Hughes Russell, Chen Xinyue, Cowley Natasha, Ottewell Penelope D, Hawkins Rhoda J, Hunter Keith D, Hobbs Jamie K, Brown Nicola J, Holen Ingunn
Department of Oncology and Metabolism, University of Sheffield, and Experimental Cancer Medicine Centre, Sheffield S10 2RX, UK.
Department of Physics and Astronomy, University of Sheffield, Sheffield S3 7RH, UK.
Cancers (Basel). 2021 Mar 18;13(6):1366. doi: 10.3390/cancers13061366.
Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.
骨转移性乳腺癌无法治愈，因此迫切需要开发新的治疗方法来提高生存率。关键在于了解控制癌细胞在骨中存活和生长的机制，这涉及恶性细胞和辅助细胞类型之间的相互作用。在这里，我们对代表转移性惰性或生长的小鼠模型中的骨微环境进行了细胞和分子比较，以确定调节癌细胞存活和命运的机制。在体内，我们发现无论其命运如何，骨中的乳腺癌细胞都占据富含成骨细胞的微环境。随着骨中成骨细胞数量的减少，维持大量乳腺癌细胞并支持转移生长的能力也会下降。在体外，成骨细胞保护乳腺癌细胞免受细胞应激诱导的死亡，并且发现通过缝隙连接的信号传导在成骨细胞与MDA-MB-231（三阴性乳腺癌）和MCF7（雌激素受体阳性）乳腺癌细胞之间提供重要的旁分泌保护机制。结合数学模型，这些发现表明播散肿瘤细胞的命运不是通过与特定血管亚型的关联来控制的。相反，成骨细胞的数量决定了保护性微环境的可用性，乳腺癌细胞在转移生长刺激之前可以在这些微环境中定植。
