p32 is an evolutionarily conserved and ubiquitously expressed multifunctional protein. Although p32 exists at diverse intra and extracellular sites, it is predominantly localized to the mitochondrial matrix near the nucleoid associated with mitochondrial transcription factor A. p32-deficient mice exhibited mid-gestation lethality associated with a severe developmental defect of the embryo. Primary embryonic fibroblasts isolated from p32-knockout embryos showed severe dysfunction of the mitochondrial respiratory chain because of severely impaired mitochondrial protein synthesis. The RNA-binding ability of p32 is well correlated with mitochondrial translation. We also found that p32 is highly expressed in prostate tumor samples and its expression is significantly associated with the Gleason score, pathologic stage, and relapse. These data suggest that p32 is critical for prostate cancer cell proliferation and may be a novel marker of clinical progression in prostate cancer.

Neuroendocrine tumors(NETs)describe a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. Pancreatic neuroendocrine tumors(pNET)are a subset of NETs which are increasing in incidence and prevalence. These tumors are generally slow growing and behave in an indolent fashion. However, when these tumors spread they can be life threatening and difficult to treat with current modalities. Recently, the basic treatment for pNET was changed with the approval of two targeted agents, sunitinib and everolimus. Clinical trials conducting various combinations of somatostatin analogues, mTOR inhibitors, tyrosine kinase inhibitors, and cytotoxic agents are ongoing under-evaluation, and a multitargeted approach to therapy will translate into improved patient outcomes.

The pathogenesis of pediatric malignant tumors is associated with congenital abnormalities. Oncogenes and antioncogenes are identified in some of these cases. Neuroblastoma arises from the adrenal medulla and sympathetic ganglia. Most neuroblastomas produce catecholamine. Urinary vanillylmandelic acid(VMA)and homovanillic acid(HVA), metabolites of catecholamine, are sensitive tumor markers. Risk stratification according to tumor stage and a combination of prognostic factors helps determine the appropriate therapeutic strategy in clinical settings. Nephroblastoma(Wilms tumor)is the most common pediatric renal tumor and is often accompanied by congenital anomalies. Surgical resection of the tumor and the involved kidney is the initial treatment recommendation in the US and Japan. Consecutive chemotherapy and radiotherapy are administered after surgical staging and a definite histopathological diagnosis. Prognosis is relatively good for most nephroblastoma cases with a favorable histology. In addition to nephroblastoma, clear cell sarcoma of the kidney, characterized by a tendency to metastasize to the bone, is a renal tumor with poor prognosis. Rhabdoid tumor of the kidney is another tumor type; however, its pathogenesis is still unknown and it is associated with extremely poor prognosis because of the lack of effective therapeutic measures. Hepatoblastoma is the most common malignant liver tumor. The serum alpha-fetoprotein level is the most effective tumor marker. Complete surgical resection of the involved liver lobe is the definitive approach for cure. Preoperative chemotherapy increases the possibility of complete surgical resection. High-risk patients have a poor prognosis.

In July 2008, cetuximab treatment for unresectable advanced or recurrent colorectal cancer was approved in Japan, but there have been few reports on this therapy in Japan.

Lymphangioleiomyomatosis (LAM) is a slowly progressive neoplastic disease characterized with proliferation of abnormal smooth muscle-like cells (LAM cells) in the lungs and along axial lymphatics. Proliferation of LAM cells are considered to be driven by dysregulated mTORC1 signaling, that is caused by mutations in either the TSC1 or TSC2 gene in LAM cells. The MILES trial has successfully demonstrated that sirolimus, a mTORC1 inhibitor, can stabilize pulmonary function in LAM, but its effect disappears once sirolimus is discontinued. Limited ability of sirolimus may be due to concomitant activation of autophagy in LAM cells when mTORC1 activity is suppressed by sirolimus. Recently animal models for LAM have been independently established by several groups, which may provide a platform for developing drugs interfering various steps in disease progression.

Patients with SCLC (Small cell lung cancer) have been treated differently from those with NSCLC (New-small cell lung cancer) as a different disease. Recently, even patients with NSCLC are treated differently according to histological subtypes. This change is associated with the development of new drugs, particularly molecular-targeted drugs. Because Bevacizumab can cause serious adverse effects, patients with squamous cell carcinoma histology and a history of hemoptysis are contraindicated for this drug. Pemetrexed has been approved with an anti-mesothelioma drug and was confirmed to be effective for NSCLC. However, its efficacy was not equally proved among the histological subtypes; only adenocarcinoma patients showed shorter progression-free and prolonged survival periods. Regarding tyrosine kinase inhibitors, the targeted gene alterations occur specifically in adenocarcinoma. Based on these findings, the current therapeutic strategy for NSCLC is based on the histological subtype and mutational status of EGFR and ALK. In this article, transition of the therapeutic strategy for NSCLC, characteristics of targeted gene alterations and efficacies of the targeted therapy are reviewed.

We examined the role of molecules related to drug resistance, such as P-glycoprotein (P-gp) and telomerase (TERT), signaling molecules of STATs and FLT3 in leukemia pathogenesis in de novo acute myeloid leukemia (AML), and myelodysplastic syndrome in the phase of overt leukemia (MDS-OL). Subjects were 18 patients with de novo AML, in which expression of P-gp, TERT, STAT3, STAT5, and FLT3 was observed in 11, 14, 16, 18, and 14 of patients, respectively. Phosphorylation of STAT3, STAT5, and FLT3 in patients with de novo AML was observed in 10 out of 14, 14 out of 18, and 10 out of 14 patients, respectively. Phosphorylation of STAT5 was associated with expression of both P-gp and TERT, suggesting that STAT5 is one of the transcription factors for these genes. On the other hand, P-gp, TERT, STAT3, STAT5, and FLT3 were expressed in 3, 1, 1, 6, and 1 of the 7 patients with MDS-OL, respectively. While phosphorylation of STAT5 was observed in 4 out of 7 patients, phosphorylation of STAT3 or FLT3 was not detected in all cases examined. Telomere length varied from 2.7 kb to 6.0 kb in de novo AML, accompanied by an increased level of telomerase activity in 4 of 5 patients with de novo AML. In contrast, all MDS-OL cases showed a similar telomere length of 4-5 kb. These results indicate that consideration should be given to the differences of molecular mechanisms in the pathogenesis of de novo AML and MDS-OL for the treatment strategy of AML.

Advances in the molecular biology and therapy of hematological malignancies have been made over the last decade. Understanding the basic cellular and molecular pathogenesis of malignant cells is vital to the development of novel treatment approaches. Recently, the expression profiles of all known genes in the human genome have been determined, and subtypes of hematological malignancies have been identified and classified using microarray technology. The expression profiles clusters of genes are useful not only to classify patients, but also to identify specific molecular targets for therapeutic intervention. Based on these investigations, more specifically targeted agents have been developed for the treatment of hematological malignancies, such as tyrosine kinase inhibitors, monoclonal antibodies, epigenetic agents, anti-angiogenic agents, and farnesyl transferase inhibitors. These new agents for targeted therapy have been introduced into the clinical setting and the outcome of the disease has markedly improved.

Cytoglobin was originally discovered from cultured rat hepatic stellate cells by using proteomics analysis in our laboratory in 2001. Cytoglobin is a hexacoordinate globin that is different from the traditional pentacoordinate globins like myoglobin and hemoglobin. Human cytoglobin has about 25% amino acid identity with vertebrate myoglobin and hemoglobin, and 16% with human neuroglobin that is another type of globin present specifically in the nervous system. Besides its function as O2, carbon monoxide, and nitric oxide-binding molecule, cytoglobin exhibits antioxidative properties under hypoxic condition. Recent analyses using clinical samples have indicated that cytoglobin may be a tumor suppressor gene because cytoglobin mRNA expression in cancer tissues is down-regulated through hypermethylation of cytoglobin gene promoter. In this review, the history of cytoglobin research, its current status and future prospects will be discussed.