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CD44⁺ cells determine fenofibrate-induced microevolution of drug-resistance in prostate cancer cell populations.

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 CD133^high and/or CD44^high 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 CD44^negative "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 CD44^high SCL cells. However, the CD44^negative 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 CD44^high 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.

SUBMITTER: Wrobel T

PROVIDER: S-EPMC7756969 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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CD44<sup>+</sup> cells determine fenofibrate-induced microevolution of drug-resistance in prostate cancer cell populations.

Wróbel Tomasz T Luty Marcin M Catapano Jessica J Karnas Elżbieta E Szczygieł Małgorzata M Piwowarczyk Katarzyna K Ryszawy Damian D Drabik Grażyna G Zuba-Surma Ewa E Siedlar Maciej M Madeja Zbigniew Z Elas Martyna M Czyż Jarosław J

Stem cells (Dayton, Ohio) 20200927

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 ...[more]

PMID: 32985018

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Project description:Vibrio parahaemolyticus is becoming the leading cause of acute bacterial gastroenteritis, but its population dynamics in aquafarms have received limited attention. To address this research gap, we selected three shellfish farms to examine the impacts of ocean currents and the transport of live aquatic animals on the transmission and microevolution of V. parahaemolyticus by using multilocus sequence typing (MLST) and whole-genome sequencing. MLST and genomic analysis revealed that the community structure of V. parahaemolyticus in Dalian and Donggang was relatively stable in the presence of ocean currents; however, horizontal gene transfer of mobile genetic elements (MGEs) between Dalian and Donggang was very common. Further analysis indicated that the transport of live aquatic animals from Dalian to Xiamen not only introduced new V. parahaemolyticus populations but also allowed the exchange of genetic material between the two sites. More interestingly, Dalian-originated strain ST722 was introduced to Xiamen farms, resulting in one MLST allele change and the acquisition of two genomic islands from indigenous isolates in Xiamen within 8 months; such alterations are thought to promote the adaptation of V. parahaemolyticus These results provide direct observations of how ocean currents and the transport of live aquatic animals contribute to the dissemination and genetic mixture of V. parahaemolyticus, which provides insights into the dynamics and microevolution of V. parahaemolyticus in aquacultural environments.IMPORTANCE Globally, V. parahaemolyticus-related gastroenteritis outbreaks caused by seafood consumption represent an increasing threat to human health. Despite advances in our understanding of the global epidemiology of pandemic V. parahaemolyticus, fundamental questions about the key driving forces for the spread of V. parahaemolyticus at regional and national scales remain unanswered. This study revealed that the transregional transport of aquatic animals and the movement of ocean currents both contributed to the mixing of V. parahaemolyticus populations. More importantly, this study demonstrated how genetic mixture occurred between introduced and endemic V. parahaemolyticus populations via the transport of aquatic animals, which accelerated bacterial adaptation by transferring ecologically important functions. These results suggest that human activities entail a risk of the emergence of new virulent populations for both aquatic animals and humans by horizontal gene transfer and provide important insights into the microevolution and population mixing of V. parahaemolyticus.

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CD44+ cells determine fenofibrate-induced microevolution of drug-resistance in prostate cancer cell populations.

Publications

CD44<sup>+</sup> cells determine fenofibrate-induced microevolution of drug-resistance in prostate cancer cell populations.

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CD44⁺ cells determine fenofibrate-induced microevolution of drug-resistance in prostate cancer cell populations.