Hensel Janine, Wetterwald Antoinette, Temanni Ramzi, Keller Irene, Riether Carsten, van der Pluijm Gabri, Cecchini Marco G, Thalmann George N
Urology, Department for BioMedical Research, University of Bern, Bern, Switzerland.
Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland.
Oncotarget. 2018 Jun 22;9(48):28877-28896. doi: 10.18632/oncotarget.25608.
Prostate and breast cancers frequently metastasize to bone. The physiological bone homeostasis is perturbed once cancer cells proliferate at the bone metastatic site. Tumors are complex structures consisting of cancer cells and numerous stroma cells. In this study, we show that osteolytic cancer cells (PC-3 and MDA-MB231) induce transcriptome changes in the bone/bone marrow microenvironment (stroma). This stroma transcriptome differs from the previously reported stroma transcriptome of osteoinductive cancer cells (VCaP). While the biological process "angiogenesis/vasculogenesis" is enriched in both transcriptomes, the "vascular/axon guidance" process is a unique process that characterizes the osteolytic stroma. In osteolytic bone metastasis, angiogenesis is denoted by vessel morphology and marker expression specific for arteries/arterioles. Interestingly, intra-tumoral neurite-like structures were in proximity to arteries. Additionally, we found that increased numbers of mesenchymal stem cells and vascular smooth muscle cells, expressing osteolytic cytokines and inhibitors of bone formation, contribute to the osteolytic bone phenotype. Osteoinductive and osteolytic cancer cells induce different types of vessels, representing functionally different hematopoietic stem cell niches. This finding suggests different growth requirements of osteolytic and osteoinductive cancer cells and the need for a differential anti-angiogenic strategy to inhibit tumor growth in osteolytic and osteoblastic bone metastasis.
前列腺癌和乳腺癌常常会转移至骨骼。一旦癌细胞在骨转移部位增殖，生理性的骨稳态就会受到干扰。肿瘤是由癌细胞和众多基质细胞组成的复杂结构。在本研究中，我们发现溶骨性癌细胞（PC-3和MDA-MB231）会诱导骨/骨髓微环境（基质）中的转录组发生变化。这种基质转录组不同于先前报道的骨诱导性癌细胞（VCaP）的基质转录组。虽然“血管生成/血管发生”这一生物学过程在两个转录组中均富集，但“血管/轴突导向”过程是溶骨性基质特有的过程。在溶骨性骨转移中，血管生成由动脉/小动脉特有的血管形态和标志物表达来表示。有趣的是，肿瘤内的神经突样结构靠近动脉。此外，我们发现表达溶骨性细胞因子和骨形成抑制剂的间充质干细胞和血管平滑肌细胞数量增加，促成了溶骨性骨表型。骨诱导性癌细胞和溶骨性癌细胞诱导不同类型的血管，代表功能不同的造血干细胞龛。这一发现表明溶骨性癌细胞和骨诱导性癌细胞有不同的生长需求，以及需要采用不同的抗血管生成策略来抑制溶骨性和成骨性骨转移中的肿瘤生长。
