Pathologic characterization of precursors and cholangiocarcinoma referring to peribiliary capillary plexus: a new pathologic approach to bile duct neoplasm.

The peribiliary capillary plexus (PCP) regularly and densely lines the basal side of the lining epithelia of normal bile ducts. To determine the pathology of the PCP in high-grade biliary intraepithelial neoplasms (BilINs) and intraductal papillary neoplasms of the bile duct (IPNBs), a precursor of cholangiocarcinoma (CCA), and CCA. Seventy-six cases of surgically resected high-grade BilIN and 83 cases of IPNB were histopathologically examined using endothelial immunostaining of PCP; all cases of high-grade BilIN and 40 cases of IPNB were associated with invasive CCA. Invasive and preinvasive neoplasms were pathologically examined referring to a two-layer pattern composed of biliary lining epithelia and underlying PCP unique to the bile duct. All high-grade BilIIN cases had an underlying single layer of capillaries, similar to PCP (PCP-like capillaries). In 43% of the 83 cases of IPNB, these capillaries were regularly distributed in almost all stalks and intervening stroma of intraluminal neoplastic components, while in the remaining 57% of IPNB, capillaries were sparsely or irregularly distributed in intraluminal components showing cribriform or solid growth patterns composed of striking atypical neoplastic epithelia. Invasive carcinomas associated with high-grade BilIN and IPNB were not lined with capillaries. The loss of PCP-like capillaries underlying high-grade BilIN and in stalks or stroma of IPNB may be involved in the malignant progression of these precursors. Immunostaining of PCP could be a new pathological tool for the evaluation of malignant progression and vascular supply in CCA and its precursors.

Depletion of glutamine enhances sodium butyrate-induced erythroid differentiation of K562 cells.

Human erytholeukemia K562 cells are induced to differentiate along the erythroid lineage by a variety of chemical compounds, including hemin, sodium butyrate and 1-ß-d-arabinofuranosylcytosine. We have investigated the induction of erythroid differentiation of K562 cells by glutamine depletion. When K562 cells were cultured in glutamine-minus medium, the induction of hemoglobin synthesis, accompanied by those of heme-biosynthetic enzymes and erythroid transcriptional factors, was observed. This induction was dependent on the temporally marked decrease of intracellular level of glutathione, followed by the marked activation of p38MAPK and SAPK/JNK, but not ERK. Under glutamine-deficient conditions, the treatment of K562 cells with sodium butyrate resulted in the marked enhancement of the induction of heme biosynthesis. Glutamine depletion also accelerated the expressions of erythroid-related factors including α-globin and heme-biosynthetic enzymes, GATA-1 and NF-E2, in sodium butyrate-induced K562 cells. The transcriptional activity of ß-globin gene promoter-reporter was markedly enhanced by these treatments, indicating that glutamine deficiency in combination with sodium butyrate treatment gives high efficiency of chemical-induced differentiation in the hematopoiesis process.