|Budget Amount *help
¥7,700,000 (Direct Cost : ¥7,700,000)
Fiscal Year 1997 : ¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 1996 : ¥4,500,000 (Direct Cost : ¥4,500,000)
In this research over the past two years, following results were obtained.
(1) Insulin resistance observed in cancer patients was associated significantly increased tissue TNF alpha mRNA levels. Both were negatively correlated. Although insulin resistance in diabetic patients were documented to be induced by tissue TNF alpha, insulin resistance in the tumor-bearing state may be induced in the similar fashion by TNF alpha. This would be the first documentation of the mechanisms of insulin resistance in the human tumor-bearing. Methodological accuracy is under further examination by using competitive RT-PCR.
(2) Gastric cancer cell lines (MKN28,45, STKM-1, STSA) were documented to have Glut1 mRNA as well as Glut4 mRNA.Glucose transport assay documented basic transport observed in all cell lines and significant stimulation by insulin in the cells showing high concentration of Glut4 protein. Whether basic transport is induced by glucose transporters or not is under further examination.
munohistochemistry of the gastric cancer specimens obtained from 70 gastric cancer patients demonstrated significant correlation of Glutl expression and tumor invasiveness in the gastric wall and vessel invasions. Expression of Glut1 was correlated with other Glut expressions except Glut4. Expression of Glut protein and Ki67 or apoptosis was not correlated.
Glut1 mRNA was rarely observed in normal gastric mucosa, while all RNA samples obtained from 25 gastric cancer specimens demonstrated Glut1 mRNA.
In parallel examination of colon cancer specimens, we found that expression of Glut was not observed in either normal colon mucosa or hyperplastic polyp, however, adenoma or cancer tissue expressed Glut more frequently.
(4) Glut 4mRNA in the gastric cancer specimens were not demonstrated by single pair of primers as in the skeletal muscle. Considering presence of some significant abnormalities in sequence, several attempts were made so far. However, definite results are not obtained yet.
Thus in this research project, several significant findings were obtained. A part of mechanisms of insulin resistance in the tumor-bearing state in humans is dissected and a possible mediator was clarified. Gastric cancer as well as colon cancer obtains the ability to transport glucose into cancer cells by newly obtaining Glut1 mRNA,whose protein expression is positively correlated with tumor invasiveness, but not with apoptosis or Ki67. Glut4 mRNA in the tumor tissue may be not of normal sequence as seen in the skeletal muscle.
Further dissection toward the mechanisms of insulin resistance and to clarify the difference between tumor and tumor-bearing hosts especially in regards to glucose metabolism will be continued. Less