Haider Marie-Therese, Smit Daniel J, Taipaleenmäki Hanna
Molecular Skeletal Biology Laboratory, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Front Oncol. 2020 Mar 13;10:335. doi: 10.3389/fonc.2020.00335. eCollection 2020.
The establishment of bone metastasis remains one of the most frequent complications of patients suffering from advanced breast cancer. Patients with bone metastases experience high morbidity and mortality caused by excessive, tumor-induced and osteoclast-mediated bone resorption. Anti-resorptive treatments, such as bisphosphonates, are available to ease skeletal related events including pain, increased fracture risk, and hypercalcemia. However, the disease remains incurable and 5-year survival rates for these patients are below 25%. Within the bone, disseminated breast cancer cells localize in "metastatic niches," special microenvironments that are thought to regulate cancer cell colonization and dormancy as well as tumor progression and subsequent development into overt metastases. Precise location and composition of this "metastatic niche" remain poorly defined. However, it is thought to include an "endosteal niche" that is composed of key bone cells that are derived from both, hematopoietic stem cells (osteoclasts), and mesenchymal stromal cells (osteoblasts, fibroblasts, adipocytes). Our knowledge of how osteoclasts drive the late stage of the disease is well-established. In contrast, much less is known about the interaction between osteogenic cells and disseminated tumor cells prior to the initiation of the osteolytic phase. Recent studies suggest that mesenchymal-derived cells, including osteoblasts and fibroblasts, play a key role during the early stages of breast cancer bone metastasis such as tumor cell homing, bone marrow colonization, and tumor cell dormancy. Hence, elucidating the interactions between breast cancer cells and mesenchymal-derived cells that drive metastasis progression could provide novel therapeutic approaches and targets to treat breast cancer bone metastasis. In this review we discuss evidences reporting the interaction between tumor cells and endosteal niche cells during the early stages of breast cancer bone metastasis, with a particular focus on mesenchymal-derived osteoblasts and fibroblasts.
骨转移的发生仍然是晚期乳腺癌患者最常见的并发症之一。骨转移患者因肿瘤诱导的破骨细胞介导的过度骨吸收而出现高发病率和死亡率。抗吸收治疗，如双膦酸盐，可用于缓解骨骼相关事件，包括疼痛、骨折风险增加和高钙血症。然而，该疾病仍然无法治愈，这些患者的5年生存率低于25%。在骨内，播散性乳腺癌细胞定位于“转移龛”，这是一种特殊的微环境，被认为可调节癌细胞的定植和休眠以及肿瘤进展和随后发展为明显转移灶。这种“转移龛”的确切位置和组成仍不清楚。然而，人们认为它包括一个“骨内膜龛”，该龛由关键的骨细胞组成，这些骨细胞来源于造血干细胞（破骨细胞）和间充质基质细胞（成骨细胞、成纤维细胞、脂肪细胞）。我们对破骨细胞如何驱动疾病晚期的认识已经很充分。相比之下，对于溶骨期开始之前成骨细胞与播散性肿瘤细胞之间的相互作用了解较少。最近的研究表明，包括成骨细胞和成纤维细胞在内的间充质来源细胞在乳腺癌骨转移的早期阶段，如肿瘤细胞归巢、骨髓定植和肿瘤细胞休眠中起关键作用。因此，阐明驱动转移进展的乳腺癌细胞与间充质来源细胞之间的相互作用，可为治疗乳腺癌骨转移提供新的治疗方法和靶点。在这篇综述中，我们讨论了报道乳腺癌骨转移早期阶段肿瘤细胞与骨内膜龛细胞之间相互作用的证据，特别关注间充质来源的成骨细胞和成纤维细胞。
