Hyaluronan (HA) is an abundant component of the bone marrow (BM) extracellular matrix. Here, we investigated the abnormal deposition of HA in the BM microenvironment and its remodelling in mediating the malignancy of breast cancer cells (BCCs). BCCs were transplanted into nude mice by intracardiac injection. The BCCs were cocultured with BM-derived stromal HS5 cells. Then, the abnormal metabolism of HA and its correlation with the malignant growth and the intracellular signalling pathways of the BCCs were investigated. After knockdown/out of the HA receptor CD44 in cancer cells by shRNA and CRISPR/Cas9, the mechanism was investigated in vivo through intratibial inoculation and in vitro by coculture with HS5 cells. The malignancy of cancer cells was highly related to the degree of accumulation of HA in the BM. Further, stromal cell-derived HA, especially the mixed complex, significantly promoted the growth of BCCs and osteolysis by binding to the CD44 receptor. Additionally, the investigation of the underlying mechanism revealed that the PI3K, Cyclin D1, and CDK4 pathways were involved in the effect of bone stromal cell-derived HA on the BCC activities. These data suggested that HA in abnormal BM stroma might be a therapeutic candidate for bone metastasis of breast cancer.

中文翻译：

---

基质透明质酸对骨髓微环境的重塑可调节乳腺癌细胞的恶性程度。

透明质酸 (HA) 是骨髓 (BM) 细胞外基质的丰富成分。在这里，我们研究了 HA 在 BM 微环境中的异常沉积及其在介导乳腺癌细胞 (BCC) 恶性过程中的重塑。通过心内注射将BCCs移植到裸鼠体内。BCC 与 BM 来源的基质 HS5 细胞共培养。然后，研究了HA的异常代谢及其与BCC恶性生长和细胞内信号通路的相关性。在通过 shRNA 和 CRISPR/Cas9 敲除/敲除癌细胞中的 HA 受体 CD44 后，通过胫内接种在体内和通过与 HS5 细胞共培养在体外研究了该机制。癌细胞的恶性程度与 BM 中 HA 的积累程度高度相关。此外，基质细胞衍生的 HA，尤其是混合复合物，通过与 CD44 受体结合，显着促进了 BCC 的生长和骨溶解。此外，对潜在机制的研究表明，PI3K、细胞周期蛋白 D1 和 CDK4 通路参与了骨基质细胞衍生的 HA 对 BCC 活性的影响。这些数据表明异常 BM 基质中的 HA 可能是乳腺癌骨转移的治疗候选者。