Conditional expression of endorepellin in the tumor vasculature attenuates breast cancer growth, angiogenesis and hyaluronan deposition

• Published in: Matrix biology Vol. 118; pp. 92 - 109
• Main Authors: Chen, Carolyn G., Kapoor, Aastha, Xie, Christopher, Moss, Alison, Vadigepalli, Rajanikanth, Ricard-Blum, Sylvie, Iozzo, Renato V.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2023
• Subjects: Animals; ATG5; Autophagy; Cancer growth; Heparan Sulfate Proteoglycans - metabolism; Hyaluronan synthase; Hyaluronan Synthases - genetics; Hyaluronic Acid; Mice; Neoplasms; Neovascularization, Pathologic - genetics; Peptide Fragments - metabolism; Proteoglycans; Tumor Microenvironment; VEGFR2; Proteoglycans; HABP; GO; ERKi; GAG; Autophagy; Hyaluronan synthase; ECM; ATG; PE; Cancer growth; TGFβ; HA; HUVEC; HAS; LG; BiNGO; ATG5
• ISSN: 0945-053X; 1569-1802; 1569-1802
• DOI: 10.1016/j.matbio.2023.03.005

•We developed a novel animal model of syngeneic mammary carcinoma allografts in which we conditionally expressed endorepellin, an anti-angiogenic fragment of the proteoglycan perlecan, in the vasculature of the growing breast tumors.•We found that de novo endorepellin expression in the vascular stroma inhibited tumor growth, angiogenesis and suppressed extracellular hyaluronan deposition within the tumor proper.•We propose a mechanism whereby an endogenous anti-angiogenic product exerts a context-dependent onco-suppressive effect in mammary carcinomas. The tumor stroma of most solid malignancies is characterized by a pathological accumulation of pro-angiogenic and pro-tumorigenic hyaluronan driving tumorigenesis and metastatic potential. Of all three hyaluronan synthase isoforms, HAS2 is the primary enzyme that promotes the build-up of tumorigenic HA in breast cancer. Previously, we discovered that endorepellin, the angiostatic C-terminal fragment of perlecan, evokes a catabolic mechanism targeting endothelial HAS2 and hyaluronan via autophagic induction. To explore the translational implications of endorepellin in breast cancer, we created a double transgenic, inducible Tie2CreERT2;endorepellin(ER)Ki mouse line that expresses recombinant endorepellin specifically from the endothelium. We investigated the therapeutic effects of recombinant endorepellin overexpression in an orthotopic, syngeneic breast cancer allograft mouse model. First, adenoviral delivery of Cre evoking intratumor expression of endorepellin in ERKi mice suppressed breast cancer growth, peritumor hyaluronan and angiogenesis. Moreover, tamoxifen-induced expression of recombinant endorepellin specifically from the endothelium in Tie2CreERT2;ERKi mice markedly suppressed breast cancer allograft growth, hyaluronan deposition in the tumor proper and perivascular tissues, and tumor angiogenesis. These results provide insight into the tumor suppressing activity of endorepellin at the molecular level and implicate endorepellin as a promising cancer protein therapy that targets hyaluronan in the tumor microenvironment.