Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions.
Aged
Antibodies, Monoclonal
/ administration & dosage
Bone Neoplasms
/ drug therapy
Breast Neoplasms
/ drug therapy
Cell Adhesion
/ drug effects
Cell Line, Tumor
Cell Movement
/ genetics
Cell Proliferation
/ genetics
Female
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Integrins
/ genetics
Kaplan-Meier Estimate
Middle Aged
Neoplasm Metastasis
Neoplasm Recurrence, Local
/ drug therapy
Osteolysis
/ genetics
Progression-Free Survival
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
10
05
2020
accepted:
03
12
2020
revised:
26
11
2020
pubmed:
10
1
2021
medline:
30
7
2021
entrez:
9
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33420367
doi: 10.1038/s41388-020-01603-6
pii: 10.1038/s41388-020-01603-6
pmc: PMC7892344
doi:
Substances chimiques
Antibodies, Monoclonal
0
ITGA5 protein, human
0
Integrins
0
volociximab
496K5Z02NW
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1284-1299Références
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