Host CYP27A1 expression is essential for ovarian cancer progression

Autor: Liqian Ma, Anna Vardanyan, Sisi He, Varsha Vembar, Amy E. Baek, Adam T Nelson, Joy J. Chen, Erik R. Nelson, Joanna E. Burdette
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Myeloid
Endocrinology
Diabetes and Metabolism
Estrogen receptor
Article
B7-H1 Antigen
Cholesterol
Dietary
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Endocrinology
Cell Line
Tumor
medicine
Animals
Humans
Liver X receptor
Cell Proliferation
Ovarian Neoplasms
Tumor microenvironment
business.industry
Myeloid-Derived Suppressor Cells
Cell Differentiation
medicine.disease
Prognosis
Xenograft Model Antitumor Assays
Immune checkpoint
Hydroxycholesterols
Progression-Free Survival
030104 developmental biology
medicine.anatomical_structure
Oncology
chemistry
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
27-Hydroxycholesterol
Cancer research
Disease Progression
Cholestanetriol 26-Monooxygenase
Female
Stem cell
Ovarian cancer
business
Zdroj: Endocr Relat Cancer
Popis: There is an urgent need for more effective strategies to treat ovarian cancer. Elevated cholesterol levels are associated with a decreased progression-free survival time (PFS) while statins are protective. 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, has been shown to modulate the activities of the estrogen receptors (ERs) and liver x receptors (LXRs) providing a potential mechanistic link between cholesterol and ovarian cancer progression. We found that high expression of CYP27A1, the enzyme responsible for the synthesis of 27HC, was associated with decreased PFS, while high expression of CYP7B1, responsible for 27HC catabolism, was associated with increased PFS. However, 27HC decreased the cellular proliferation of various ovarian cancer cell lines in an LXR-dependent manner. Intriguingly, ID8 grafts were unable to effectively establish in CYP27A1−/− mice, indicating involvement of the host environment. Tumors from mice treated with 27HC had altered myeloid cell composition, and cells from the marrow stem cell lineage were found to be responsible for the effects in CYP27A1−/− mice. While inhibition of CYP27A1 or immune checkpoint did not significantly alter tumor size, their combination did, thereby highlighting this axis as a therapeutic target.
Databáze: OpenAIRE
Externí odkaz: