Abstract
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.
Highlights
Cancer is the second leading cause of death in the United States
To determine the role of Axl in tumor cell metastatic phenotypes, human breast (MDA-MB-231) and prostate cancer cell lines (PC3ML and DU-145) were transduced with lentiviral short hairpin RNA (shRNA) against scrambled non-target sequence or AXL, and the transduction efficiency was confirmed by Western Blot (Fig. 1a–c)
Given that bone is the most common site of metastasis for breast and prostate cancers, we evaluated the effects of Axl knockdown tumor cells on bone colonization in vivo
Summary
Cancer is the second leading cause of death in the United States. Prostate and breast cancer are the most commonly diagnosed cancers and the second leading cause of cancer deaths for both men and women in the United States, respectively [1]. Bone is the most common site of metastasis for both prostate and breast cancers [10]. Successful development of metastatic lesions in the bone involves multiple steps, including (1) colonization of the bone, (2) dormancy and adaptation into the new microenvironment, (3) reactivation and proliferation from the dormant state, and (4) cancer-induced bone remodeling [11]
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