Molecular portraits of intratumoral heterogeneity in human ovarian cancer

Cancer Lett. 2011 Aug 1;307(1):62-71. doi: 10.1016/j.canlet.2011.03.018. Epub 2011 Apr 9.


One of the most common characteristic profiles of cancer is intratumoral heterogeneity (ITH). We aimed to clarify the molecular profiles and biological significance of ITH with relation to cancer stem cell (CSC). We analyzed five primary cultured clones generated from different spatial zones, front and rear zone, of a fresh-frozen ovarian tumor tissue, performing ATP-CRA, conventional RT-PCR, side population (SP) analysis, flow cytometry immunophenotyping, and cell proliferation assays. We also carried out array CGH and Ingenuity Pathways Analysis (IPA) between SP and non-SP (NSP) cells. Clones from tumor front zone showed phenotypically and genetically distinct subpopulations with relatively higher SP proportions, CD24(+) and CD117(+) expression, and chemotherapeutic resistance. We demonstrate that phenotype of SP cells in heterogeneous clones of human ovarian cancer was closely related to CD24(+), CD117(+), and combined CD117(+)/CD24(+) fractions. Chromosomal alterations in SP cells relative to NSP cells were closely related to the novel core networks of cancer stem cell-like cells (CSCs), such as cycle checkpoint regulation, notch, PTEN, wnt/β-catenin, PI3K/AKT, integrin, and cytokine and chemokine signaling. ITH could arise from clonal diversity closely related to CSC-like molecules, as evidenced by accumulated genetic, transcriptional and gene products alterations in SP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Proliferation / drug effects
  • Chromosome Aberrations
  • Clone Cells
  • Comparative Genomic Hybridization
  • Female
  • Gene Expression Profiling*
  • Humans
  • Immunophenotyping
  • Middle Aged
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology*
  • Oligonucleotide Array Sequence Analysis
  • Ovarian Neoplasms / classification*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Phenotype
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Side-Population Cells / pathology*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • RNA, Messenger
  • Adenosine Triphosphate