Masanobu Shindo

Dominant-Negative Hypoxia-Inducible Factor-1α Reduces Tumorigenicity of Pancreatic Cancer Cells through the Suppression of Glucose Metabolism

In the tumor cells exposed to hypoxia, hypoxia-inducible factor-1 (HIF-1)-mediated adaptation responses such as angiogenesis and anaerobic metabolism are induced for their survival. We have recently reported that the constitutive expression of HIF-1 alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and glucose deprivation. We then established dominant-negative HIF-1 alpha (dnHIF-1 alpha) transfectants and examined their susceptibility to apoptosis and growth inhibition induced by hypoxia and glucose deprivation in vitro and their tumorigenicity in SCID mice. We further examined the expressions of aldolase A and Glut-1 in vitro and Glut-1 expression and glucose uptake in the tumor tissues and microvessel counts in the tumor tissues. As a result, dnHIF-1 alpha rendered the pancreatic cancer cells sensitive to apoptosis and growth inhibition induced by hypoxia and glucose deprivation. Also it abrogated the enhanced expression of Glut-1 and aldolase A mRNAs under hypoxia and reduced the expression of Glut-1 and the glucose uptake in the tumor tissues and consequently in vivo tumorigenicity. We found no significant difference in the microvessel counts among the tumor tissues. From these results, we suggest that the disruption of the HIF-1 pathway might be effective in the treatment of pancreatic cancers.

Selective secretion of chemoattractants for haemopoietic progenitor cells by bone marrow endothelial cells: a possible role in homing of haemopoietic progenitor cells to bone marrow.

To elucidate the mechanisms by which haemopoietic progenitor cells lodge in the bone marrow, we examined the secretion of chemoattractants for haemopoietic progenitor cells by bone marrow and lung endothelial cells. The bone marrow endothelial cells, but not lung endothelial cells, secreted chemoattractants for the haemopoietic progenitor cell line, FDCP‐2, and normal haemopoietic progenitor cells. Checkerboard analysis demonstrated that the conditioned medium of the bone marrow endothelial cells had chemotactic activity and random motility‐stimulating activity. The bone marrow endothelial cells expressed stromal‐cell‐derived factor‐1 (SDF‐1) mRNA and produced SDF‐1 protein, whereas the lung endothelial cells did not. Adhesion of FDCP‐2 cells to the bone marrow endothelial cells was partially inhibited by anti‐SDF‐1 antibody. These findings suggest that the chemoattractants for haemopoietic progenitor cells including SDF‐1 and random motility‐stimulating factor(s) selectively secreted by the bone marrow endothelial cells may contribute to the homing of haemopoietic progenitor cells to bone marrow.

Adrenomedullin antagonist suppresses in vivo growth of human pancreatic cancer cells in SCID mice by suppressing angiogenesis

Since it is reported that adrenomedullin (AM) upregulated by hypoxia inhibits hypoxic cell death, we examined the effects of AM antagonist (AM C-terminal fragment; AM(22–52)) on the growth of pancreatic cancer cells. We, for the first time, demonstrated that AM antagonist significantly reduced the in vivo growth of the pancreatic cancer cell line. Immunohistochemical analysis demonstrated that the mean diameter of blood vessels was significantly smaller in the tumor tissues treated with AM antagonist than in those treated with AM N-terminal fragment (AM(1–25)), and that the PCNA-labeling index was lower in the former than in the latter. Then we demonstrated that AM antagonist showed no effect on the in vitro growth of the pancreatic cancer cell line. These results showed that AM played an important role in the growth of pancreatic cancer cells in vivo, suggesting that AM antagonist might be a useful tool for treating pancreatic cancers.

A comparison of diagnostic tools for Sjögren syndrome, with emphasis on sialography, histopathology, and ultrasonography

OBJECTIVE The present study examined the reliability and correlation of sialography, salivary gland biopsy, and ultrasonography for Sjögren syndrome (SS) and evaluated the usefulness of ultrasonography as a diagnostic tool for SS compared with sialography and histopathology. STUDY DESIGN Seventy-three patients who underwent sialography, ultrasonography, and salivary gland biopsy were included in this study. The study evaluated the diagnostic reliability and correlation of each kind of examination with SS. RESULTS There was a statistically significant difference in the sensitivities of sialography and histopathology, in the specificities of sialography and ultrasonography, and in the accuracies of sialography and both ultrasonography and histopathology. The correlation coefficient (r) between sialography and ultrasonography was significantly higher than the others and indicated a good correlation. CONCLUSIONS Ultrasonography can be used as a diagnostic tool for SS, with its advantage of noninvasiveness and ease of use.