Department of Urology, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Cell and Molecular Biology, Science for Life Laboratory, National Bioinformatics Infrastructure Sweden, Uppsala University, 75124, Uppsala, Sweden.
Clin Exp Metastasis. 2022 Oct;39(5):801-814. doi: 10.1007/s10585-022-10179-2. Epub 2022 Aug 16.
Metastasis to bone is the leading cause of death from prostate cancer. Interaction between tumor cells and bone cells can promote progression and influence tumor phenotype. It is known that prostate cancer cells support osteoclast differentiation, and degradation of bone matrix by osteoclasts releases growth factors stimulating tumor cell proliferation and invasion. In the present study osteolytic (PC-3) and osteoblastic (LNCaP-19) castration-resistant prostate cancer (CRPC) cells were co-cultured with mature osteoclasts or their precursor cells (RAW 264.7) to characterize direct effects of mature osteoclasts on CRPC cells. Osteoclasts increased proliferation and decrease apoptosis of CRPC cells as assessed with flow cytometry. RNA sequencing revealed that osteolytic CRPC cells were more responsive to osteoclast stimulation regarding gene expression, but the overall induced expression patterns were similar between the prostate cancer cell lines. Genes related to DNA repair were upregulated by osteoclasts, while genes related to endoplasmic reticulum stress-induced apoptosis and cholesterol synthesis were downregulated. The results of this study shows that osteoclasts directly influence CRPC cells, increasing proliferation, decreasing apoptosis, and affecting gene expression pathways that can affect sensitivity to DNA damage and endoplasmic reticulum function. This suggests targeting of osteoclasts to be a possible way to affect efficacy of other drugs by combination regimens in treating prostate cancer metastases.
转移到骨骼是导致前列腺癌死亡的主要原因。肿瘤细胞与骨细胞之间的相互作用可以促进肿瘤的进展并影响肿瘤表型。已知前列腺癌细胞支持破骨细胞的分化，而破骨细胞对骨基质的降解释放出刺激肿瘤细胞增殖和侵袭的生长因子。在本研究中，溶骨性（PC-3）和成骨性（LNCaP-19）去势抵抗性前列腺癌（CRPC）细胞与成熟破骨细胞或其前体细胞（RAW 264.7）共培养，以表征成熟破骨细胞对 CRPC 细胞的直接影响。通过流式细胞术评估，破骨细胞增加了 CRPC 细胞的增殖并减少了细胞凋亡。RNA 测序表明，溶骨性 CRPC 细胞对破骨细胞刺激的基因表达更敏感，但两条前列腺癌细胞系之间的总体诱导表达模式相似。破骨细胞上调了与 DNA 修复相关的基因，而下调了与内质网应激诱导的细胞凋亡和胆固醇合成相关的基因。本研究的结果表明，破骨细胞直接影响 CRPC 细胞，增加增殖，减少凋亡，并影响可能影响 DNA 损伤和内质网功能敏感性的基因表达途径。这表明通过联合治疗方案靶向破骨细胞可能是影响治疗前列腺癌转移的其他药物疗效的一种方法。
