In vitro high concentrations of palmitate glucose
In vitro, high concentrations of palmitate, glucose, or both combined cause beta cell endoplasmic reticulum (ER) stress and apoptosis. Beta cell ER stress is a known feature of type 2 diabetes in humans and animal models (). Cells respond to ER stress by activating the unfolded protein response (UPR) signaling pathway. If the ER stress is mild, UPR signaling results in reduced overall cellular protein synthesis and increased transcription of ER chaperones to relieve the ER stress. However, in severe or prolonged ER stress conditions, pro-apoptotic factors, including CHOP, become activated resulting in cell death.
The evidence for a role for beta cell ER stress in type 2 diabetes comes from electron microscopy of ER appearance, as well as protein and mRNA expression studies in pancreas sections and islets of organ donors with type 2 diabetes (). Using electron microscopy, Marroqui and co-workers observed an increase in the volume density of the ER in both alpha and beta poly ic in pancreases from type 2 diabetic subjects, a hallmark of the UPR (). The authors also used electron microscopy to confirm previous reports using TUNEL staining to show an increase in the number of apoptotic beta cells, but not alpha cells, in pancreases of type 2 diabetic organ donors compared with those from non-diabetic donors (). This suggested that while both cell types respond to the metabolic stress conditions of type 2 diabetes, only the beta cells succumb to apoptotic ER stress.
Although considerable progress has been made in treatments of hepatocellular carcinoma (HCC), no effective systemic cytotoxic chemotherapy has been established (). Surgical resection or percutaneous intervention (radiofrequency ablation and ethanol injection) therapy is effective only at an early stage of HCC. Approximately 70% of these patients develop recurrent tumors within five years. Transarterial chemoembolization is reserved for patient intermediate stage HCC without portal invasion or extrahepatic metastasis. Molecular target therapy, especially that targeting the angiogenesis pathway, is now developing as a novel anti-HCC therapy. However to date, none of these novel has exhibited superior efficacy to sorafenib. Although, sorafenib is the only currently available therapeutic option for patients with advanced-stage HCC, they are required to have a performance status of 0–2 and an A Child–Pugh classification (). Overall, with the currently available diagnostic techniques and therapies, the prognosis of HCC depends on the stage of the disease at the time of diagnosis and remaining liver function. Thus, lesions detected at screening must be aggressively investigated because treatment of early HCC has a high cure rate. Patients at risk for HCC should undergo surveillance with ultrasonography, CT scan, or MRI at 6-monthly intervals. Serum-α-fetoprotein (AFP) and protein induced vitamin K absence (PIVKA)-II are the most common markers available to detect HCC. Des gamma carboxyprothrombin (DCP), AFP-L3 (a glycosylated form of AFP which is produced in higher concentration by HCC than normal liver), Golgi membrane protein 73 (GP73), and glypican 3 (GPC3) have been proposed as surveillance tests for HCC. In patients with small tumors or in well-to-moderately differentiated HCC, serum markers rarely elevated. Therefore, there is a need for the development of more sensitive and specific methods that supplement these tumor markers for the early detection of HCC. In the past few years, the potential utility of autoantibody to tumor-associated antigens (TAA) as cancer biomarker for early detection as indicators of disease prognosis has been explored. In this issue of , Hong Y and colleagues investigate the serum autoantibodies to TAA, and identify that CENPF and HSP 60 were new biomarkers that would add to current markers and increase the sensitivity and specificity of early stage of HCC (). Anti-TAA antibodies might reflect molecular events associated with tumorigenesis, we could use anti-TAA antibodies for screening populations at high risk of developing HCC, which may lead to early preventive and therapeutic interventions aimed at suppressing or slowing the appearance of a tumor.