Abstract 3105: 4-Methylumbelliferone (4Mu) turns CD133+ lung cancer stem cells (CSCs) more susceptible to conventional chemotherapy

Abstract

Abstract Non-small cell lung cancer (NSCLC) is the most common cause of cancer death worldwide. Taxane-platin chemotherapy is widely used for NSCLC treatment; however, the majority of patients will ultimately progress or relapse. In the tumor microenvironment (TME) cancer cells co-exist with cellular and non-cellular components that drive tumor processes such as chemotherapy resistance. A small group of tumor cells called cancer stem cells (CSCs) that express some markers such as CD133, CD44 and ALHD1 have particularly different proliferative, differentiation and self-renewal potential. In fact, CD133+ NSCLC cells showed significantly higher abilities of self-renewal and drug resistance characteristics when compared to CD133- cells. It has been partly described how the TME component hyaluronan (HA) regulates CSCs function. We have previously demonstrated that 4-Methylumbelliferone (4Mu), a modulator of HA synthesis, reduces CSCs properties in hepatocarcinoma. Here, we observed that HA was present Lewis Lung Carcinoma (LLC) tumors from mice. We found HA+ LLC cells; thus cancer cells produced, at least in part, the HA observed in tumors. We also observed about 6.58 ± 0.83 % of CD133+ CSCs on in vitro cultured LLC cells. Isolated CD133+ cells showed higher expression of HA and CD44 in comparison with non-CSCs population (p<0.05). Analysis of HA synthases (HAS), hyaluronidases (HYAL) and the CSCs transcription factors KLF4 and SOX2 expression from NSCLC patients using The Cancer Genome Atlas data showed that while HAS3 positively correlates with levels of KLF4 and SOX2, HYAL2 inversely correlates with SOX2 expression. Also, 4Mu treatment of whole, CD133+ or CD133- LLC cells showed an inhibitory concentration 50 (IC50) of 0.90mM, 0.60mM and 1.06mM respectively, while non tumor cells showed an IC50 of 4.22mM (p<0.01). When CD133+ cells were treated with 4Mu plus pemetrexed or paclitaxel we observed a significant decrease in viability with an IC50 of 0.4nM pemetrexed (Pe) vs. 0.05nM Pe+4M, and 9.3nM paclitaxel (Pa) vs. 0.80nM Pa + 4Mu. (p<0.05). Our results suggest that HA a principal ligand of CD44 is involved in CD133+ cells phenotype and their modulation by 4Mu could increases chemo sensibility of lung cancer stem cells. Citation Format: Ana L. Bezazian, Maria Amanda Escribano, Marco A. Diaz Gutierrez, Mariel Fusco, Paula Roselló, Juan Braga Menendez, Esteban J. Fiore, Juan M. Bayo Fina, Manglio M. Rizzo, Mariana Malvicini. 4-Methylumbelliferone (4Mu) turns CD133+ lung cancer stem cells (CSCs) more susceptible to conventional chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3105.