Abstract
BackgroundHyaluronan (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).MethodsBCCs 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.ResultsThe 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.ConclusionThese data suggested that HA in abnormal BM stroma might be a therapeutic candidate for bone metastasis of breast cancer.19kbyyRgNofaNy4kV-u_efVideo Graphical abstract
Highlights
Hyaluronan (HA) is an abundant component of the bone marrow (BM) extracellular matrix
Abnormal metabolism of HA in the BM stromal microenvironment To explore whether HA in tumour-metastasized BM was abnormally metabolized, we constructed a model of breast cancer bone metastasis by injecting MDA-MB231BO cells into the left ventricle of the mice
In summary, our results showed that stromal HA in tumourassociated BM was abnormally distributed and that remodelling of the microenvironment may influence the growth of breast cancer cells (BCCs)
Summary
Hyaluronan (HA) is an abundant component of the bone marrow (BM) extracellular matrix. We investigated the abnormal deposition of HA in the BM microenvironment and its remodelling in mediating the malignancy of breast cancer cells (BCCs). Bone is one of the most common sites for the localization of breast tumour cells [4, 5]. The bone marrow (BM) microenvironment contains many cytokines and high levels of extracellular matrix (ECM), which constitute the complex microenvironment of the BM. Hyaluronan (HA) is a nonprotein molecule in the BM matrix [7] and is one of the most abundant components of the ECM. Whether HA from BM stroma is altered and its subsequent effects on the growth of metastatic breast cancer cells (BCCs) in bone need to be elucidated
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