2. Academic Validation
  3. Mesenchymal stromal cells confer breast cancer doxorubicin resistance by producing hyaluronan

Mesenchymal stromal cells confer breast cancer doxorubicin resistance by producing hyaluronan

  • Oncogene. 2023 Sep 14. doi: 10.1038/s41388-023-02837-w.
Zhanhong Liu 1 2,  Pengbo Hou 1 2,  Jiankai Fang 1,  Jingyu Zhu 3,  Juanmin Zha 4,  Rui Liu 1 2,  Yayun Ding 1,  Muqiu Zuo 1,  Peishan Li 1,  Lijuan Cao 1,  Chao Feng 1,  Gerry Melino 2,  Changshun Shao 5,  Yufang Shi 6
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
  • 2 Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.
  • 3 School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu, China.
  • 4 Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
  • 5 The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China. shaoc@suda.edu.cn.
  • 6 The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China. yfshi@suda.edu.cn.
PMID: 37704784 DOI: 10.1038/s41388-023-02837-w
Abstract

Chemotherapy resistance represents a major cause of therapeutic failure and mortality in Cancer patients. Mesenchymal stromal cells (MSCs), an integral component of tumor microenvironment, are known to promote drug resistance. However, the detailed mechanisms remain to be elucidated. Here, we found that MSCs confer breast Cancer resistance to doxorubicin by diminishing its intratumoral accumulation. Hyaluronan (HA), a major extracellular matrix (ECM) product of MSCs, was found to mediate the chemoresistant effect. The chemoresistant effect of MSCs was abrogated when hyaluronic acid synthase 2 (HAS2) was depleted or inhibited. Exogenous HA also protected tumor grafts from doxorubicin. Molecular dynamics simulation analysis indicates that HA can bind with doxorubicin, mainly via hydrophobic and hydrogen bonds, and thus reduce its entry into breast Cancer cells. This mechanism is distinct from the reported chemoresistant effect of HA via its receptor on cell surface. High HA serum levels were also found to be positively associated with chemoresistance in breast Cancer patients. Our findings indicate that the HA-doxorubicin binding dynamics can confer Cancer cells chemoresistance. Reducing HA may enhance chemotherapy efficacy.

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