title: Molecular portraits of intratumoral heterogeneity in human ovarian cancer.
abstract: 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.
authors.affiliation: BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoon Pyo
authors.initials: YP
authors.lastname: Choi
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyo Sup
authors.initials: HS
authors.lastname: Shim
authors.affiliation: BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Gao
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Suki
authors.initials: S
authors.lastname: Kang
authors.affiliation: BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: cho1988@yuhs.ac.
authors.forename: Nam Hoon
authors.initials: NH
authors.lastname: Cho
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002869:Chromosome Aberrations; D002999:Clone Cells; D055028:Comparative Genomic Hybridization; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058985:Side-Population Cells / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D000255:Adenosine Triphosphate