title: Gallium, a promising candidate to disrupt the vicious cycle driving osteolytic metastases.
abstract: Bone metastases of breast cancer typically lead to a severe osteolysis due to an excessive osteoclastic activity. On the other hand, the semi-metallic element gallium (Ga) displays an inhibitory action on osteoclasts, and therefore on bone resorption, as well as antitumour properties. Thus, we explored in vitro Ga effects on osteoclastogenesis in an aggressive bone metastatic environment based on the culture of pre-osteoclast RAW 264.7 cells with conditioned medium from metastatic breast tumour cells, i.e. the breast tumour cell line model MDA-MB-231 and its bone-seeking clone MDA-231BO. We first observed that Ga dose-dependently inhibited the tumour cells-induced osteoclastic differentiation of RAW 264.7 cells. To mimic a more aggressive environment where pro-tumourigenic factors are released from bone matrix due to osteoclastic resorption, metastatic breast tumour cells were stimulated with TGF-β, a mayor cytokine in bone metastasis vicious cycle. In these conditions, we observed that Ga still inhibited cancer cells-driven osteoclastogenesis. Lastly, we evidenced that Ga affected directly and strongly the proliferation/viability of both cancer cell lines, as well as the expression of major osteolytic factors in MDA-231BO cells. With the exception of two small scale clinical studies from 1980s, this is the first time that antitumour properties of Ga have been specifically studied in the context of bone metastases. Our data strongly suggest that, through its action against the vicious cycle involving bone cells and tumour cells, Ga represents a relevant and promising candidate for the local treatment of bone metastases in patients with breast cancer.
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, iBV, France; GRAFTYS SA, 13854 Aix en Provence, cedex 3, France.
authors.forename: Ivana
authors.initials: I
authors.lastname: Strazic-Geljic
authors.affiliation: INSERM, U791, LIOAD, Nantes F-44042, France.
authors.forename: Iva
authors.initials: I
authors.lastname: Guberovic
authors.affiliation: INSERM, U791, LIOAD, Nantes F-44042, France.
authors.forename: Blanka
authors.initials: B
authors.lastname: Didak
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, iBV, France.
authors.forename: Heidy
authors.initials: H
authors.lastname: Schmid-Antomarchi
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, iBV, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Schmid-Alliana
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, iBV, France; GRAFTYS SA, 13854 Aix en Provence, cedex 3, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Boukhechba
authors.affiliation: Université Nantes, CNRS, Nantes, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Bouler
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, iBV, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Scimeca
authors.affiliation: INSERM, U791, LIOAD, Nantes F-44042, France. Electronic address: elise.verron@univ-nantes.fr.
authors.forename: Elise
authors.initials: E
authors.lastname: Verron
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D017077:Culture Media, Conditioned / Q000378:metabolism; D005260:Female; D005708:Gallium / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000517:prevention & control*; D000067996:RAW 264.7 Cells; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D050071:Bone Density Conservation Agents; D017077:Culture Media, Conditioned; D053773:Transforming Growth Factor beta1; D005708:Gallium; C027235:gallium nitrate
keywords: Bone metastases; Breast cancer; Gallium; MDA-231BO cells; MDA-MB-231 cells; Osteoclastogenesis