an-oncogenic-hepatocyte-induced-orthotopic-mouse-model-hepatocellular

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis

The absence of a clinically relevant animal model addressing the typical immune characteristics of hepatocellular cancer (HCC) has significantly impeded ...

University of Missouri-Columbia

We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible anti-tumor chemoimmunotherapeutic strategy.

Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model.

Ceramide, a sphingolipid metabolite, affects T-cell signaling, induces apoptosis of cancer cells, and slows tumor growth in mice. However, it has not been used as a chemotherapeutic agent because of its cell impermeability and precipitation in aqueous solution. We developed a nanoliposome-loaded C6-ceremide (LipC6) to overcome this limitation and investigated its effects in mice with liver tumors.

Nanoliposome C6-Ceramide Increases the Anti-tumor Immune Response and Slows Growth of Liver Tumors in Mice.

Sorafenib and sunitinib are multiple tyrosine kinase inhibitors. Both of them have been approved by the US FDA in the treatment of patients with malignancies. In order to develop an effective and clinically useful chemoimmunotherapy modality against hepatocellular cancer (HCC), we investigate their tumoricidal and immune modulatory effect in the setting of HCC.  experiments suggested that sunitinib and sorafenib both induced HCC cell apoptosis at an equivalent level, but stronger suppressive function to cell proliferation was detected in sorafenib. Correspondingly, treatment of tumor-bearing mice with sorafenib led to the suppression of tumor growth to a larger extent than sunitinib. Flow cytometry showed that treatment with sunitinib, not sorafenib, significantly reduced the frequency of regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) in tumor-bearing mice; and allowed splenic lymphocytes to produce equivalent levels of IFN-γ and TNF-α in response to vaccination as that in wild type mice. This activation was not detected in control and sorafenib-treated tumor mice. In addition, treatment of tumor-bearing mice with sunitinib followed by adoptive transfer of tumor antigen-specific CD8 T cells and immunization resulted in the additional suppression to tumor growth compared to sunitinib monotherapy. These results imply treatment with sunitinib, not sorafenib, is able to prevent tumor-induced immunotolerance and activate antitumorimmunity. Our data suggest that sunitinib may be a preferable chemotherapeutic agent to use in combination with immunotherapy for the treatment of HCC.

Sunitinib and Sorafenib Modulating Antitumor Immunity in Hepatocellular Cancer.

Liver-intestine cadherin (CDH17) has been known to function as a tumor stimulator and diagnostic marker for almost two decades. However, its function in highly malignant pancreatic cancer (PC) has yet to be elucidated. Using different strategies including siRNA, shRNA, and CRISPR technology, we successfully induced knockdown and knockout of CDH17 in Panc02-H7 cells and established the corresponding stable cell lines. With these cells, we demonstrated that loss of CDH17 function not only suppressed Panc02-H7 cell growth in vitro but also significantly slowed orthotopic tumor growth in vivo, resulting in the significant life extension. In vitro studies demonstrated that impairing CDH17 inhibited cell proliferation, colony formation, and motility by mechanistically modulating pro- and anti-apoptosis events in PC cells, as CDH17 suppression obviously increased expression of Bad, cytochrome C, cleaved caspase 3, and cleaved PARP, and reduced expression of Bcl-2, Survivin, and pAkt. In vivo studies showed CDH17 knockout resulted in apoptotic PC tumor death through activating caspase-3 activity. Taken together, CDH17 functions as an oncogenic molecule critical to PC growth by regulating tumor apoptosis signaling pathways and CDH17 could be targeted to develop an anti-PC therapeutic approach.

Article	Year
Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model. Journal of hepatology\| PubMed ID: 27520877	2017
Nanoliposome C6-Ceramide Increases the Anti-tumor Immune Response and Slows Growth of Liver Tumors in Mice. Gastroenterology\| PubMed ID: 29408569	2018
Sunitinib and Sorafenib Modulating Antitumor Immunity in Hepatocellular Cancer. Journal of immunology research and therapy\| PubMed ID: 30123861	2018
Disruption of oncogenic liver-intestine cadherin (CDH17) drives apoptotic pancreatic cancer death. Cancer letters\| PubMed ID: 31004701	2019

Xiaoqiang Qi

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