isolation-of-tissue-extracellular-vesicles-from-the-liver

Isolation of Tissue Extracellular Vesicles from the Liver

Extracellular vesicles (EVs) can be released from many different cell types and detected in most, if not all, body fluids. EVs can participate in ...

Mayo Clinic

Aberrant activation of β-catenin signaling is frequently observed in hepatocellular cancer. Although Wnt/β-catenin signaling can be targeted by vitamin D, therapeutic use of vitamin D for this purpose is not currently established. We evaluated the therapeutic use of vitamin D or its analogs using a synthetic transgenic mouse of hepatocarcinogenesis induced by mutant β-catenin, and MET overexpression in which 75% of mice develop well-differentiated HCC within 8 weeks in the absence of fibrosis. Vitamin D receptor expression was similar in both tumoral and nontumoral tissue. There was no significant difference in overall survival, or in tumor progression assessed by imaging, biochemical, or tumor cell burden assessments in mice receiving a vitamin D-supplemented diet containing 12.0 IU VD/g (HVD) compared with a standard diet (SD) containing 2.3 IU VD/g. Furthermore, systemic treatment with calcitriol [vitamin D analog 1α,25(OH)₂D₃] or EB1089 (synthetic vitamin D analog) by intraperitoneal injection for 4 weeks prolonged median survival but did not increase overall survival compared with controls. Although tumor formation was delayed in males compared with that in females, there was no difference in overall survival between males and females. In conclusion, although 1α,25(OH)₂D₃ is reported to inhibit β-catenin signaling, as well as proliferation, migration, and differentiation in cancer cells, neither dietary supplementation with vitamin D nor treatment with vitamin D analogs altered the formation or growth of HCC associated with β-catenin activation. These results conclusively demonstrate the lack of utility of targeting vitamin D for therapy of HCC in this setting.

Therapeutic Efficacy of Vitamin D in Experimental c-MET-β-Catenin-Driven Hepatocellular Cancer.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although HCC can respond to immune checkpoint inhibitors, such as monoclonal antibodies against programmed death 1 (PD-1), many patients fail to respond or develop secondary resistance. Activation of Wnt/β-catenin signaling can contribute to immune evasion. Mutations in β-catenin are among the most frequent mutations associated with HCC. Thus, our aim was to directly target β-catenin to enhance the therapeutic response to immune checkpoint inhibition. A synthetic transgenic mouse model of experimental HCC induced by tyrosine-protein kinase Met/β-catenin expression and extracellular vesicles (EVs) as a therapeutic delivery agent was used to evaluate the efficacy of directly targeting β-catenin on the response to anti-PD-1. These studies showed that (1) oncogenic β-catenin could be therapeutically targeted using a biological nanoparticle-based delivery approach, (2) targeting β-catenin using small interfering RNA (siRNA) delivered within EVs can reduce tumor growth, and (3) the therapeutic response to anti-PD-1 can be enhanced by concomitantly targeting β-catenin using therapeutic EVs. These preclinical studies establish the efficacy of the use of biological nanoparticles as an endogenous delivery vehicle for therapeutic RNA delivery and support the use of therapeutic strategies targeting tumor-intrinsic β-catenin as an adjunct to anti-PD-1-based therapy.  Combination therapy with anti-PD-1 and β-catenin siRNA delivered using biological nanoparticles provides an effective strategy for the treatment of HCC. This strategy could be further exploited into targeted approaches for immune potentiation by countering oncogene-mediated resistance to immunotherapies.

Article	Year
Therapeutic Efficacy of Vitamin D in Experimental c-MET-β-Catenin-Driven Hepatocellular Cancer. Gene expression\| PubMed ID: 30157994	2019
Extracellular Vesicle-Based Therapeutic Targeting of β-Catenin to Modulate Anticancer Immune Responses in Hepatocellular Cancer. Hepatology communications\| PubMed ID: 30976743	2019

Kaori Ishiguro

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