LOX, but not LOXL2, promotes bone metastasis formation and bone destruction in triple-negative breast cancer
The primary function of the lysyl oxidase (LOX) family, including LOX and its paralogue LOX-like (LOXL)-2, is to catalyze the covalent crosslinking of collagen and elastin in the extracellular matrix. LOX and LOXL2 are also facilitating breast cancer invasion and metastatic spread to visceral organs...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-02-01
|
| Series: | Journal of Bone Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212137424000022 |
| _version_ | 1797319508238532608 |
|---|---|
| author | Paola Di Mauro Martine Croset Lamia Bouazza Philippe Clézardin Caroline Reynaud |
| author_facet | Paola Di Mauro Martine Croset Lamia Bouazza Philippe Clézardin Caroline Reynaud |
| author_sort | Paola Di Mauro |
| collection | DOAJ |
| description | The primary function of the lysyl oxidase (LOX) family, including LOX and its paralogue LOX-like (LOXL)-2, is to catalyze the covalent crosslinking of collagen and elastin in the extracellular matrix. LOX and LOXL2 are also facilitating breast cancer invasion and metastatic spread to visceral organs (lungs, liver) in vivo. Conversely, the contribution of LOX and LOXL2 to breast cancer bone metastasis remains scant. Here, using gene overexpression or silencing strategies, we investigated the role of LOX and LOXL2 on the formation of metastatic osteolytic lesions in animal models of triple negative breast cancer. In vivo, the extent of radiographic metastatic osteolytic lesions in animals injected with LOX-overexpressing [LOX(+)] tumor cells was 3-fold higher than that observed in animals bearing tumors silenced for LOX [LOX(−)]. By contrast, the extent of osteolytic lesions between LOXL2(+) and LOXL2(−) tumor-bearing animals did not differ, and was comparable to that observed with LOX(−) tumor-bearing animals. In situ, TRAP staining of bone tissue sections from the hind limbs of LOX(+) tumor-bearing animals was substantially increased compared to LOX(−), LOXL2(+) and LOXL2(−)-tumor-bearing animals, which was indicative of enhanced active-osteoclast resorption. In vitro, tumor-secreted LOX increased osteoclast differentiation induced by RANKL, whereas LOXL2 seemed to counteract LOX’s pro-osteoclastic activity. Furthermore, LOX (but not LOXL2) overexpression in tumor cells induced a robust production of IL-6, the latter being a pro-osteoclastic cytokine. Based on these findings, we propose a model in which LOX and IL-6 secreted from tumor cells act in concert to enhance osteoclast-mediated bone resorption that, in turn, promotes metastatic bone destruction in vivo. |
| first_indexed | 2024-03-08T04:07:54Z |
| format | Article |
| id | doaj.art-bfb25f545266488499aaaac6100a6acc |
| institution | Directory Open Access Journal |
| issn | 2212-1374 |
| language | English |
| last_indexed | 2024-03-08T04:07:54Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Bone Oncology |
| spelling | doaj.art-bfb25f545266488499aaaac6100a6acc2024-02-09T04:48:08ZengElsevierJournal of Bone Oncology2212-13742024-02-0144100522LOX, but not LOXL2, promotes bone metastasis formation and bone destruction in triple-negative breast cancerPaola Di Mauro0Martine Croset1Lamia Bouazza2Philippe Clézardin3Caroline Reynaud4INSERM, UMR1033, F-69372 Lyon, France; University of Lyon, F-69622 Villeurbanne, FranceINSERM, UMR1033, F-69372 Lyon, France; University of Lyon, F-69622 Villeurbanne, FranceINSERM, UMR1033, F-69372 Lyon, France; University of Lyon, F-69622 Villeurbanne, FranceINSERM, UMR1033, F-69372 Lyon, France; University of Lyon, F-69622 Villeurbanne, France; Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; Corresponding author at: INSERM, UMR1033, Faculté de Médecine Lyon-Est (domaine Laennec), Rue Guillaume Paradin, 69372 Lyon cedex 08, France.INSERM, UMR1033, F-69372 Lyon, France; University of Lyon, F-69622 Villeurbanne, FranceThe primary function of the lysyl oxidase (LOX) family, including LOX and its paralogue LOX-like (LOXL)-2, is to catalyze the covalent crosslinking of collagen and elastin in the extracellular matrix. LOX and LOXL2 are also facilitating breast cancer invasion and metastatic spread to visceral organs (lungs, liver) in vivo. Conversely, the contribution of LOX and LOXL2 to breast cancer bone metastasis remains scant. Here, using gene overexpression or silencing strategies, we investigated the role of LOX and LOXL2 on the formation of metastatic osteolytic lesions in animal models of triple negative breast cancer. In vivo, the extent of radiographic metastatic osteolytic lesions in animals injected with LOX-overexpressing [LOX(+)] tumor cells was 3-fold higher than that observed in animals bearing tumors silenced for LOX [LOX(−)]. By contrast, the extent of osteolytic lesions between LOXL2(+) and LOXL2(−) tumor-bearing animals did not differ, and was comparable to that observed with LOX(−) tumor-bearing animals. In situ, TRAP staining of bone tissue sections from the hind limbs of LOX(+) tumor-bearing animals was substantially increased compared to LOX(−), LOXL2(+) and LOXL2(−)-tumor-bearing animals, which was indicative of enhanced active-osteoclast resorption. In vitro, tumor-secreted LOX increased osteoclast differentiation induced by RANKL, whereas LOXL2 seemed to counteract LOX’s pro-osteoclastic activity. Furthermore, LOX (but not LOXL2) overexpression in tumor cells induced a robust production of IL-6, the latter being a pro-osteoclastic cytokine. Based on these findings, we propose a model in which LOX and IL-6 secreted from tumor cells act in concert to enhance osteoclast-mediated bone resorption that, in turn, promotes metastatic bone destruction in vivo.http://www.sciencedirect.com/science/article/pii/S2212137424000022LOXLOXL2BoneMetastasisBreast cancerOsteoclast |
| spellingShingle | Paola Di Mauro Martine Croset Lamia Bouazza Philippe Clézardin Caroline Reynaud LOX, but not LOXL2, promotes bone metastasis formation and bone destruction in triple-negative breast cancer Journal of Bone Oncology LOX LOXL2 Bone Metastasis Breast cancer Osteoclast |
| title | LOX, but not LOXL2, promotes bone metastasis formation and bone destruction in triple-negative breast cancer |
| title_full | LOX, but not LOXL2, promotes bone metastasis formation and bone destruction in triple-negative breast cancer |
| title_fullStr | LOX, but not LOXL2, promotes bone metastasis formation and bone destruction in triple-negative breast cancer |
| title_full_unstemmed | LOX, but not LOXL2, promotes bone metastasis formation and bone destruction in triple-negative breast cancer |
| title_short | LOX, but not LOXL2, promotes bone metastasis formation and bone destruction in triple-negative breast cancer |
| title_sort | lox but not loxl2 promotes bone metastasis formation and bone destruction in triple negative breast cancer |
| topic | LOX LOXL2 Bone Metastasis Breast cancer Osteoclast |
| url | http://www.sciencedirect.com/science/article/pii/S2212137424000022 |
| work_keys_str_mv | AT paoladimauro loxbutnotloxl2promotesbonemetastasisformationandbonedestructionintriplenegativebreastcancer AT martinecroset loxbutnotloxl2promotesbonemetastasisformationandbonedestructionintriplenegativebreastcancer AT lamiabouazza loxbutnotloxl2promotesbonemetastasisformationandbonedestructionintriplenegativebreastcancer AT philippeclezardin loxbutnotloxl2promotesbonemetastasisformationandbonedestructionintriplenegativebreastcancer AT carolinereynaud loxbutnotloxl2promotesbonemetastasisformationandbonedestructionintriplenegativebreastcancer |