Boston - American Association for Thoracic Surgery

AMERICAN ASSOCIATION FOR THORACIC SURGERYT7. High Resolution Analysis of Lung Cancer Stem and ProgenitorCells in Primary Non-Small Cell AdenocarcinomaVera S. Donnenberg, 1 Rodney J. Landreneau, 2* James D. Luketich, 2*Albert D. Donnenberg 11. Surgery, University of Pittsburgh, Pittsburgh, PA, USA; 2. Hillman Cancer Center,Pittsburgh, PA, USAInvited Discussant: Thomas A. D’AmicoOBJECTIVE: Recurrence following initial response to therapy can occur after longintervals suggesting that therapy resistant cells can lay dormant and subsequentlyreactivate. Distinguishing cancer and normal stem cells is important from thestandpoint of therapy. Here we characterize normal and cancer stem/progenitor-likecells in non-small cell adenocarcinomas of the lung (NSCLCA).METHODS: We used multiparameter flow cytometry to examine tissue stem cellmarkers CD44, CD90, CD117, and CD133, and epithelial markers cytokeratin andEpCAM (TACSTD1), on freshly isolated from untreated NSCLCA (15 malignanteffusions, 82 tumor and adjacent far tissue, 65 bone marrows, 4 normal BM,) 0.5 to10 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 cellswere resting (low light scatter, 2N DNA), cytokeratin negative and either CD90dimor CD117+. The major progenitor population was morphologically complex andCD90 positive. Largely non-overlapping populations of cytokeratin dim CD117+and CD133+ progenitor cells were detected. This complex pattern is retained intactin well differentiated adenocarcinoma, but is deranged in poorly differentiated andmetastatic lung cancer; the most common pattern being overexpression of cytokeratinon stem/progenitor populations. Stem and progenitor cells are 10 to 100 timesmore prevalent in lung tumors than in normal lung. Cytokeratin+ stem/progenitorcells were not detected in bone marrow samples isolated from rib fragmentsobtained during lung resection.CONCLUSION: According to the cancer stem cell paradigm, we hypothesize thatamong the minority of tumor cells capable of propagating a tumor, only thosewhich retain the tissue stem cell properties responsible for self-renewal and selfprotectionwill survive therapy. Of these, cells with a normal stem-like phenotyperemain in a predominantly resting mode, and can be reactivated to cause late recurrentdisease after apparently successful therapy. Therefore it is of great importanceto determine phenotypic differences that distinguish tumor stem cells from normaltissue stem cells, both for differential targeting and for evaluation of clinicalresponses.WEDNESDAYMorning* AATS Member207