Malignant phyllodes tumors display mesenchymal stem cell features and aldehyde dehydrogenase/disialoganglioside identify their tumor stem cells
Journal
Breast Cancer Research
Journal Volume
16
Journal Issue
2
Pages
R29
Date Issued
2014
Author(s)
Lin J.-J.
Yu J.
Liao G.-S.
Hung J.-T.
Lin R.-J.
Chou F.-P.
Yeh K.-T.
Yu A.L.
Abstract
Introduction: Although breast phyllodes tumors are rare, there is no effective therapy other than surgery. Little is known about their tumor biology. A malignant phyllodes tumor contains heterologous stromal elements, and can transform into rhabdomyosarcoma, liposarcoma and osteosarcoma. These versatile properties prompted us to explore their possible relationship to mesenchymal stem cells (MSCs) and to search for the presence of cancer stem cells (CSCs) in phyllodes tumors.Methods: Paraffin sections of malignant phyllodes tumors were examined for various markers by immunohistochemical staining. Xenografts of human primary phyllodes tumors were established by injecting freshly isolated tumor cells into the mammary fat pad of non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. To search for CSCs, xenografted tumor cells were sorted into various subpopulations by flow cytometry and examined for their in vitro mammosphere forming capacity, in vivo tumorigenicity in NOD-SCID mice and their ability to undergo differentiation.Results: Immunohistochemical analysis revealed the expression of the following 10 markers: CD44, CD29, CD106, CD166, CD105, CD90, disialoganglioside (GD2), CD117, Aldehyde dehydrogenase 1 (ALDH), and Oct-4, and 7 clinically relevant markers (CD10, CD34, p53, p63, Ki-67, Bcl-2, vimentin, and Globo H) in all 51 malignant phyllodes tumors examined, albeit to different extents. Four xenografts were successfully established from human primary phyllodes tumors. In vitro, ALDH+ cells sorted from xenografts displayed approximately 10-fold greater mammosphere-forming capacity than ALDH- cells. GD2+ cells showed a 3.9-fold greater capacity than GD2- cells. ALDH+/GD2+cells displayed 12.8-fold greater mammosphere forming ability than ALDH-/GD2- cells. In vivo, the tumor-initiating frequency of ALDH+/GD2+ cells were up to 33-fold higher than that of ALDH+ cells, with as few as 50 ALDH+/GD2+ cells being sufficient for engraftment. Moreover, we provided the first evidence for the induction of ALDH+/GD2+ cells to differentiate into neural cells of various lineages, along with the observation of neural differentiation in clinical specimens and xenografts of malignant phyllodes tumors. ALDH+ or ALDH+/GD2+ cells could also be induced to differentiate into adipocytes, osteocytes or chondrocytes.Conclusions: Our findings revealed that malignant phyllodes tumors possessed many characteristics of MSC, and their CSCs were enriched in ALDH+ and ALDH+/GD2+ subpopulations. ? 2014 Lin et al.; licensee BioMed Central Ltd.
SDGs
Other Subjects
activated leukocyte cell adhesion molecule; aldehyde dehydrogenase; beta1 integrin; CD34 antigen; common acute lymphoblastic leukemia antigen; disialoganglioside; endoglin; ganglioside; globo h protein; Hermes antigen; Ki 67 antigen; oct7 protein; octamer transcription factor 4; paraffin; protein bcl 2; protein p53; protein p63; stem cell factor receptor; Thy 1 antigen; tumor marker; unclassified drug; vascular cell adhesion molecule 1; vimentin; aldehyde dehydrogenase; ganglioside; sialogangliosides; tumor marker; adipocyte; animal cell; animal model; article; cancer stem cell; carcinogenicity; cartilage cell; cell differentiation; cell lineage; cell selection; cell subpopulation; controlled study; cystosarcoma phylloides; engraftment; female; flow cytometry; human; human cell; immunohistochemistry; in vitro study; malignant neoplastic disease; mesenchymal stem cell; mouse; nerve cell differentiation; nonhuman; osteocyte; protein expression; tumor xenograft; animal; breast tumor; cancer stem cell; classification; confocal microscopy; cystosarcoma phylloides; metabolism; nerve cell; nonobese diabetic mouse; pathology; SCID mouse; tumor cell culture; xenograft; Adipocytes; Aldehyde Dehydrogenase; Animals; Breast Neoplasms; Cell Differentiation; Chondrocytes; Female; Flow Cytometry; Gangliosides; Humans; Immunohistochemistry; Mice, Inbred NOD; Mice, SCID; Microscopy, Confocal; Neoplastic Stem Cells; Neurons; Osteocytes; Phyllodes Tumor; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Markers, Biological
Publisher
BioMed Central Ltd.
Type
journal article