title: Controlled extracellular matrix degradation in breast cancer tumors improves therapy by trastuzumab.
abstract: Extracellular matrix (ECM) in solid tumors affects the effectiveness of therapeutics through blocking of intratumoral diffusion and/or physical masking of target receptors on malignant cells. In immunohistochemical studies of tumor sections from breast cancer patients and xenografts, we observed colocalization of ECM proteins and Her2/neu, a tumor-associated antigen that is the target for the widely used monoclonal antibody trastuzumab (Herceptin). We tested whether intratumoral expression of the peptide hormone relaxin (Rlx) would result in ECM degradation and the improvement of trastuzumab therapy. As viral gene delivery into epithelial tumors with extensive tumor ECM is inefficient, we used a hematopoietic stem cell (HSC)-based approach to deliver the Rlx gene to the tumor. In mouse models with syngeneic breast cancer tumors, HSC-mediated intratumoral Rlx expression resulted in a decrease of ECM proteins and enabled control of tumor growth. Moreover, in a model with Her2/neu-positive BT474-M1 tumors and more treatment-refractory tumors derived from HCC1954 cells, we observed a significant delay of tumor growth when trastuzumab therapy was combined with Rlx expression. Our results have implications for antibody therapy of cancer as well as for other anticancer treatment approaches that are based on T-cells or encapsulated chemotherapy drugs.
authors.affiliation: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Beyer
authors.forename: Zongyi
authors.initials: Z
authors.lastname: Li
authors.forename: Jonas
authors.initials: J
authors.lastname: Persson
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Ruan
authors.initials: R
authors.lastname: van Rensburg
authors.forename: Roma
authors.initials: R
authors.lastname: Yumul
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Zhang
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: André
authors.initials: A
authors.lastname: Lieber
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012065:Relaxin / Q000235:genetics / Q000378:metabolism; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D012065:Relaxin; D000068878:Trastuzumab