Pantano Francesco, Croset Martine, Driouch Keltouma, Bednarz-Knoll Natalia, Iuliani Michele, Ribelli Giulia, Bonnelye Edith, Wikman Harriet, Geraci Sandra, Bonin Florian, Simonetti Sonia, Vincenzi Bruno, Hong Saw See, Sousa Sofia, Pantel Klaus, Tonini Giuseppe, Santini Daniele, Clézardin Philippe
INSERM, UMR_S1033, LYOS, Lyon, France.
Univ Lyon, Villeurbanne, France.
Oncogene. 2021 Feb;40(7):1284-1299. doi: 10.1038/s41388-020-01603-6. Epub 2021 Jan 8.
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.
骨转移仍然是乳腺癌患者死亡和发病的主要原因。因此，迫切需要更好地筛选出高风险患者，以便调整患者的治疗方案并预防骨转移复发。在此，我们发现与肺、肝或脑转移相比，整合素α5（ITGA5）在骨转移中高表达。原发性肿瘤中ITGA5的高表达与早期乳腺癌患者（n = 268；p = 0.039）骨髓穿刺液中播散肿瘤细胞的存在相关。在两个独立的临床数据集（n = 855，HR = 1.36，p = 0.018和n = 427，HR = 1.62，p = 0.024）中，ITGA5也可预测无骨转移生存期较差。在多变量分析中，这种预后价值仍然显著（p = 0.028）。实验表明，ITGA5沉默会损害肿瘤细胞与纤连蛋白的粘附、迁移和存活能力。ITGA5沉默还会减少肿瘤细胞在骨髓中的定植以及体内溶骨性病变的形成。相反，ITGA5过表达会促进骨转移。用人源化单克隆抗体M200（沃洛昔单抗）对ITGA5进行药理抑制，可在体外重现ITGA5沉默对肿瘤细胞功能的抑制作用，并在体内抑制肿瘤细胞在骨髓中的定植。M200还显著减少了骨转移或肿瘤发生实验模型中的肿瘤生长，并减轻了癌症相关的骨质破坏。ITGA5不仅在肿瘤细胞中表达，在破骨细胞中也有表达。在这方面，M200可在体外减少人破骨细胞介导的骨吸收。总体而言，本研究确定ITGA5是乳腺至骨转移的介质，并提出沃洛昔单抗/M200可重新用于治疗ITGA5阳性的骨转移乳腺癌患者的可能性。
