Autonomous stimulation of cancer cell plasticity by the human NKG2D lymphocyte receptor coexpressed with its ligands on cancer cells

• Published in: PloS one Vol. 9; no. 10; p. e108942
• Main Authors: Cai, Xin, Dai, Zhenpeng, Reeves, Rebecca S, Caballero-Benitez, Andrea, Duran, Kate L, Delrow, Jeffrey J, Porter, Peggy L, Spies, Thomas, Groh, Veronika
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07-10-2014; Public Library of Science (PLoS)
• Subjects: Animals; Bioinformatics; Biology and Life Sciences; Breast; Breast cancer; Breast carcinoma; Cancer; Cancer cells; Cell adhesion & migration; Cell Line, Tumor; Diagnostic systems; Disease Models, Animal; Epithelial-Mesenchymal Transition - genetics; Flow cytometry; Functional plasticity; Gene Expression; Heterografts; Humans; Immunosurveillance; Invasiveness; Kinases; Ligands; Lymphocytes; Malignancy; Medical research; Medicine and Health Sciences; Mesenchyme; Metastases; Metastasis; Mice; Microscopy; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Neoplastic Stem Cells - metabolism; NK Cell Lectin-Like Receptor Subfamily K - genetics; NK Cell Lectin-Like Receptor Subfamily K - metabolism; Ovarian cancer; Pancreatic cancer; Phenotypic plasticity; Phosphatidylinositol 3-Kinases - metabolism; Plastic properties; Plasticity; Protein expression; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Signaling; Sox9 protein; Stem cells; Stimulation; Tactics; Transcription; Tumors; Xenografts; Xenotransplantation; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0108942

The stimulatory NKG2D receptor on lymphocytes promotes tumor immune surveillance by targeting ligands selectively induced on cancer cells. Progressing tumors counteract by employing tactics to disable lymphocyte NKG2D. This negative dynamic is escalated as some human cancer cells co-opt expression of NKG2D, thereby complementing the presence of its ligands for autonomous stimulation of oncogenic signaling. Clinical association data imply relationships between cancer cell NKG2D and metastatic disease. Here we show that NKG2D promotes cancer cell plasticity by induction of phenotypic, molecular, and functional signatures diagnostic of the epithelial-mesenchymal transition, and of stem-like traits via induction of Sox9, a key transcriptional regulator of breast stem cell maintenance. These findings obtained with model breast tumor lines and xenotransplants were recapitulated by ex vivo cancer cells from primary invasive breast carcinomas. Thus, NKG2D may have the capacity to drive high malignancy traits underlying metastatic disease.