In View: Research Highlights
Dual Shp2 and Pten Deficiencies Promote Nonalcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells
Luo X, Liao R, Hanley KL, et al. Cell Rep. 2016;17(11):2979–93.
Nonalcoholic fatty liver disease has become a serious public health problem worldwide; nonalcoholic steatohepatitis (NASH), an advanced state of nonalcoholic fatty liver disease, is characterized by hepatic steatosis, injury, inflammation with or without fibrosis. NASH patients carry an increased risk of hepatocarcinogenesis.
The authors investigated the effect of the oncoproteins Shp2 and Ptpn11 in cooperation with Pten, a phospatase and tensin homolog deleted from chromosome 10, in a mouse hepatocarcinogenesis model. It is well known that a deficiency or mutation in Pten results in human cancer.1
Deleting both Shp2 and Pten had a marked effect on liver tumorigenesis as well as on early onset NASH in the mouse model. Deleting both Pten and Shp2 in a double knockout mouseline resulted in a 100% incidence of liver tumours at 7 months, as well as a more aggressive tumor type and earlier onset lung metastasis compared to mice in which either Shp2 or Pten were deleted to result in a single knockout mouseline. Hepatosteatosis developed more rapidly in double knockout mice compared to single knockout mice. Moreover, the additional deletion of Shp2 resulted in loss of Pten which aggravated hepatosteatosis.
The authors then investigated 45 samples of human hepatocellular carcinoma specimens and found that a low expression of Shp2 or Pten was significantly associated with a shorter survival time.
By deleting Shp2 and Pten, the authors have established a NASH-HCC model which may become useful for extensive research of molecular signals that link NASH to HCC.
- Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012;13:283–296.
Biopatterned CTLA4/FC Matrices Facilitate Local Immunomodulation, Engraftment, and Glucose Homeostasis After Pancreatic Islet Transplantation
Zhang W, Gorantla VS, Campbell PG, et al. Diabetes. 2016;65(12):3660–6.
The authors tested a human acellular dermal matrix (ADM) scaffold using inkjet-based biopatterning technology to create an immunoregulatory microenvironment for pancreatic islet allografts in mice. ADM squares were printed with cytotoxic T lymphocyte antigen 4 fusion protein (CTLA4-Ig) that had been proven to have a downregulating effect on alloimmune and autoimmune responses.1 Pancreatic B cells were transplanted between these ADM strips under the renal capsule of streptozotocin-induced diabetic mice. The biopatterned CTLA4/Fc was in direct contact with the islet allografts. In a control group, the CTLA/FC was injected intraperitoneally or implanted under the contralateral kidney capsule.
In mice treated with local biopatterned CTLA4/Fc ADM, islet allograft survival was significantly prolonged compared with the control groups. The mice who received biopatterned CTLA4/Fc locally also had increased levels of interleukin 4 and decreased levels of interferon gamma and interleukin 6 resulting in a markedly improved graft acceptance in the presence of increased Foxp3 cells. There was also an increase of CD4 + Fox p3 T regulatory cells in peripheral blood and lymph nodes compared with the control group mice.
Histological examination confirmed decreased lymphocyte infiltration and long-term preserved islet allograft with increased Foxp3 staining in the biopatterned CTLA4/Fc-treated recipients, suggesting a protective effect of biopatterned CTLA4/Fc in situ against alloreactive effector T cell responses.
This study confirms the unique advantage of using solid-phase delivery of therapeutic proteins in extremely low dosages compared with the less effective intraperitoneal injection or contralaterally implanted CTLA4/Fc.
- Orban T, Bundy B, Becker DJ, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;378:412–419.