Erythropoietin production in hepatocellular carcinoma cells associated with polycythemia: Immunohistochemical evidence

Abstract

Patients with hepatocellular carcinoma sometimes have erythrocytosis and high plasma erythropoietin levels. However, previous studies have not revealed direct evidence that the carcinoma cells produce the erythropoietin. To address this question, we carried out light and electron microscopic immunohistochemical studies, using a human erythropoietin antibody to the liver in three male patients with hepatocellular carcinoma and erythrocytosis. alpha-Feto-protein localization was also examined in serial liver sections by light microscopic immunohistochemistry with an antibody to alpha-fetoprotein. All three patients demonstrated high hemoglobin levels (16.7, 17.6 and 18.1 gm/dl) and high plasma erythropoietin levels (227, 266 and 280 mU/ml). In one patient the plasma erythropoietin level in the hepatic vein was significantly higher than that in the hepatic artery. The levels of plasma erythropoietin, as well as such tumor markers for hepatocellular carcinoma as serum alpha-fetoprotein and plasma des-gamma-carboxyprothrombin, were significantly reduced after treatment with an anticancer drug, cisplatin. Light microscopic immunohistochemistry showed that erythropoietin was definitely present in the cytoplasm of the hepatocellular carcinoma cells, but not in normal hepatocytes around the carcinoma lesion or in other nonparenchymal cells such as vascular endothelial cells and Kupffer cells. In electron microscopic immunohistochemistry, reaction products for erythropoietin were revealed in the cisternae of the endoplasmic reticulum in the carcinoma cells, suggesting the production of erythropoietin by these cells. Light microscopic immunohistochemistry showed that alpha-fetoprotein was localized in the hepatocellular carcinoma cells that were erythropoietin positive in the serial sections. These findings indicated that hepatocellular carcinoma cells produced erythropoietin as well as alpha-fetoprotein in these cases, leading to the complication of erythrocytosis.

Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

“…Taken together, our data suggest that HIF2␣ binding to EpoHE, which contains an HRE, triggers Epo production in the liver and that EpoHE is the only cis-regulatory element for hypoxia-inducible Epo gene expression in hepatocytes (12). Patients with hepatocellular carcinoma occasionally present both polycythemia and Epo overproduction (58). In these cases, PHDs or other HIF suppression systems might be disrupted in the malignant cells.…”

HIF-2α phosphorylation by CK1δ promotes erythropoietin secretion in liver cancer cells under hypoxia

“…It has also been observed that some cases of hepatocellular carcinoma (HCC) are associated with abnormally high levels of erythrocytes. This HCC-associated erythrocytosis is thought to result from increased EPO production by the HCC cells, and many HCC patients have high plasma EPO levels (Sakisaka et al, 1993).…”

Hepatocellular carcinoma – diagnostic dilemmas

“…U ok. 5% chorych z HCC guz produkuje insulinopodobny czynnik wzrostu typu II (agonista insuliny), który może wywołać ciężką postać hipoglikemii [15,16]. Erytrocytoza jest efektem produkcji przez HCC erytropoetyny [17,18]. Mimo że zwiększone stężenia erytropoetyny w surowicy obserwowano u ok. 23% chorych z HCC, zwiększenie liczby erytrocytów i stężenia hemoglobiny stwierdzano tylko u niewielu z nich [18].…”