may be the promising diagnostic and therapeutic targets in breast cancer.