INVESTIGATIVE TREATMENT DIVISION

21.INVESTIGATIVE TREATMENT DIVISION

    The main goal of the research in this division is the development of innovative new strategies for cancer prevention, diagnosis and treatment based on a better understanding of the biology of cancer tissues and interactions between a cancer and the host. Improvement of preexisting modalities of cancer diagnosis and treatment is also within the scope of our research activity.
Biochemical and Molecular Bases of Induced Tolerance to Nutrient Starvation

    Induction of tolerance to glucose starvation was discovered. The tolerance was found to be induced by treatment with either hypoxia or nitric oxide or both in both normal and cancer cell lines. The tolerance to glucose starvation under hypoxia was totally unexpected because it has long been believed that glucose is the major source of energy production under hypoxia. Nitric oxide and hypoxia were found to stimulate tumor angiogenesis factor, VEGF synthesis through the activation of HIF-1,^(221,²²²⁾ but HIF-1 was found not to be involved in the tolerance induction by pharmacological experiments. The induced tolerance to glucose starvation was found to be dependent on some amino acids, indicating that hypoxia and nitric oxide switch substrates for energy production from glucose to amino acids. The above findings point to a new biological role for nitric oxide in response to ischemia.^(223,²²⁴⁾
Analysis of constitutive tolerance of cancer cells to nutrient-starvation

    The tolerance to glucose starvation was assumed to be a physiological response of cells to insufficient blood supply. A hypothesis was postulated that some cancer cells might have acquired constitutive tolerance to nutrient starvation because they evolved through a continuous shortage of blood supply due to their excessive demand for oxygen and nutrients. This possibility was examined directly by culturing cancer cell lines in various deficient media and was found to be true. Some undifferentiated cancer cell lines including pancreatic cancer cells were extremely resistant to nutrient deficiency.⁽²²⁵⁾ The molecular mechanisms for constitutive tolerance were analyzed and the involvement of PKB/Akt and AMP kinase were found. This tolerance is similar to the stringent control of E. coli and dauer formation of nematodes. This tolerance might be a new target for cancer therapy.
High alcohol dehydrogenase activity of normal oral microflora, Neisseria

    The association between high alcohol consumption and head and neck cancer has been firmly proven by epidemiological studies. Recently it was demonstrated that not only alcohol itself but also the activity of alcohol- metabolizing enzymes, especially aldehyde dehydrogenase, strongly influence the risk for esophageal and head and neck cancers.⁽²²⁶⁾ This raised the possibility that acetaldehyde concentration might be a determinant of risk. The possibility of local production of aldehyde was examined, and normal oral microflora, Neisseria, was found to have extremely high alcohol dehydrogenase activity.⁽²²⁷⁾ The proportion of oral microflora was examined in volunteers having various lifestyles in terms of alcohol consumption and smoking, and those people consuming alcohol frequently were found to have a high Neisseria content. Case-control and ecological studies are ongoing.
Studies on tumor progression

    Tumors progression is the process of tumor cells acquiring a more malignant phenotype through multiple genetic alterations. In addition to these genetic alterations, changes in the biological characteristics of preceding tissue is also important. Intestinal metaplasia is one representative preceding tissue of human cancer. Expression of CYP 1A1 and CYP 1A2, which are responsible for the mutagenic activation of various environmental mutagens including heterocyclic amines, was discovered in intestinal metaplasia and this biochemical change was assumed to have a big impact on human carcinogenesis. Instability of methylation of the genome was also found in intestinal metaplasia tissue, even in the X chromosome.⁽²²⁸⁾ K-ras mutation is frequently found in cancer cells and even in cells of precancerous tissue. The biological significance of different types of K-ras mutation has been analyzed using primary epithelial cells and fibroblasts.




21.INVESTIGATIVE TREATMENT DIVISION



	The main goal of the research in this division is the development of innovative new strategies for cancer prevention, diagnosis and treatment based on a better understanding of the biology of cancer tissues and interactions between a cancer and the host. Improvement of preexisting modalities of cancer diagnosis and treatment is also within the scope of our research activity. Biochemical and Molecular Bases of Induced Tolerance to Nutrient Starvation Induction of tolerance to glucose starvation was discovered. The tolerance was found to be induced by treatment with either hypoxia or nitric oxide or both in both normal and cancer cell lines. The tolerance to glucose starvation under hypoxia was totally unexpected because it has long been believed that glucose is the major source of energy production under hypoxia. Nitric oxide and hypoxia were found to stimulate tumor angiogenesis factor, VEGF synthesis through the activation of HIF-1,^(221,²²²⁾ but HIF-1 was found not to be involved in the tolerance induction by pharmacological experiments. The induced tolerance to glucose starvation was found to be dependent on some amino acids, indicating that hypoxia and nitric oxide switch substrates for energy production from glucose to amino acids. The above findings point to a new biological role for nitric oxide in response to ischemia.^(223,²²⁴⁾ Analysis of constitutive tolerance of cancer cells to nutrient-starvation The tolerance to glucose starvation was assumed to be a physiological response of cells to insufficient blood supply. A hypothesis was postulated that some cancer cells might have acquired constitutive tolerance to nutrient starvation because they evolved through a continuous shortage of blood supply due to their excessive demand for oxygen and nutrients. This possibility was examined directly by culturing cancer cell lines in various deficient media and was found to be true. Some undifferentiated cancer cell lines including pancreatic cancer cells were extremely resistant to nutrient deficiency.⁽²²⁵⁾ The molecular mechanisms for constitutive tolerance were analyzed and the involvement of PKB/Akt and AMP kinase were found. This tolerance is similar to the stringent control of E. coli and dauer formation of nematodes. This tolerance might be a new target for cancer therapy. High alcohol dehydrogenase activity of normal oral microflora, Neisseria The association between high alcohol consumption and head and neck cancer has been firmly proven by epidemiological studies. Recently it was demonstrated that not only alcohol itself but also the activity of alcohol- metabolizing enzymes, especially aldehyde dehydrogenase, strongly influence the risk for esophageal and head and neck cancers.⁽²²⁶⁾ This raised the possibility that acetaldehyde concentration might be a determinant of risk. The possibility of local production of aldehyde was examined, and normal oral microflora, Neisseria, was found to have extremely high alcohol dehydrogenase activity.⁽²²⁷⁾ The proportion of oral microflora was examined in volunteers having various lifestyles in terms of alcohol consumption and smoking, and those people consuming alcohol frequently were found to have a high Neisseria content. Case-control and ecological studies are ongoing. Studies on tumor progression Tumors progression is the process of tumor cells acquiring a more malignant phenotype through multiple genetic alterations. In addition to these genetic alterations, changes in the biological characteristics of preceding tissue is also important. Intestinal metaplasia is one representative preceding tissue of human cancer. Expression of CYP 1A1 and CYP 1A2, which are responsible for the mutagenic activation of various environmental mutagens including heterocyclic amines, was discovered in intestinal metaplasia and this biochemical change was assumed to have a big impact on human carcinogenesis. Instability of methylation of the genome was also found in intestinal metaplasia tissue, even in the X chromosome.⁽²²⁸⁾ K-ras mutation is frequently found in cancer cells and even in cells of precancerous tissue. The biological significance of different types of K-ras mutation has been analyzed using primary epithelial cells and fibroblasts.