title: The α2β1 binding domain of chondroadherin inhibits breast cancer-induced bone metastases and impairs primary tumour growth: a preclinical study.
abstract: cyclicCHAD is a peptide representing the α2β1 integrin binding sequence of the matrix protein chondroadherin (CHAD), which in our hands proved effective at counteracting bone loss in ovariectomised mice by inhibiting osteoclastogenesis. Given that bone metastases are characterised by exacerbated osteoclast activity as well, we tested this therapy in mice intracardiacally injected with the osteotropic human breast cancer cell line MDA-MB-231. Treatment with cyclicCHAD significantly decreased cachexia and incidence of bone metastases, and induced a trend of reduction of visceral metastasis volume, while in orthotopically injected mice cyclicCHAD reduced tumour volume. In vitro studies showed its ability to impair tumour cell motility and invasion, suggesting a direct effect not only on osteoclasts but also on the tumour cell phenotype. Interestingly, when administered together with a suboptimal, poorly effective, dose of doxorubicin (DXR), cyclicCHAD improved survival and reduced visceral metastases volume to a level similar to that of the optimal dose of DXR alone. Taken together, these preclinical data suggest that cyclicCHAD is a new inhibitor of bone metastases, with an appreciable direct effect also on tumour growth and a synergistic activity in combination with low dose chemotherapy, underscoring an important translational impact.
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy. Electronic address: nadia.rucci@univaq.it.
authors.forename: Nadia
authors.initials: N
authors.lastname: Rucci
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Capulli
authors.affiliation: Department of Clinical Chemistry, Ullevaal University Hospital, Institute of Medical Biochemistry, University of Oslo, Oslo, Norway.
authors.forename: Ole K
authors.initials: OK
authors.lastname: Olstad
authors.affiliation: Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Önnerfjord
authors.affiliation: Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden.
authors.forename: Viveka
authors.initials: V
authors.lastname: Tillgren
authors.affiliation: Department of Clinical Chemistry, Ullevaal University Hospital, Institute of Medical Biochemistry, University of Oslo, Oslo, Norway.
authors.forename: Kaare M
authors.initials: KM
authors.lastname: Gautvik
authors.affiliation: Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden.
authors.forename: Dick
authors.initials: D
authors.lastname: Heinegård
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D001862:Bone Resorption / Q000188:drug therapy / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002100:Cachexia / Q000188:drug therapy; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D016326:Extracellular Matrix Proteins / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D017434:Protein Structure, Tertiary
chemical_list: D016326:Extracellular Matrix Proteins; D038982:Integrin alpha2beta1; C088980:chondroadherin; D004317:Doxorubicin
keywords: Bone metastases; Breast cancer; Doxorubicin; cyclicCHAD