Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

Autor: Angelo Sparaneo, Reza Bayat Mokhtari, Sushil Kumar, Herman Yeger, Narges Baluch, Evgeniya Morgatskaya, Hai Ling Cheng, Sheyun Zhao, Bikul Das, Lucia Anna Muscarella
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
medicine.medical_treatment
Cell Culture Techniques
Neuroendocrine tumors
Bronchial carcinoid
Mice
0302 clinical medicine
Isothiocyanates
Antineoplastic Combined Chemotherapy Protocols
3D spheroids
education.field_of_study
Chemistry
Bronchial Neoplasms
Nanog Homeobox Protein
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Gene Expression Regulation
Neoplastic
Oncology
030220 oncology & carcinogenesis
Sulfoxides
Neoplastic Stem Cells
Female
Research Article
Homeobox protein NANOG
Orthotopic lung model
Combination therapy
Cell Survival
Population
Carcinoid Tumor
lcsh:RC254-282
03 medical and health sciences
Stroma
Cell Line
Tumor
Spheroids
Cellular
Genetics
medicine
Animals
Anticarcinogenic Agents
Humans
education
Cell Proliferation
Growth factor
SOXB1 Transcription Factors
Spheroid
medicine.disease
Xenograft Model Antitumor Assays
Acetazolamide
030104 developmental biology
Cell culture
Cancer research
Octamer Transcription Factor-3
Sulforaphane
Zdroj: BMC Cancer, Vol 19, Iss 1, Pp 1-19 (2019)
BMC Cancer
ISSN: 1471-2407
Popis: Background Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior. Methods Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids. Results Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice. Conclusions Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.
Databáze: OpenAIRE
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