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Obtaining Cancer Stem Cell Spheres from Gynecological and Breast Cancer Tumors
Published on: March 1, 2020
Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal
Pasquale Sansone1, Marjan Berishaj1, Vinagolu K Rajasekhar1
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ERlo/Notchhi feed-forward loop responsible for the generation of CD133hi CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221hi CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to de novo HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133hi cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133hi CSCs. Conversely, in models of CD133neg, HT-sensitive cancer cells, both murine and human CAFs promoted de novo HT resistance via the generation of CD133hi CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. Cancer Res; 77(8); 1927-41. ©2017 AACR.
Insights
Cancer-associated fibroblasts transfer microRNAs via microvesicles, promoting therapy resistance in breast cancer. This study shows how this process generates cancer stem cells (CSCs) and offers potential therapeutic targets.
Area of Science:
- Molecular Oncology
- Cancer Biology
- Cellular Communication
Background:
- The role of microvesicle-mediated miRNA transfer in converting non-cancer stem cells into cancer stem cells (CSCs) and driving therapy resistance is largely unexplored.
- Hormonal therapy resistance (HTR) in breast cancer is a significant clinical challenge, often linked to the emergence of CSCs.
Purpose of the Study:
- To investigate whether microvesicle-mediated miRNA transfer from cancer-associated fibroblasts (CAFs) can induce CSCs and lead to hormonal therapy resistance in breast cancer.
- To elucidate the molecular mechanisms, including specific miRNAs and signaling pathways, involved in this process.
Main Methods:
- Utilized models of luminal breast cancer, including patient-derived xenografts (PDX) and experimental models.
- Analyzed microvesicles derived from CAFs for miRNA content (specifically miR-221) and their transfer to tumor cells.
- Investigated the activation of signaling pathways (ER/Notch, IL6-pStat3) and the generation of CD133+ CSCs.
- Employed IL6 receptor blockade and CAF depletion strategies to assess therapeutic interventions.
Main Results:
- Demonstrated that CAFs release microvesicles containing miR-221, which are transferred to breast cancer cells, promoting HTR.
- Identified an ERlo/Notchhi feed-forward loop activated by CAF-derived miR-221, leading to the generation of CD133hi CSCs.
- Found high miR-221 levels in microvesicles from patients with HTR metastatic disease and confirmed the role of the IL6-pStat3 pathway in CAF microvesicle biogenesis.
- Showed that CAF depletion or IL6R blockade reversed HTR and reduced CSC populations in experimental and PDX models.
Conclusions:
- Microvesicle-mediated horizontal transfer of miR-221 from CAFs to cancer cells is a key mechanism driving the evolution of hormonal therapy resistance in breast cancer.
- This process generates CSCs and establishes pro-tumorigenic stromal CSC niches, highlighting the critical role of the tumor microenvironment.
- Targeting CAF-derived microvesicles or associated signaling pathways (e.g., IL6-pStat3) presents a promising therapeutic strategy for overcoming therapy resistance in breast cancer.
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