骨/骨髓是最常见的实体肿瘤转移部位之一。此外，肿瘤微环境是癌症平衡的重要组成部分。之前的研究表明，细胞色素P450酶（CYPs）在骨髓（BM）微环境中存在，尤其是在间质基质细胞中，其水平与肝细胞相当。研究发现，CYPs不仅在滋养和维护正常造血干细胞方面发挥重要作用，同时也对多发性骨髓瘤和白血病细胞起保护作用，使其免受有毒侵害。因此就假设，在骨髓微环境中的CYPs也可能在实体肿瘤转移到骨髓的过程中发挥类似的作用。研究建立了骨髓微环境与惯常转移至骨骼处的恶性细胞（肺癌、乳腺癌或前列腺癌）之间的交互作用模型。通过遗传工程和药理学方法，研究了滋养环境中肌动蛋白色素P450 3A4（CYP3A4）在体外和体内niche-cancer模型中药物耐受性促进作用。BM结缔组织保护前列腺、乳腺和肺癌细胞免于细胞毒性化疗的作用，其中CYP3A4至少在体外和体内发挥了部分作用。研究还表明，使用克拉霉素抑制CYP3A4可克服BM结缔组织介导的癌症细胞的耐药性。这些结果表明，类似于造血系统恶性肿瘤的观察结果，BM微环境通过CYPs的表达为实体肿瘤的化疗创造了一个避难所。以此为靶点，可能有助于消除实体肿瘤在骨骼处的转移。©2023 The Authors. 癌症发表于代表美国癌症学会的Wiley Periodicals LLC。

The bone/bone marrow is one of the most common sites for metastatic solid tumors. Moreover, the tumor microenvironment is an essential part of cancer homeostasis. Previously, it was shown that cytochrome P450 enzymes (CYPs) are present in the bone marrow (BM) microenvironment, particularly in the mesenchymal stroma cells, at levels comparable to those of hepatocytes. It was found that the CYPs play important roles in nurturing and maintaining normal hematopoietic stem cells as well as multiple myeloma and leukemia cells, including protecting them from toxic insults. It was hypothesized that the CYPs in the BM microenvironment might play a similar role in solid tumors metastatic to bone.The interaction between the BM microenvironment and malignant cells that routinely metastasize to the bone (lung, breast, and prostate cancer) was modeled. Via genetic engineering and pharmacological approaches, the role of stromal cytochrome P450 3A4 (CYP3A4) in drug resistance promoted by the BM microenvironment in niche-cancer models in vitro and in vivo was interrogated.BM stroma protected prostate, breast, and lung cancer cells from cytotoxic chemotherapy. Stromal CYP3A4 was at least partially responsible for this protection in vitro and in vivo. Moreover, inhibiting CYP3A4 with clarithromycin overcame the stroma-mediated chemoresistance toward prostate, breast, and lung cancer cells.These results suggest that, similar to observations from hematologic malignancies, the BM microenvironment, through expression of CYPs, creates a sanctuary site from chemotherapy for metastatic solid tumors. Targeting these sanctuaries holds promise for eradicating bone metastasis in solid tumors.© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.