Analysis of prediction of breast and colon cancer stemness in the treatment of chemoterapeutic agents using mathematical modeling tools

[A .R. Hamzagić]

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Uvod: Kompleksna tumorska mikrosredina sa heterogenim vrstama ćelija predstavlja brojne izazove u terapijskom pristupu jer i nakon hemioterapije, kancerske matične ćelije CSCc ostaju vijabilne i ponovo mogu indukovati nastanak tumora i metastaza. Zbog navedenog, detaljna analiza tumorske mikrosredine i identifikacija drajver markera i ćelija sa različitim fenotipom je neophodna. Cilj: Osnovni cilj ovog istraživanja je detekcija markera koji učestvuju u terapijskom ishodu i identifikacija noksi (poliestirenska nanoplastika) koje doprinose razvoju tumora. Materijal i metode: Markeri rezistencije i malignosti koji su bili ispitivani su: CD24, CD44, ABCG2 i ALDH1. Obuhvaćena je analiza 24 različite kombinacije ovih markera kao i ispitivanje uticaja 5-fluorouracila, leukovorina, irinotekana, oksaliplatine i poliestirenske nanoplastike na modelu ćelijskih linija kancera kolona (HCT-116) i dojke (MDA-MB-231). Matematička analiza omogućila nam je bolju karakterizaciju malignog fenotipa. Rezultati: Uticaj hemioterapeutika i nanoplastike na izlečenje, nastanak i progresiju tumora, predstavljaju najznačajniji doprinos ovog istraživanja. Stepen malignosti određivan je na osnovu zastupljenosti populacije CSC, koja je definisana ekspresijom markera matičnosti metodama protočne citometrije i qRT-PCR. U proceni vijabilnosti koristili smo in vitro metode (MTT i RTCA). Zaključak: Rezultati ovog istraživanja po prvi put pokazuju da su ispitivane linije karcinoma heterogena populacija tumorskih ćelija koje sadrže i CSC. Takođe da konvencionalni hemioterapeutici mogu da pomognu ali mogu i da promovišu proliferaciju CSC. Polistirenska nanoplastika predstavlja značajnu noksu u nastanku malignog fenotipa. Implementacija matematičkog modeliranja predstavnja važan faktor u razumevanju tumora i izboru terapije.

Introduction: The complex tumor microenvironment with heterogeneous cell types poses challenges in the therapy because even after chemotherapy, CSC remain viable and can again induce tumor formation and metastasis. Therefore, a detailed analysis of the tumor microenvironment, driver markers and cells with different phenotypes are crucial. Aim: The main objective of this study was the detection of markers that participate in the therapeutic outcome and the identification of noxi that contribute to tumor growth and development. Material and methods: Markers of resistance to chemotherapeutic drugs and malignancy were CD24, CD44, ABCG2 and ALDH1. Study included anylysis of 24 marker combinations and effects of 5-fluorouracil, leucovorin, irinotecan, oxaliplatin and polyester nanoplastics in a model of colon (HCT-116) and breast cancer cell lines (MDA-MB-231). Mathematical analysis allowed us to better characterize the malignant phenotype. Results: The impact of chemotherapeutics and nanoplastics on the cure, formation and progression of tumors represent the most significant contribution of this research. The degree of malignancy was determined on the presence of the CSC population, which was defined by the expression of stem markers by flow cytometry and qRT-PCR methods.Viability was evaluated using in vitro methods (MTT and RTCA). Conclusion: Our results showed for the first time that the examined cancer lines are a heterogeneous population of tumor cells that also contain CSCs. Conventional chemotherapeutic agents can help, but also promote the proliferation of CSCs. Polystyrene nanoplastics represent a significant factor in the formation of a malignant phenotype. The implementation of mathematical modeling is an important tool in understanding tumors and choosing a therapy.

Kancerske matične ćelije, matematičko modeliranje, hemioterapeutici, polistirenska nanoplastika

Cancer stem cells, mathematical modeling, chemotherapeutic agent, polystyrene nanoplastics

575:616-006.6(043.3)

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