Tumors are known to be composed of heterogeneous cell populations derived from a single clone. Cells with tumorigenic potential are limited to a small population, called cancer-initiating cells (CICs). CICs efficiently efflux anti-tumor chemicals, and show high aldehyde dehydrogenase (ALDH) activity. To date, no studies on CICs have been done in endometrial adenocarcinoma of uterus. Here, we examined the ALDH activity in uterine endometrioid adenocarcinoma. In uterine endometrioid adenocarcinoma cell line, a small number of cells showed high ALDH activity, which was more resistant against anti-cancer drugs, invasive, and tumorigenic as compared to cells with low ALDH activity. Immunohistochemistry revealed that ALDH staining was limited to a small portion of tumor cells in most cases. Clinically, high-level of ALDH1 expression in tumor cells was correlated with T category, lymphatic invasion, recurrence, and prognosis of patients. Patients with high ALDH1 expression showed poorer prognosis than those with low expression. ALDH1 appeared to be a candidate for CIC marker for uterine endometrioid adenocarcinoma.
Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). However, the relevance of CSC model in humans remains uncertain. Acute myeloid leukemia (AML) follows a CSC model and organized from leukemia stem cells (LSCs) defined by using a sensitive xenograft assay. Analysis of gene expression from functionally validated LSC populations and normal hematopoietic stem cells (HSCs) yielded an LSC- and HSC- specific gene signatures, respectively. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying ‘stemness’ properties. Both stem cell programs are highly significant independent predictors of patient survival and are found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.
Tumors consist of heterogeneous cell populations derived from a single clone. Recently, it has been demonstrated that tumor cells with tumorigenic potential are limited to a small population, called cancer-initiating cells (CICs), in several tumors, such as leukemia, breast, brain, and colon cancers. CICs efficiently efflux anti-tumor chemicals, degradate reactive oxygen species (ROS) and have high aldehyde dehydrogenase (ALDH) activity. To date, such kind of population has not been identified in malignant lymphomas. Here, we examined the presence of such population in Hodgkin lymphoma cell lines from viewpoint of ROS level. Hodgkin lymphoma cell lines L1236 and L428 consist of heterogeneous sized cells; single-nucleated small-sized cells (S cells) and multinucleated large-sized cells (M cells) like Reed-Sternberg cells. In semi-solid cultures and NOD/SCID mice injection, S cells formed colonies and tumors more efficiently than M cells. A part of S cells contained lower levels of ROS than M cells. ROS-low cells also formed colonies and tumors more efficiently than ROS-high cells. The expression of FoxO3a, a transcription factor regulating ROSdegrading enzymes, was higher in ROS-low populations than in ROS-high. These findings suggest that ROS-low S cells might play an important role in tumorigenesis of Hodgkin lymphoma.
Paroxysmal nocturnal hemoglobinuria (PNH) is a hematologic disorder characterized by the clonal expansion of hematopoietic stem cells that are incapable of glycosylphosphatidylinositol (GPI) -anchor biosynthesis, due to an acquired somatic mutation in the phosphatidylinositol glycan class A-gene. The detection of GPI-anchored protein deficient cells by flow cytometry (FCM) is essential for the diagnosis of PNH. Moreover, it helps to predict response to immunosuppressive therapy in patients with bone marrow failure (BMF) such as aplastic anemia (AA). However, the clinical significance of such PNH-type cells has not been assessed in a multi-centered, large-scale study. A nationwide multi-center prospective observational study (OPTIMA study) was conducted to determine the prevalence of increased PNH-type cells and its correlation with prognosis in patients who develop BMF. PNH-type cells were detected with a high-resolution FCM method with liquid fluorescent aerolysin and antibodies against CD55 and CD59 that was established by Kanazawa University. The sensitivity and specificity of the assay (granulocytes, ≧0.003%; erythrocytes, ≧0.005%) were validated by six laboratories using a positive sample containing 0.01% PNH-type cells as well as a negative sample from a healthy individual. Of 664 cases examined so far, 240 (36.1%) had PNH-type cells and 76 (11.4%) had ≧1% PNH-type cells. In patients who had ≧1% PNH-type cells, 50% showed lactate dehydrogenase levels ≧1.5×upper limits of normal cases. Thus, we confirmed the feasibility for different laboratories to detect PNHtype cells less than 0.1% precisely with a standardized high-resolution FCM method.
Th17 cells constitute a subset of T-helper cells involved in host defense and several immune disorders. An intriguing feature of Th17 cells is their selective and constitutive presence in the intestinal lamina propria. Germ-free mice exhibit much lower concentrations of luminal ATP, accompanied by fewer lamina propria Th17 cells, compared to specificpathogen-free mice. Systemic administration of ATP into these germ-free mice results in a marked increase in the number of lamina propria Th17 cells. A CD70+CD11cint cell, which is a unique subset in the lamina propria, leads to the differentiation of Th17 cells. A CD70+CD11cint subset of the lamina propria cells expresses Il-6, Il23a and Itgav, in response to ATP stimulation, and preferentially induces Th17 differentiation of co-cultured naive T cells. Now we try to identify intestinal antigen presenting cells in human lamina propria which induce Th17 differentiation.