title: The CD44(high) tumorigenic subsets in lung cancer biospecimens are enriched for low miR-34a expression.
abstract: Cellular heterogeneity is an integral part of cancer development and progression. Progression can be associated with emergence of cells that exhibit high phenotypic plasticity (including "de-differentiation" to primitive developmental states), and aggressive behavioral properties (including high tumorigenic potentials). We observed that many biomarkers that are used to identify Cancer Stem Cells (CSC) can label cell subsets in an advanced clinical stage of lung cancer (malignant pleural effusions, or MPE). Thus, CSC-biomarkers may be useful for live sorting functionally distinct cell subsets from individual tumors, which may enable investigators to hone in on the molecular basis for functional heterogeneity. We demonstrate that the CD44(hi) (CD44-high) cancer cell subsets display higher clonal, colony forming potential than CD44(lo) cells (n=3) and are also tumorigenic (n=2/2) when transplanted in mouse xenograft model. The CD44(hi) subsets express different levels of embryonal (de-differentiation) markers or chromatin regulators. In archived lung cancer tissues, ALDH markers co-localize more with CD44 in squamous cell carcinoma (n=5/7) than Adeno Carcinoma (n=1/12). MPE cancer cells and a lung cancer cell line (NCI-H-2122) exhibit chromosomal abnormalities and 1p36 deletion (n=3/3). Since miR-34a maps to the 1p36 deletion site, low miR-34a expression levels were detected in these cells. The colony forming efficiency of CD44(hi) cells, characteristic property of CSC, can be inhibited by mir-34a replacement in these samples. In addition the highly tumorigenic CD44(hi) cells are enriched for cells in the G2 phase of cell cycle.
authors.affiliation: Wadsworth Stem Cell Institute, Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS), Los Angeles, California, United States of America ; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Saroj K
authors.initials: SK
authors.lastname: Basak
authors.forename: Mysore S
authors.initials: MS
authors.lastname: Veena
authors.forename: Scott
authors.initials: S
authors.lastname: Oh
authors.forename: Chi
authors.initials: C
authors.lastname: Lai
authors.forename: Sitaram
authors.initials: S
authors.lastname: Vangala
authors.forename: David
authors.initials: D
authors.lastname: Elashoff
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: Sanjai
authors.initials: S
authors.lastname: Sharma
authors.forename: Nagesh P
authors.initials: NP
authors.lastname: Rao
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rao
authors.forename: Ryan
authors.initials: R
authors.lastname: Phan
authors.forename: Eri S
authors.initials: ES
authors.lastname: Srivatsan
authors.forename: Raj K
authors.initials: RK
authors.lastname: Batra
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology*; D002878:Chromosomes, Human, Pair 1; D017931:DNA Primers; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology*; D035683:MicroRNAs / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; D018960:Hyaluronan Receptors; C522425:MIRN34 microRNA, human; D035683:MicroRNAs
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