Related Experiment Video
Updated: Dec 7, 2025
Isolation, Culture, and Characterization of Prostate Cancer-Associated Fibroblasts
Published on: August 1, 2025
CD44+ cells determine fenofibrate-induced microevolution of drug-resistance in prostate cancer cell populations
Tomasz Wróbel1, Marcin Luty1, Jessica Catapano1
1Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
Abstract:
Combinations of metabolic blockers (incl. fenofibrate) with chemotherapeutic drugs interfere with the drug-resistance of prostate cancer cells. However, their effect on cancer stem cells-dependent microevolution of prostate cancer malignancy remains unaddressed. Here, we hypothesize that the combined docetaxel/fenofibrate treatment prompts the selective expansion of cancer stem cells that affects the microevolution of their progenies. Accordingly, we adapted a combined in vitro/in vivo approach to identify biological and therapeutic consequences of this process. Minute subpopulations of docetaxel-resistant CD133high and/or CD44high cancer stem cell-like (SCL) cells were found in prostate cancer DU145 and PC3 cell populations. When pretreated with docetaxel, they readily differentiated into docetaxel-resistant CD44negative "bulk" cells, thus accounting for the microevolution of drug-resistant cell lineages. Combined docetaxel/fenofibrate treatment induced the generation of poly(morpho)nuclear giant cells and drug-resistant CD44high SCL cells. However, the CD44negative offspring of docetaxel- and docetaxel/fenofibrate-treated SCLs remained relatively sensitive to the combined treatment, while retaining enhanced resistance to docetaxel. Long-term propagation of drug-resistant SCL-derived lineages in the absence of docetaxel/fenofibrate resulted in their reverse microevolution toward the drug-sensitivity and invasive phenotype. Consequently, prostate tumors were able to recover from the combined docetaxel/fenofibrate stress after the initial arrest of their expansion in vivo. In conclusion, we have confirmed the potential of fenofibrate for the metronomic treatment of drug-resistant prostate tumors. However, docetaxel/fenofibrate-induced selective expansion of hyper-resistant CD44high SCL prostate cells and their "bulk" progenies prompts the microevolution of prostate tumor drug-resistance. This process can limit the implementation of metabolic chemotherapy in prostate cancer treatment.
Insights
Fenofibrate combined with docetaxel may increase prostate cancer stem cell resistance. This combination can lead to drug-resistant cell evolution, potentially limiting its effectiveness in treating advanced prostate cancer.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Metabolic blockers like fenofibrate combined with chemotherapy can impact prostate cancer drug resistance.
- The effect of these combinations on cancer stem cell (CSC)-driven microevolution in prostate cancer remains unclear.
Purpose of the Study:
- To investigate the hypothesis that combined docetaxel/fenofibrate treatment promotes selective expansion of CSCs, influencing their progeny's microevolution.
- To identify the biological and therapeutic consequences of this CSC-driven process using in vitro and in vivo models.
Main Methods:
- Utilized a combined in vitro and in vivo approach to study prostate cancer cell lines (DU145, PC3).
- Identified and isolated docetaxel-resistant CD133high and/or CD44high cancer stem cell-like (SCL) populations.
- Analyzed the differentiation, drug resistance, and microevolutionary patterns of SCLs and their offspring under docetaxel and docetaxel/fenofibrate treatments.
Main Results:
- Docetaxel treatment selected for resistant CD44high SCLs, which differentiated into resistant CD44-negative bulk cells, demonstrating lineage microevolution.
- Combined docetaxel/fenofibrate treatment generated giant cells and expanded drug-resistant CD44high SCLs.
- While SCL offspring showed some sensitivity to the combined treatment, they retained docetaxel resistance; however, long-term culture led to reversion towards drug sensitivity and invasiveness, allowing tumor recovery in vivo.
Conclusions:
- Fenofibrate shows potential for metronomic treatment of drug-resistant prostate tumors.
- The docetaxel/fenofibrate combination selectively expands hyper-resistant CD44high prostate CSCs and their progeny, driving tumor drug resistance microevolution.
- This CSC-driven microevolutionary process may limit the clinical application of metabolic chemotherapy in prostate cancer treatment.
