Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
J Cell Mol Med. 2022 Jan;26(2):343-353. doi: 10.1111/jcmm.17084. Epub 2021 Nov 28.
Colorectal cancer (CRC) is a high-incidence malignancy worldwide which still needs better therapy options. Therefore, the aim of the present study was to investigate the responses of normal or malignant human intestinal epithelium to bone morphogenetic protein (BMP)-9 and to find out whether the application of BMP-9 to patients with CRC or the enhancement of its synthesis in the liver could be useful strategies for new therapy approaches. In silico analyses of CRC patient cohorts (TCGA database) revealed that high expression of the BMP-target gene ID1, especially in combination with low expression of the BMP-inhibitor noggin, is significantly associated with better patient survival. Organoid lines were generated from human biopsies of colon cancer (T-Orgs) and corresponding non-malignant areas (N-Orgs) of three patients. The N-Orgs represented tumours belonging to three different consensus molecular subtypes (CMS) of CRC. Overall, BMP-9 stimulation of organoids promoted an enrichment of tumour-suppressive gene expression signatures, whereas the stimulation with noggin had the opposite effects. Furthermore, treatment of organoids with BMP-9 induced ID1 expression (independently of high noggin levels), while treatment with noggin reduced ID1. In summary, our data identify the ratio between ID1 and noggin as a new prognostic value for CRC patient outcome. We further show that by inducing ID1, BMP-9 enhances this ratio, even in the presence of noggin. Thus, BMP-9 is identified as a novel target for the development of improved anti-cancer therapies of patients with CRC.
结直肠癌(CRC)是一种全球高发的恶性肿瘤,仍需要更好的治疗选择。因此,本研究旨在研究正常或恶性人肠上皮细胞对骨形态发生蛋白(BMP)-9的反应,并找出将 BMP-9 应用于 CRC 患者或增强其在肝脏中的合成是否可能是新治疗方法的有用策略。对 CRC 患者队列(TCGA 数据库)的计算机分析表明,BMP 靶基因 ID1 的高表达,特别是与 BMP 抑制剂 noggin 的低表达相结合,与患者的生存显著相关。从三名患者的结肠癌活检(T-Orgs)和相应的非恶性区域(N-Orgs)生成类器官系。N-Orgs 代表属于 CRC 三种不同共识分子亚型(CMS)的肿瘤。总体而言,BMP-9 对类器官的刺激促进了肿瘤抑制基因表达特征的富集,而 noggin 的刺激则产生相反的效果。此外,BMP-9 处理类器官诱导 ID1 表达(与高 noggin 水平无关),而 noggin 处理则降低 ID1。总之,我们的数据确定 ID1 和 noggin 之间的比值作为 CRC 患者预后的新预后价值。我们进一步表明,通过诱导 ID1,BMP-9 即使在 noggin 存在的情况下也增强了这种比值。因此,BMP-9 被确定为开发 CRC 患者改进抗癌疗法的新靶标。
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