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14. Extracellular Vesicle-Mediated Modulation of Stem-like Phenotype in Breast Cancer Cells under Fluid Shear Stress.

Author

Brown, Spenser R., Radcliffe, Margaret E., Danner, Joseph T., Andújar Cruz, Wilmer J., Lackey, Kimberly H., Park, Han-A, Weinman, Steven T., and Kim, Yonghyun

Subjects
METASTATIC breast cancer, CANCER stem cells, GENE expression, METASTASIS, SHEARING force
Abstract

Circulating tumor cells (CTCs) are some of the key culprits that cause cancer metastasis and metastasis-related deaths. These cells exist in a dynamic microenvironment where they experience fluid shear stress (FSS), and the CTCs that survive FSS are considered to be highly metastatic and stem cell-like. Biophysical stresses such as FSS are also known to cause the production of extracellular vesicles (EVs) that can facilitate cell–cell communication by carrying biomolecular cargos such as microRNAs. Here, we hypothesized that physiological FSS will impact the yield of EV production, and that these EVs will have biomolecules that transform the recipient cells. The EVs were isolated using direct flow filtration with and without FSS from the MDA-MB-231 cancer cell line, and the expression of key stemness-related genes and microRNAs was characterized. There was a significantly increased yield of EVs under FSS. These EVs also contained significantly increased levels of miR-21, which was previously implicated to promote metastatic progression and chemotherapeutic resistance. When these EVs from FSS were introduced to MCF-7 cancer cells, the recipient cells had a significant increase in their stem-like gene expression and CD44+/CD24− cancer stem cell-like subpopulation. There was also a correlated increased proliferation along with an increased ATP production. Together, these findings indicate that the presence of physiological FSS can directly influence the EVs' production and their contents, and that the EV-mediated transfer of miR-21 can have an important role in FSS-existing contexts, such as in cancer metastasis. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C

Author

Dunn, Winston, O'Neil, Maura, Zhao, Jie, Wu, Chuang Hong, Roberts, Benjamin, Chakraborty, Shweta, Sherman, Craig, Weaver, Brandy, Taylor, Ryan, Olson, Jody, Olyaee, Mojtaba, Gilroy, Richard, Schmitt, Timothy, Wan, Yu‐Jui Yvonne, and Weinman, Steven A

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Digestive Diseases, Hepatitis - C, Emerging Infectious Diseases, Infectious Diseases, Transplantation, Organ Transplantation, Hepatitis, Genetics, Chronic Liver Disease and Cirrhosis, Clinical Research, Liver Disease, 4.1 Discovery and preclinical testing of markers and technologies, Good Health and Well Being, Biopsy, Cohort Studies, Disease Progression, Female, Follow-Up Studies, Genotype, Hepatitis C, Humans, Lipase, Liver, Liver Cirrhosis, Liver Transplantation, Male, Membrane Proteins, Middle Aged, Multivariate Analysis, Polymorphism, Single Nucleotide, Retrospective Studies, Tissue Donors, Treatment Outcome, Medical Biochemistry and Metabolomics, Clinical Sciences, Immunology, Gastroenterology & Hepatology, Clinical sciences
Abstract

UnlabelledThe rs738409 G>C single nucleotide polymorphism occurring in the patatin-like phospholipase 3 gene has been identified as a novel genetic marker for hepatic steatosis. Recent studies also associated rs738409 with fibrosis in hepatitis C (HCV). Therefore, we sought to determine the impact of donor and recipient rs738409 genotype on the progression of fibrosis after liver transplantation for HCV. This cohort study included 101 patients infected with HCV who underwent liver transplantation between January 2008, and June 2011. Donor and recipient rs738409 genotypes were determined from donor wedge biopsies and recipient explants. The time to Ishak stage 3 fibrosis, or HCV-related mortality/graft loss was analyzed by the Cox model adjusting for HCV-Donor Risk Index, warm ischemic time, pretransplant Model for Endstage Liver Disease (MELD) and viral load. The rs738409 CC variant was present in 56% of donors and 57% of recipients. The median follow-up period was 620 days. A total of 39 patients developed the primary outcome of ≥stage 3 fibrosis or HCV-related mortality/graft loss, the time to which differed by donor (P = 0.019) but not recipient (P = 0.89) genotype. In the multivariate model, donor GC or GG variants had 2.53 times the risk (95% confidence interval [CI] 1.25-5.02, P = 0.008) compared to CC variants. In the alternative endpoint: stage 3 fibrosis or all-cause mortality/graft loss, the effect of donor genotype was attenuated but remained significant at 1.98 (95% CI 1.11-3.53).ConclusionsThe rs738409 genotype is an important predictor of posttransplant outcome in HCV. Liver, and not adipocytes, is the site at which this effect occurs. Our finding may be useful in donor selection for liver transplantation with HCV, and may guide decisions regarding early antiviral treatment.

Published
2014

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