Tumorigenic Potential of Mononucleated Small Cells of Hodgkin Lymphoma Cell Lines

Department of Pathology, Graduate School of Medicine, Osaka University, Yamada-oka 2-2, Suita 565-0871, Japan.
American Journal Of Pathology (Impact Factor: 4.59). 10/2010; 177(6):3081-8. DOI: 10.2353/ajpath.2010.100089
Source: PubMed


Tumor cells with tumorigenic potential are limited to a small cell population known as cancer stem cells (CSCs). CSCs yield both CSCs and non-CSCs, whereas non-CSCs do not yield CSCs. CSCs have not been identified in any malignant lymphomas. Hodgkin lymphoma (HL) is a mostly B-cell neoplasm that can be diagnosed by the presence of multinucleated (Reed-Sternberg; RS) cells admixed with Hodgkin cells with distinct nucleoli and various inflammatory cells. Here, the tumorigenic potential of cells with a single nucleus (S) and cells with multiple nuclei (M), which may be equivalent to Hodgkin and RS cells, respectively, was examined in HL cell lines L1236 and L428. Cultures of single S cells yielded both S and M cells, whereas M cell cultures yielded only M cells. When either cultured in methylcellulose or inoculated into NOD/SCID mice, the colony number and tumor size were both larger in S than in M cells. Concentrations of intracellular reactive oxygen species (ROS) were at low levels in a portion of S cells that abundantly expressed FoxO3a, a transcription factor that regulates ROS-degrading enzymes. In clinical samples of HL, FoxO3a was expressed in mononuclear Hodgkin cells but not in multinucleated RS cells. These findings suggest that smaller cells or Hodgkin cells that show low-ROS concentrations and high FoxO3a expression levels might be candidates for HL CSCs.

Download full-text


Available from: Suhana Mamat, Apr 29, 2014
  • Source
    • "Likewise a very recent report comparing the tumorigenic potential of multinucleated (Reed-Sternberg; RS) (M) and single nucleated cells (Hodgkin cells) (S) from two HL cell lines revealed a novel functional heterogeneity of the HL clone [28]. S cells, through their enhanced tumorigenicity in NOD/SCID mice and ability to generate both S and M cells along with low intracellular ROS concentration, high FOXO3a expression level, SP phenotype and dauxorubicine resistance, may be putative candidates for HL initiation [30,31]. Although links between mononucleated cells and clonotypic B cells from HL have to be defined, the lymphoma-initiating capacities remain to be formally proven in an appropriate murine model. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The concept of cancer stem cells has revolutionized our current vision of cancer development and was validated in solid tumors and cancers of the primitive hematopoietic compartment. Proof of the principle is still lacking, however, in malignancies of differentiated B-cells. We review here the current literature, which nevertheless suggests hierarchical organizations of the tumor clone for mostly incurable B-cell cancers such as multiple myeloma, lymphomas and B-chronic lymphocytic leukemia. We propose two models accounting for cancer stem cells in these contexts: a "top-to-bottom" clonal hierarchy from memory B-cells and a "bottom-to-top" model of clonal reprogramming. Selection pressure on the growing tumor can drive such reprogramming and increase its genetic diversity.
    Full-text · Article · Dec 2011 · Cancers

  • No preview · Chapter · Jan 2005
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a prevalent, progressive, and incurable fibroproliferative lung disease. The phenotype of IPF fibroblasts is characterized by their ability to elude the proliferation-suppressive properties of polymerized type I collagen. The mechanism underlying this pathological response is incompletely understood but involves aberrant activation of the phosphatidylinositol 3-kinase-Akt signaling pathway owing to inappropriately low phosphatase and tensin homolog phosphatase activity. Akt can phosphorylate and inactivate the forkhead box O3a (FoxO3a) transcriptional factor, which, when transcriptionally active, increases the expression of the CDK inhibitor p27 and promotes cell cycle arrest. Herein, we demonstrate that IPF fibroblasts display high levels of inactive FoxO3a compared with nonfibrotic control fibroblasts because of their high Akt activity. We found that p27 levels are decreased in IPF compared with control fibroblasts cultured on polymerized collagen. Furthermore, overexpression of FoxO3a in IPF fibroblasts increases p27 levels and suppresses the ability of IPF fibroblasts to proliferate on polymerized collagen. In contrast, the expression of dominant-negative FoxO3a augmented control fibroblast proliferation. IHC examination of fibroblastic foci in IPF lung tissue demonstrates the presence of inactive FoxO3a in cells within fibroblastic foci. These data indicate that the ability of IPF fibroblasts to circumvent the proliferation-suppressive properties of polymerized collagen involves inactivation of FoxO3a by high Akt activity, resulting in down-regulation of p27.
    Full-text · Article · Sep 2011 · American Journal Of Pathology
Show more