Delineation of a Cellular Hierarchy in Lung Cancer Reveals an Oncofetal Antigen Expressed on Tumor-Initiating Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-06, Vol.71 (12), p.4236-4246
• Main Authors: DAMELIN, Marc, GELES, Kenneth G, BEHRENS, Carmen, CHOE, Sung E, RIOS, Carol, GRUZAS, Janet, SRIDHARAN, Latha, DOUGHER, Maureen, KUNZ, Arthur, HAMANN, Philip R, EVANS, Deborah, ARMELLINO, Douglas, FOLLETTIE, Maximillian T, KHANDKE, Kiran, MARQUETTE, Kimberly, TCHISTIAKOVA, Lioudmila, BOGHAERT, Erwin R, ABRAHAM, Robert T, WISTUBA, Ignacio I, ZHOU, Bin-Bing S, PING YUAN, BAXTER, Michelle, GOLAS, Jonathon, DIJOSEPH, John F, KARNOUB, Maha, SHUGUANG HUANG, DIESL, Veronica
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - analysis; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; CD24 Antigen - analysis; Cell Line, Tumor; Epithelial-Mesenchymal Transition; General pharmacology; Humans; Hyaluronan Receptors - analysis; Immunotoxins - therapeutic use; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Medical sciences; Membrane Glycoproteins - analysis; Membrane Glycoproteins - physiology; Mice; Miscellaneous; Neoplastic Stem Cells - immunology; Pharmacology. Drug treatments; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-3919

Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.