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Updated: Jul 16, 2025
Isolation and Functional Assessment of Human Breast Cancer Stem Cells from Cell and Tissue Samples
Published on: October 2, 2020
Mesenchymal stromal cells confer breast cancer doxorubicin resistance by producing hyaluronan
Zhanhong Liu1,2, Pengbo Hou1,2, Jiankai Fang1
1The 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.
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.
Insights
Mesenchymal stromal cells (MSCs) promote breast cancer doxorubicin resistance by producing hyaluronan (HA). HA binds doxorubicin, reducing its cell entry and enhancing chemoresistance, suggesting HA reduction may improve treatment efficacy.
Area of Science:
- Oncology
- Cancer Biology
- Drug Resistance Mechanisms
Background:
- Chemotherapy resistance is a primary driver of cancer treatment failure and mortality.
- Mesenchymal stromal cells (MSCs) within the tumor microenvironment are implicated in promoting drug resistance, but mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of Mesenchymal Stromal Cells (MSCs) and their products in conferring resistance to doxorubicin in breast cancer.
- To elucidate the specific molecular mechanisms by which MSCs mediate chemotherapy resistance.
Main Methods:
- Investigated MSC-mediated doxorubicin resistance in breast cancer models.
- Assessed the role of hyaluronan (HA) and its synthesis enzyme (HAS2).
- Utilized molecular dynamics simulations to analyze HA-doxorubicin interactions.
- Correlated serum HA levels with clinical chemoresistance data.
Main Results:
- MSCs reduce doxorubicin accumulation in tumors, conferring chemoresistance.
- Hyaluronan (HA), an extracellular matrix component produced by MSCs, mediates this chemoresistant effect.
- Depletion or inhibition of hyaluronic acid synthase 2 (HAS2) abrogated MSC-induced chemoresistance.
- Exogenous HA protected tumor grafts from doxorubicin.
- Molecular dynamics simulations revealed HA binds doxorubicin via hydrophobic and hydrogen bonds, hindering its cellular uptake.
- High serum HA levels correlated positively with chemoresistance in breast cancer patients.
Conclusions:
- Hyaluronan (HA) directly confers chemoresistance by binding doxorubicin and preventing its entry into cancer cells.
- This HA-doxorubicin binding mechanism is a novel pathway contributing to chemotherapy failure.
- Targeting or reducing HA levels presents a potential strategy to enhance chemotherapy efficacy in breast cancer.
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