Depletion of Lipid Efflux Pump ABCG1 Triggers the Intracellular Accumulation of Extracellular Vesicles and Reduces Aggregation and Tumorigenesis of Metastatic Cancer Cells

Frontiers in Oncology

Takanori Eguchi¹  Eriko Aoyama¹  Masaharu Takigawa¹  Kazumi Ohyama²  Chiharu Sogawa²  Mami Itagaki²  Yuka Okusha²  Ken-ichi Kozaki²  Kisho Ono²  Kuniaki Okamoto²  Jun Murakami³  Hotaka Kawai⁴  Yuri Namba⁵  Jun-ichi Asaumi⁵  Stuart K. Calderwood⁶ 

[1] Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan;Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan;Department of Oral Diagnosis and Dentomaxillofacial Radiology, Okayama University Hospital, Okayama, Japan;Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan;Department of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan;Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States;

关键词: ABCG transporter;    ABCG1;    tumoroids;    extracellular vesicle;    metastatic cancer;    hypoxia;   

DOI  :  10.3389/fonc.2018.00376

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown