Targeted Proapoptotic Peptides Depleting Adipose Stromal Cells Inhibit Tumor Growth

Molecular Therapy : the Journal of the American Society of Gene Therapy
Alexes C DaquinagMikhail G Kolonin

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, r...Continue Reading

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Citations

Oct 11, 2016·Molecular Therapy. Methods & Clinical Development·Giuseppe RonzittiFederico Mingozzi
Feb 1, 2017·Current Rheumatology Reports·Ilja L Kruglikov
Nov 22, 2018·Nature Reviews. Endocrinology·Daniela F Quail, Andrew J Dannenberg
Jul 11, 2020·The Biochemical Journal·Yasuhiro OnogiSiegfried Ussar
Apr 8, 2020·Cells·Kristin Eckel-MahanMikhail G Kolonin
Nov 27, 2019·International Journal of Molecular Sciences·Gaetano AurilioRodolfo Montironi

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