GROWTH FACTOR DIVISION

7.GROWTH FACTOR DIVISION

　Basic and clinical research directed at the development of novel molecular therapeutics for cancer, the pathophysiology of ectopic hormone/ cytokine syndromes, new modalities for cancer diagnosis and genetic testing for familial cancer syndromes are currently being undertaken in the Growth Factor Division.
Molecular Therapeutics in Cancer

　The search for new molecular targets and anti- cancer agents is continuing.⁽¹³³⁾ To identify cancer- related genes, advanced RNA differential display ⁽¹³⁴⁾ was used to screen for differentially expressed genes in various cancer cells and two novel genes, DAM1 and LDOC1 were identified. The DAM1 gene was found to be up- regulated as a result of amplification in MCF- 7 and BT- 20 human breast cancer cell lines. This new gene was mapped to chromosome 1p13.3- 21, which is frequently altered in human breast cancer, and this is the first evidence of amplification within this 1p13.3- 21 region.⁽¹³⁵⁾ The LDOC1 gene, which encodes a leucine zipper protein, and was localized to chromosome Xq27, was shown to be down- regulated in a series of human pancreatic and gastric cancer cell lines but was expressed in corresponding normal tissues.⁽¹³⁶⁾ Identification of the genes involved in neuronal differentiation was pursued by exploiting a model system of neuroblastoma cell differentiation, and revealed the presence of cellular machinery that counteracts the decline of cAMP- induced gene expression regulated by staurosporine.⁽¹³⁷⁾ To identify new molecular targets, two isoforms of the orphan nuclear receptor NGFI- B were identified.⁽¹³⁸⁾ They are expressed under separate promoters, and play different roles in biological processes.
Pathogenesis of Cancer Cachexia

　Cancer cachexia is a morbidity that develops in cancer patients and experimental animals bearing tumors. Based on the concept of "toxohormone", a tumor- derived factor that induces cachexia in tumor- bearing animals, studies were undertaken to identify toxohormones responsible for this syndrome that developed in nude mice bearing human cancer cell lines. In four out of eight animal models, toxohormones were cytokines such as leukemia inhibitory factor, interleukin (IL)- 6 and IL- 11, indicating that cytokines play an important role in the development of cancer cachexia syndromes. In the remaining four models, however, toxohormones have not yet been identified, suggesting that the syndrome is caused by multiple factors. Alterations of central neural regulation of appetite and body weight may also play a role in the pathogenesis of cancer cachexia. Analysis of the central regulatory mechanism in cancer cachexia animal models is ongoing.
New Modalities for Cancer Diagnosis

　Previous studies demonstrated that pro- gastrin- releasing peptide(31- 98), or ProGRP, is a specific tumor marker in small- cell lung cancer (SCLC)patients. In the Caucasian population, comparability of ProGRP to neuron specific enolase (NSE), CYFRA 21- 1 and CEA was examined by analyzing sera of 272 patients with histologically proven carcinomas of the lung (87 small cell lung carcinoma, 185 non- small cell lung carcinoma). ProGRP showed a very high specificity and good sensitivity for small cell lung carcinomas and therefore enables diagnosis of small cell lung carcinoma in patients with lung tumors of unknown origin as well as good control of efficiency of therapy.⁽¹³⁹⁾
Familial Cancer Syndromes: Basic and Clinical Approaches

　Multiple endocrine neoplasia type 1 (MEN1)and type 2 (MEN2)are dominantly inherited familial cancer syndromes caused by heterozygous germline mutations in the tumor suppressor gene MEN1 and a proto- oncogene RET, respectively. Menin, the gene product of MEN1, is a nuclear protein ⁽¹⁴⁰⁾ of unknown function and has a highly conserved structure between human, the rat and the mouse,⁽¹⁴¹⁾ whereas RET encodes membrane receptor tyrosine kinase RET. Although DNA testing for MEN1 and RET germline mutations is useful to identify individuals predisposed to these syndromes, the identification of the causative mutations is sometimes difficult, especially in atypical cases. An intronic nucleotide substitution in the MEN1 gene, which was previously considered to be a benign polymorphism, has been shown to be a causative splicing mutation of MEN1.⁽¹⁴²⁾ Also, a new mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism was found. A novel genotype of the combination of germline Y804M and Y806C mutations in the RET gene was found in an atypical MEN2B patient without the M918T mutation,⁽¹⁴³⁾ which is usually associated with MEN2B. These findings indicate that further mutation analysis is necessary to understand the full spectrum of disease- causing mutations of familial cancer syndromes.




7.GROWTH FACTOR DIVISION



	Basic and clinical research directed at the development of novel molecular therapeutics for cancer, the pathophysiology of ectopic hormone/ cytokine syndromes, new modalities for cancer diagnosis and genetic testing for familial cancer syndromes are currently being undertaken in the Growth Factor Division. Molecular Therapeutics in Cancer 　The search for new molecular targets and anti- cancer agents is continuing.⁽¹³³⁾ To identify cancer- related genes, advanced RNA differential display ⁽¹³⁴⁾ was used to screen for differentially expressed genes in various cancer cells and two novel genes, DAM1 and LDOC1 were identified. The DAM1 gene was found to be up- regulated as a result of amplification in MCF- 7 and BT- 20 human breast cancer cell lines. This new gene was mapped to chromosome 1p13.3- 21, which is frequently altered in human breast cancer, and this is the first evidence of amplification within this 1p13.3- 21 region.⁽¹³⁵⁾ The LDOC1 gene, which encodes a leucine zipper protein, and was localized to chromosome Xq27, was shown to be down- regulated in a series of human pancreatic and gastric cancer cell lines but was expressed in corresponding normal tissues.⁽¹³⁶⁾ Identification of the genes involved in neuronal differentiation was pursued by exploiting a model system of neuroblastoma cell differentiation, and revealed the presence of cellular machinery that counteracts the decline of cAMP- induced gene expression regulated by staurosporine.⁽¹³⁷⁾ To identify new molecular targets, two isoforms of the orphan nuclear receptor NGFI- B were identified.⁽¹³⁸⁾ They are expressed under separate promoters, and play different roles in biological processes. Pathogenesis of Cancer Cachexia 　Cancer cachexia is a morbidity that develops in cancer patients and experimental animals bearing tumors. Based on the concept of "toxohormone", a tumor- derived factor that induces cachexia in tumor- bearing animals, studies were undertaken to identify toxohormones responsible for this syndrome that developed in nude mice bearing human cancer cell lines. In four out of eight animal models, toxohormones were cytokines such as leukemia inhibitory factor, interleukin (IL)- 6 and IL- 11, indicating that cytokines play an important role in the development of cancer cachexia syndromes. In the remaining four models, however, toxohormones have not yet been identified, suggesting that the syndrome is caused by multiple factors. Alterations of central neural regulation of appetite and body weight may also play a role in the pathogenesis of cancer cachexia. Analysis of the central regulatory mechanism in cancer cachexia animal models is ongoing. New Modalities for Cancer Diagnosis 　Previous studies demonstrated that pro- gastrin- releasing peptide(31- 98), or ProGRP, is a specific tumor marker in small- cell lung cancer (SCLC)patients. In the Caucasian population, comparability of ProGRP to neuron specific enolase (NSE), CYFRA 21- 1 and CEA was examined by analyzing sera of 272 patients with histologically proven carcinomas of the lung (87 small cell lung carcinoma, 185 non- small cell lung carcinoma). ProGRP showed a very high specificity and good sensitivity for small cell lung carcinomas and therefore enables diagnosis of small cell lung carcinoma in patients with lung tumors of unknown origin as well as good control of efficiency of therapy.⁽¹³⁹⁾ Familial Cancer Syndromes: Basic and Clinical Approaches 　Multiple endocrine neoplasia type 1 (MEN1)and type 2 (MEN2)are dominantly inherited familial cancer syndromes caused by heterozygous germline mutations in the tumor suppressor gene MEN1 and a proto- oncogene RET, respectively. Menin, the gene product of MEN1, is a nuclear protein ⁽¹⁴⁰⁾ of unknown function and has a highly conserved structure between human, the rat and the mouse,⁽¹⁴¹⁾ whereas RET encodes membrane receptor tyrosine kinase RET. Although DNA testing for MEN1 and RET germline mutations is useful to identify individuals predisposed to these syndromes, the identification of the causative mutations is sometimes difficult, especially in atypical cases. An intronic nucleotide substitution in the MEN1 gene, which was previously considered to be a benign polymorphism, has been shown to be a causative splicing mutation of MEN1.⁽¹⁴²⁾ Also, a new mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism was found. A novel genotype of the combination of germline Y804M and Y806C mutations in the RET gene was found in an atypical MEN2B patient without the M918T mutation,⁽¹⁴³⁾ which is usually associated with MEN2B. These findings indicate that further mutation analysis is necessary to understand the full spectrum of disease- causing mutations of familial cancer syndromes.