Shropshire Daniel Brian, Acosta Francisca M, Fang Kun, Benavides Jaime, Sun Lu-Zhe, Jin Victor X, Jiang Jean X
Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, United States.
Division of Biostatistics and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI, United States.
Front Med (Lausanne). 2022 Sep 15;9:965429. doi: 10.3389/fmed.2022.965429. eCollection 2022.
Bone metastasis is a common and devastating consequence of several major cancer types, including breast and prostate. Osteocytes are the predominant bone cell, and through connexin (Cx) 43 hemichannels release ATP to the bone microenvironment that can be hydrolyzed to adenosine. Here, we investigated how genes related to ATP paracrine signaling are involved in two common bone-metastasizing malignancies, estrogen receptor positive (ER) breast and prostate cancers. Compared to other sites, bone metastases of both cancer types expressed higher levels of ENTPD1 and NT5E, which encode CD39 and CD73, respectively, and hydrolyze ATP to adenosine. ADORA3, encoding the adenosine A3 receptor, had a similar expression pattern. In primary ER breast cancer, high levels of the triplet ENTPD1/NT5E/ADORA3 expression signature was correlated with lower overall, distant metastasis-free, and progression-free survival. In ER bone metastasis biopsies, this expression signature is associated with lower survival. This expression signature was also higher in bone-metastasizing primary prostate cancers than in those that caused other tumor events or did not lead to progressive disease. In 3D culture, a non-hydrolyzable ATP analog inhibited the growth of breast and prostate cancer cell lines more than ATP did. A3 inhibition also reduced spheroid growth. Large-scale screens by the Drug Repurposing Hub found ER breast cancer cell lines were uniquely sensitive to adenosine receptor antagonists. Together, these data suggest a vital role for extracellular ATP degradation and adenosine receptor signaling in cancer bone metastasis, and this study provides potential diagnostic means for bone metastasis and specific targets for treatment and prevention.
骨转移是包括乳腺癌和前列腺癌在内的几种主要癌症类型常见且具有破坏性的后果。骨细胞是主要的骨细胞，通过连接蛋白（Cx）43半通道将ATP释放到骨微环境中，ATP可水解为腺苷。在此，我们研究了与ATP旁分泌信号相关的基因如何参与两种常见的骨转移性恶性肿瘤，即雌激素受体阳性（ER）乳腺癌和前列腺癌。与其他部位相比，这两种癌症类型的骨转移灶中分别编码CD39和CD73并将ATP水解为腺苷的ENTPD1和NT5E表达水平更高。编码腺苷A3受体的ADORA3具有相似的表达模式。在原发性ER乳腺癌中，ENTPD1/NT5E/ADORA3三联体高表达特征与较低的总生存率、无远处转移生存率和无进展生存率相关。在ER骨转移活检中，这种表达特征与较低的生存率相关。这种表达特征在发生骨转移的原发性前列腺癌中也高于那些导致其他肿瘤事件或未导致疾病进展的前列腺癌。在三维培养中，一种不可水解的ATP类似物比ATP更能抑制乳腺癌和前列腺癌细胞系的生长。A3受体抑制也减少了球体生长。药物再利用中心的大规模筛选发现ER乳腺癌细胞系对腺苷受体拮抗剂具有独特的敏感性。总之，这些数据表明细胞外ATP降解和腺苷受体信号在癌症骨转移中起着至关重要的作用，本研究为骨转移提供了潜在的诊断方法以及治疗和预防的特定靶点。
