title: Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines, tumor xenografts and patients of breast, lung and ovarian cancer.
abstract: Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients. TF-targeted agents, i.e., a factor VII (fVII)-conjugated photosensitizer (fVII-PS for targeted photodynamic therapy) and fVII-IgG1Fc (Immunoconjugate or ICON for immunotherapy), can eradicate CSC via the induction of apoptosis and necrosis and via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, respectively. In conclusion, these results demonstrate that TF is a novel surface therapeutic oncotarget for CSC, in addition to cancer cell TF and tumor angiogenic vascular endothelial TF. Moreover, this research highlights that TF-targeting therapeutics can effectively eradicate CSCs, without drug resistance, isolated from breast, lung and ovarian cancer with potential to translate into other most commonly diagnosed solid cancer, in which TF is also highly expressed.
authors.affiliation: Department of Surgery, Division of Surgical Oncology, The Ohio State University Medical Center and The James Comprehensive Cancer Center, Columbus, OH, USA.|Yale University School of Medicine Department of Obstetrics, Gynecology and Reproductive Sciences, New Haven, CT, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Yale University School of Medicine Department of Obstetrics, Gynecology and Reproductive Sciences, New Haven, CT, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Yale University School of Medicine Department of Obstetrics, Gynecology and Reproductive Sciences, New Haven, CT, USA.
authors.forename: Jijun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Biomedical Sciences Graduate Program, The Ohio State University Medical Center and The James Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McMichael
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University Medical Center and The James Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Surgery, Division of Surgical Oncology, The Ohio State University Medical Center and The James Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010778:Photochemotherapy; D013925:Thromboplastin / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D008665:Metalloporphyrins; C069117:tin(IV) chlorin e6; D013925:Thromboplastin
keywords: cancer stem cells; solid cancer; targeted immunotherapy; targeted photodynamic therapy; tissue factor