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 CD44hi (CD44-high) cancer cell subsets display higher clonal, colony forming potential than CD44lo cells (n = 3) and are also tumorigenic (n = 2/2) when transplanted in mouse xenograft model. The CD44hi 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 CD44hi cells, characteristic property of CSC, can be inhibited by mir-34a replacement in these samples. In addition the highly tumorigenic CD44hi cells are enriched for cells in the G2 phase of cell cycle.
Highlights
Tumor heterogeneity can be characterized by differential expression of cell surface markers, genetic and epigenetic differences, and/or differences in key signaling molecules or effectors of cell function
Whereas many investigations have opted to associate cell surface markers in tumor cells found at the primary tumor site with Cancer Stem Cells (CSC)-behavioral properties, we observed that clinically advanced stages are enriched for cell subsets bearing CSC-biomarkers
All subjects in the study underwent written informed consent by a process approved by the institutional review board (IRB) at the Veterans Affairs-Greater Los Angeles Healthcare System (VAGLAHS) and the study was approved by IRB-VAGLAHS
Summary
Tumor heterogeneity can be characterized by differential expression of cell surface markers, genetic and epigenetic differences, and/or differences in key signaling molecules or effectors of cell function. Whereas many investigations have opted to associate cell surface markers in tumor cells found at the primary tumor site with CSC-behavioral properties, we observed that clinically advanced stages are enriched for cell subsets bearing CSC-biomarkers. We postulated that advanced stage disease does not prohibit (and may be advantageous) for associating specific biomarkers with functional phenotypes. For comprehending the biology underlying this high mortality, we have selected an advanced stage disease model (MPE). The MPE bulk tumor population is comprised of heterogeneous subpopulations [5]. In part, this heterogeneity can be characterized by biomarkers typically associated with features of CSC (CD44, ALDH, cMET, CD166, MDR-1, uPAR, PTEN, OCT-4, BMI-1, hTERT, SUZ12, EZH2)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call