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High Resolution Analysis of Lung Cancer Stem and Progenitor Cells in Primary Non Small Cell Adenocarcinoma
Vera S. Donnenberg1, Rodney J. Landreneau2, James D. Luketich2, Albert D. Donnenberg1; 1Surgery, University of Pittsburgh, Pittsburgh, PA; 2Hillman Cancer Center, Pittsburgh, PA
READER COMMENTS
Objective: Recurrence following initial response to therapy can occur after long intervals suggesting that therapy resistant cells can lay dormant and subsequently reactivate. Distinguishing cancer and normal stem cells is important from the standpoint of therapy. Here we characterize normal and cancer stem/progenitor-like cells in non-small cell adenocarcinomas of the lung (NSCLCA).
Methods: We used multiparameter flow cytometry to examine tissue stem cell markers CD44, CD90, CD117, and CD133, and epithelial markers cytokeratin and EpCAM (TACSTD1), on freshly isolated from untreated NSCLCA (15 malignant effusions, 82 tumor and adjacent far tissue, 65 bone marrows, 4 normal BM,) 0.5 to 10 million cells were stained (nucleated cells: DAPI; Hematopoietic: CD45-APC.Cy7, CD14+CD33+glycophorin-PE.Cy5; Adhesion molecule CD44-PE; Epithelial: HEA-APC, intracellular pancytokeratin (CK)-FITC; Stem/Progenitor: CD90-PE.TxRed, CD117-PE.Cy7, CD133-PE).
Results: We are able to assign these immunophenotypic profiles: Stem cells were resting (low light scatter, 2N DNA), cytokeratin negative and either CD90dim or CD117+. The major progenitor population was morphologically complex and CD90 positive. Largely non-overlapping populations of cytokeratin dim CD117+ and CD133+ progenitor cells were detected. This complex pattern is retained intact in well differentiated adenocarcinoma, but is deranged in poorly differentiated and metastatic lung cancer; the most common pattern being overexpression of cytokeratin on stem/progenitor populations. Stem and progenitor cells are 10 to 100 times more prevalent in lung tumors than in normal lung. Cytokeratin+ stem/progenitor cells were not detected in bone marrow samples isolated from rib fragments obtained during lung resection.
Conclusion: According to the cancer stem cell paradigm, we hypothesize that among the minority of tumor cells capable of propagating a tumor, only those which retain the tissue stem cell properties responsible for self-renewal and self-protection will survive therapy. Of these, cells with a normal stem-like phenotype remain in a predominantly resting mode, and can be reactivated to cause late recurrent disease after apparently successful therapy. Therefore it is of great importance to determine phenotypic differences that distinguish tumor stem cells from normal tissue stem cells, both for differential targeting and for evaluation of clinical responses.
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