Growth Factor Division

7. Growth Factor Division

　Basic and clinical research on growth factors, cytokines and hormones is currently underway in the Growth Factor Division. These include the development of molecular therapeutics for cancer, the pathophysiology of ectopic hormone/cytokine syndromes and genetic testing for familial cancer syndromes.
Molecular Therapeutics in Cancer

　The search for new molecular targets and anti-cancer agents is continuing. Neuron-derived orphan receptor (NOR-1) and its closely related orphan nuclear receptors, NURR1 and NGFI-B, are potential molecular targets for cancer therapy.^(118,119) There are several isoforms of human NOR-1 mRNA, which are generated by alternative splicing.⁽¹²⁰⁾ An isoform of NURR1 functions as a negative inhibitor of NGFI-B family signaling. NOR-1 gene expression was found to be enhanced by exposure of Chinese hamster cells to high density 50 Hz magnetic fields.⁽¹²¹⁾ Expression of a novel calcium-binding protein in amniotic fluid-1, CAAF-1, is associated with cell growth arrest in human esophageal epithelial cells.⁽¹²²⁾ A synthetic bleomycin-like ligand was found to induce apoptosis in human pancreatic carcinoma cells.⁽¹²³⁾
Ectopic Hormone/Cytokine Syndromes

　Hypercalcemia is the most frequent paraneoplastic syndrome to develop in cancer patients. The morbidity in children with rhabdomyosarcoma was evaluated.⁽¹²⁴⁾ Cytokines are frequently produced by cancer cells and they explain various types of paraneoplastic syndromes. Clinical studies demonstrated that serum interleukin-6 levels are elevated in patients with pancreatic cancer.⁽¹²⁵⁾ It is possible that this cytokine is associated with cachexia frequently observed in pancreatic cancer patients.
Familial Cancer Syndromes: Genetic Testing and Clinical Approaches

　The usefulness of genetic testing in patients with multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) has been increasingly recognized in the clinic. Although identification of a heterozygous germline mutation of the tumor suppressor gene MEN1 is essential for genetic diagnosis of MEN1, ordinary PCR-based sequencing analysis fails to identify mutations in some MEN1 families. A large germline deletion of the MEN1 gene, which escaped detection by the PCR-based analysis, was found in a Japanese family with MEN1.⁽¹²⁶⁾ Gene dosage measurement by double competitive PCR could successfully detect the gene deletion.⁽¹²⁶⁾ The correlation between specific germline mutations of the RET gene and clinical features was studied in Japanese patients with MEN2.⁽¹²⁷⁾ This study revealed that specific genotypes are correlated not only with MEN2 subtypes such as MEN2A, MEN2B and familial medullary tyroid carcinoma but also with clinical aggressiveness of medullary thyroid carcinoma developing in MEN2 patients.⁽¹²⁸⁾




	7. Growth Factor Division



		Basic and clinical research on growth factors, cytokines and hormones is currently underway in the Growth Factor Division. These include the development of molecular therapeutics for cancer, the pathophysiology of ectopic hormone/cytokine syndromes and genetic testing for familial cancer syndromes. Molecular Therapeutics in Cancer 　The search for new molecular targets and anti-cancer agents is continuing. Neuron-derived orphan receptor (NOR-1) and its closely related orphan nuclear receptors, NURR1 and NGFI-B, are potential molecular targets for cancer therapy.^(118,119) There are several isoforms of human NOR-1 mRNA, which are generated by alternative splicing.⁽¹²⁰⁾ An isoform of NURR1 functions as a negative inhibitor of NGFI-B family signaling. NOR-1 gene expression was found to be enhanced by exposure of Chinese hamster cells to high density 50 Hz magnetic fields.⁽¹²¹⁾ Expression of a novel calcium-binding protein in amniotic fluid-1, CAAF-1, is associated with cell growth arrest in human esophageal epithelial cells.⁽¹²²⁾ A synthetic bleomycin-like ligand was found to induce apoptosis in human pancreatic carcinoma cells.⁽¹²³⁾ Ectopic Hormone/Cytokine Syndromes 　Hypercalcemia is the most frequent paraneoplastic syndrome to develop in cancer patients. The morbidity in children with rhabdomyosarcoma was evaluated.⁽¹²⁴⁾ Cytokines are frequently produced by cancer cells and they explain various types of paraneoplastic syndromes. Clinical studies demonstrated that serum interleukin-6 levels are elevated in patients with pancreatic cancer.⁽¹²⁵⁾ It is possible that this cytokine is associated with cachexia frequently observed in pancreatic cancer patients. Familial Cancer Syndromes: Genetic Testing and Clinical Approaches 　The usefulness of genetic testing in patients with multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) has been increasingly recognized in the clinic. Although identification of a heterozygous germline mutation of the tumor suppressor gene MEN1 is essential for genetic diagnosis of MEN1, ordinary PCR-based sequencing analysis fails to identify mutations in some MEN1 families. A large germline deletion of the MEN1 gene, which escaped detection by the PCR-based analysis, was found in a Japanese family with MEN1.⁽¹²⁶⁾ Gene dosage measurement by double competitive PCR could successfully detect the gene deletion.⁽¹²⁶⁾ The correlation between specific germline mutations of the RET gene and clinical features was studied in Japanese patients with MEN2.⁽¹²⁷⁾ This study revealed that specific genotypes are correlated not only with MEN2 subtypes such as MEN2A, MEN2B and familial medullary tyroid carcinoma but also with clinical aggressiveness of medullary thyroid carcinoma developing in MEN2 patients.⁽¹²⁸⁾