Abstract
The ATP-binding cassette transporter G1 (ABCG1) is a cholesterol lipid efflux pump whose role in tumor growth has been largely unknown. Our transcriptomics revealed that ABCG1 was powerfully expressed in rapidly metastatic, aggregative colon cancer cells, in all the ABC transporter family members. Coincidently, genetic amplification of ABCG1 is found in 10–35% of clinical samples of metastatic cancer cases. Expression of ABCG1 was further elevated in three-dimensional tumoroids (tumor organoids) within stemness-enhancing tumor milieu, whereas depletion of ABCG1 lowered cellular aggregation and tumoroid growth in vitro as well as hypoxia-inducible factor 1α in cancer cells around the central necrotic areas in tumors in vivo. Notably, depletion of ABCG1 triggered the intracellular accumulation of extracellular vesicles (EVs) and regression of tumoroids. Collectively, these data suggest that ABCG1 plays a crucial role in tumorigenesis in metastatic cancer and that depletion of ABCG1 triggers tumor regression with the accumulation of EVs and their derivatives and cargos, implicating a novel ABCG1-targeting therapeutic strategy by which redundant and toxic substances may be accumulated in tumors leading to their regression.
Highlights
The mechanism underlying unlimited tumor growth and metastasis are unsolved problems in medicine and biology
We examined the gene expression levels of the ATP-binding cassette (ABC) genes among the aggregative metastatic cells compared to nonaggregative less-metastatic cells by analyzing their transcriptome
Hypoxia-inducible erythropoietin (EPO) gene expression was shown in human neuroblastoma cells [56], downregulation of Epo mRNA was found in LuM1 aggregates as compared with Colon26 cells, We examined whether ATP-binding cassette transporter G1 (ABCG1) depletion altered hypoxia-inducible factor (HIF)-1α levels in tumors
Summary
The mechanism underlying unlimited tumor growth and metastasis are unsolved problems in medicine and biology We have approached these issues by: (i) study of differently metastatic cancer cells [1, 2], (ii) using a three-dimensional (3D) organoid/tumoroid developed in stemness-enhancing medium compared with popularly-used two-dimensional (2D) culture milieu [2], and (iii) characterization of extracellular vesicles (EVs) secreted by metastatic cancer cells [2,3,4]. We aimed to investigate the autocrine roles of EVs involving ABCG1-mediated EV lipid metabolism using 3D tumoroid model. We showed that depletion of the ABCG1 pump triggers the accumulation of autocrine EVs that could trigger regression of malignant tumors
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