19. 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 cancer and host cells. The improvement of preexisting modalities of cancer diagnosis and treatment is also within the scope of our research activities.

Analysis of Precancerous Lesions

A better understanding of the histogenesis of cancer and biology of precancerous lesions is essential for the development of new strategies of prevention, diagnosis and treatment of cancer. Several lines of research on histogenesis and genetic changes of preneoplastic lesions and conditions have been conducted.^(230-236) Through these studies, it was found that hyperplastic polyps of the colorectum and endometriosis of the ovary, which had been considered nonneoplastic lesions, may be neoplastic lesions.^{(231, 232, 234)} When 19 hyperplastic polyps were analyzed for K-ras mutations, 9 polyps were found to contain K-ras activation at codons 12 or 13; although none of them showed nuclear accumulation of p53 protein. These findings strongly suggested that at least some proportion of these lesions are truly neoplastic. Ten ovarian endometrial cysts were analyzed for clonality by X-chromosomal inactivation using human androgen recptor or phosphoglycerate kinase genes, and all of the cysts were found to be monoclonal.⁽²³²⁾ Although monoclonality does not necessarily imply a neoplastic nature, this finding was completely unexpected and pointed to the possiblity that some fraction of epithelial ovarian cancer whose origin has long been controversial could originate from this nonmalignant lesion.

Analysis of Lung Cancer Patients with Extreme Clinicopathological Features

The enormous clinical impact of smoking hides most of the factors in the etiological analysis of lung cancer. A subset of lung cancer patients having extreme clinicopathological features was chosen to analyze the genetic factors of lung cancer. Genetic contributions might be bigger in patients with very young onset. For this reason, the contribution of replication errors was analyzed in lung cancer patients 40 years old or younger, and it was found that the rate of RER is higher than in older patients.^(237-239) Patients with familial clustering of cancer were also analyzed and lung cancers in these patients were found to be associated with RER at a higher frequency (in press). Lung adenocarcinoma is sometimes associated with atypical adenomatous hyperplasia, a putative preneoplastic lesion. Some patients with lung adenocarcinoma were found to have an extremely large number of AAH, and tuberous sclerosis gene-associated regions were found to be frequently deleted in the lung adenocarcinoma of these patients.

Implication of Nitric Oxide in Carcinogenesis and Clinical Course of Cancer

The molecular mechanisms of gene regulation of nitric oxide synthases and biochemical consequences of nitric oxide production were studied.^(240-243) The mechanisms of iNOS gene induction in the human neuroblastoma NB-39-nu cell line were analyzed. Results clearly showed that the iNOS gene is regulated by TNF-a through the TNF type II receptor even when it is induced by anticancer drugs.⁽²⁴⁴⁾ The dilatation of blood vessels is one major biological role of nitric oxide. The effect of nitric oxide on hypoxia response gene expression was analyzed in connection with the hypoxic reaction, which is critical for tumor progression. When several tumor cell lines were treated with nitric oxide-generating compounds, VEGF gene expression was remarkably stimulated.⁽²⁴⁵⁾ Together with VEGF expression, the expression of some hypoxia response genes was also stimulated. These findings suggest that nitric oxide produced by either tumor cells or surrounding tissue could be a determining factor of tumor vascular formation. In connection to cancer chemotherapy, nitric oxide was found to be a drug resistance factor. When several tumor cell lines were treated with nitric oxide, they were found to become more resistant to apoptosis induced by vincristine, vinblastine and paclitaxel (in press). The mechanisms of resistance to apoptosis were analyzed and found to be due, at least in part, to inhibition of caspase 3 activation.⁽²⁴⁶⁾ In addition to modulating apoptosis, nitric oxide also modulates cell cycle progression and cellular oxygen consumption.⁽²⁴⁷⁾ It is known that nitric oxide is produced when cells and tissue are exposed to hypoxia, DNA damaging agents and nutrient deficiency. These suggest the possibility that nitric oxide could be an important factor mediating the response of tissue to damaging effects.