Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
GenCure, a Subsidiary of BioBridge Global, San Antonio, TX, 78201, USA.
Clin Exp Metastasis. 2021 Jun;38(3):321-335. doi: 10.1007/s10585-021-10093-z. Epub 2021 Mar 31.
Approximately 90% of cancer-related deaths result from cancer metastasis. In prostate and breast cancers, bone is the most common site of cancer cell dissemination. Key steps in the metastatic cascade are promoted through upregulation of critical cell signaling pathways in neoplastic cells. The present study assessed the role of the receptor tyrosine kinase Axl in prostate and breast cancer cell metastasis to bones using (i) Axl knockdown neoplastic cells and osteoclast progenitor cells in vitro, (ii) intracardiac injection of Axl knockdown tumor cells in vivo, and (iii) selective Axl inhibitor BGB324. Axl inhibition in neoplastic cells significantly decreased their metastatic potential, and suppression of Axl signaling in osteoclast precursor cells also reduced the formation of mature osteoclasts. In vivo, Axl knockdown in prostate and breast cancer cells significantly suppressed the formation and progression of bone metastases. Hence, therapeutic targeting of Axl may impair tumor metastasis to the bones through neoplastic and host cell signaling axes.
约 90%的癌症相关死亡是由癌症转移引起的。在前列腺癌和乳腺癌中，骨骼是癌细胞扩散最常见的部位。转移级联中的关键步骤是通过上调肿瘤细胞中关键的细胞信号通路来促进的。本研究使用（i）体外 Axl 敲低的肿瘤细胞和破骨细胞祖细胞，（ii）体内心脏内注射 Axl 敲低的肿瘤细胞，和（iii）选择性 Axl 抑制剂 BGB324，评估了受体酪氨酸激酶 Axl 在前列腺癌和乳腺癌细胞向骨骼转移中的作用。肿瘤细胞中 Axl 的抑制显著降低了其转移潜能，而破骨细胞前体细胞中 Axl 信号的抑制也减少了成熟破骨细胞的形成。在体内，前列腺癌和乳腺癌细胞中 Axl 的敲低显著抑制了骨转移的形成和进展。因此，通过肿瘤细胞和宿主细胞信号轴，靶向 Axl 的治疗可能会损害肿瘤向骨骼的转移。
