title: Targeted Proapoptotic Peptides Depleting Adipose Stromal Cells Inhibit Tumor Growth.
abstract: Progression of many cancers is associated with tumor infiltration by mesenchymal stromal cells (MSC). Adipose stromal cells (ASC) are MSC that serve as adipocyte progenitors and endothelium-supporting cells in white adipose tissue (WAT). Clinical and animal model studies indicate that ASC mobilized from WAT are recruited by tumors. Direct evidence for ASC function in tumor microenvironment has been lacking due to unavailability of approaches to specifically inactivate these cells. Here, we investigate the effects of a proteolysis-resistant targeted hunter-killer peptide D-WAT composed of a cyclic domain CSWKYWFGEC homing to ASC and of a proapoptotic domain KLAKLAK2. Using mouse bone marrow transplantation models, we show that D-WAT treatment specifically depletes tumor stromal and perivascular cells without directly killing malignant cells or tumor-infiltrating leukocytes. In several mouse carcinoma models, targeted ASC cytoablation reduced tumor vascularity and cell proliferation resulting in hemorrhaging, necrosis, and suppressed tumor growth. We also validated a D-WAT derivative with a proapoptotic domain KFAKFAK2 that was found to have an improved cytoablative activity. Our results for the first time demonstrate that ASC, recruited as a component of tumor microenvironment, support cancer progression. We propose that drugs targeting ASC can be developed as a combination therapy complementing conventional cancer treatments.
authors: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Alexes C
authors: AC
authors: Daquinag
authors: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Chieh
authors: C
authors: Tseng
authors: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Yan
authors: Y
authors: Zhang
authors: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Felipe
authors: F
authors: Amaya-Manzanares
authors: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Fernando
authors: F
authors: Florez
authors: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Ali
authors: A
authors: Dadbin
authors: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Tao
authors: T
authors: Zhang
authors: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors: Mikhail G
authors: MG
authors: Kolonin
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D016026:Bone Marrow Transplantation; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D010455:Peptides