Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

Autor: Keltouma Driouch, Sandra Geraci, Michele Iuliani, Philippe Clézardin, Martine Croset, Bruno Vincenzi, Klaus Pantel, Francesco Pantano, Giulia Ribelli, Natalia Bednarz-Knoll, Edith Bonnelye, Daniele Santini, Giuseppe Tonini, Harriet Wikman, Florian Bonin, Sofia Sousa, Saw See Hong, Sonia Simonetti
Přispěvatelé: Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biologie tumorale [Institut Curie, Paris], Institut Curie [Paris], Service de génétique, Institut Curie Paris, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), BONNELYE, Edith, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Rok vydání: 2021
Předmět:
0301 basic medicine
Integrins
Cancer Research
Volociximab
[SDV.CAN]Life Sciences [q-bio]/Cancer
Bone Neoplasms
Breast Neoplasms
Kaplan-Meier Estimate
Osteolysis
Biology
medicine.disease_cause
Article
Bone resorption
Metastasis
03 medical and health sciences
0302 clinical medicine
Breast cancer
[SDV.CAN] Life Sciences [q-bio]/Cancer
Cell Movement
Cell Line
Tumor
Cell Adhesion
Genetics
medicine
Humans
Neoplasm Metastasis
Molecular Biology
Aged
Cell Proliferation
Bone metastases
Antibodies
Monoclonal
Cancer
Bone metastasis
Middle Aged
medicine.disease
Progression-Free Survival
3. Good health
Gene Expression Regulation
Neoplastic
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Cancer research
Female
Bone marrow
Neoplasm Recurrence
Local
Carcinogenesis
medicine.drug
Zdroj: Oncogene
Oncogene, In press, ⟨10.1038/s41388-020-01603-6⟩
Oncogene, Nature Publishing Group, In press, ⟨10.1038/s41388-020-01603-6⟩
ISSN: 1476-5594
0950-9232
Popis: Bone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.
Databáze: OpenAIRE
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