Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands.
Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
Sci Adv. 2023 Oct 20;9(42):eabp9530. doi: 10.1126/sciadv.abp9530. Epub 2023 Oct 18.
Although initially successful, treatments with chemotherapy often fail because of the recurrence of chemoresistant metastases. Since these tumors develop after treatment, resistance is generally thought to occur in response to chemotherapy. However, alternative mechanisms of intrinsic chemoresistance in the chemotherapy-naïve setting may exist but remain poorly understood. Here, we study drug-naïve murine breast cancer brain metastases (BCBMs) to identify how cancer cells growing in a secondary site can acquire intrinsic chemoresistance without cytotoxic agent exposure. We demonstrate that drug-naïve murine breast cancer cells that form cancer lesions in the brain undergo vascular mimicry and concomitantly express the adenosine 5'-triphosphate-binding cassette transporter breast cancer resistance protein (BCRP), a common marker of brain endothelial cells. We reveal that expression of BCRP by the BCBM tumor cells protects them against doxorubicin and topotecan. We conclude that BCRP overexpression can cause intrinsic chemoresistance in cancer cells growing in metastatic sites without prior chemotherapy exposure.
尽管最初取得了成功，但由于化疗耐药转移的复发，化疗治疗常常失败。由于这些肿瘤是在治疗后发展起来的，因此通常认为耐药性是对化疗的反应。然而，在未经化疗的情况下，肿瘤细胞可能存在内在耐药的其他机制，但目前仍了解甚少。在这里，我们研究了未经化疗的小鼠乳腺癌脑转移瘤（BCBMs），以确定在没有细胞毒性药物暴露的情况下，生长在继发性部位的癌细胞如何获得内在耐药性。我们证明，在大脑中形成癌病变的未经化疗的小鼠乳腺癌细胞会发生血管模拟，同时表达三磷酸腺苷结合盒转运蛋白乳腺癌耐药蛋白（BCRP），这是脑内皮细胞的常见标志物。我们揭示了 BCBM 肿瘤细胞中 BCRP 的表达可以保护它们免受多柔比星和拓扑替康的侵害。我们的结论是，BCRP 的过表达可以在没有先前化疗暴露的情况下导致转移性部位生长的癌细胞产生内在耐药性。
