Casadei Lucia, Pollock Raphael E
The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Oncoscience. 2020 Feb 1;7(1-2):10-13. doi: 10.18632/oncoscience.497. eCollection 2020 Jan.
Dedifferentiated liposarcoma (DDLPS) is molecularly characterized by wt p53 and MDM2 gene amplification causing MDM2 protein over-production, the key oncogenic process in DDLPS. Commonly located in fat-bearing retroperitoneal areas, almost 60% of DDLPS patients undergo multifocal recurrence, typically amenable to palliative treatment only, and occasionally develop distant metastasis. These factors lead to an abysmal 10% 10 year overall survival rate. Tumor cell-derived extracellular vesicles (EVs) can facilitate loco-regional malignancy dissemination by depositing molecular factors that participate in the development of pre-metastatic niches for tumor cell implantation and growth. High number of MDM2 DNA molecules was identified within EVs from DDLPS patient serum (ROC vs normal; 0.95) as well as from DDLPS cell lines. This MDM2 DNA could be transferred to preadipocytes (P-a), a major and ubiquitous cellular component of the DDLPS tumor microenvironment (TME), with subsequent P-a production of matrix metalloproteinase 2 (MMP2), a critical component in the metastatic cascade. From here the hypothesis that the DDLPS microenvironment (specifically P-a cells) may participate in DDLPS recurrence events. Since multifocal loco-regional DDLPS spreading is the main cause of the remarkably high lethality of this disease, a better understanding of the underlying oncogenic processes and their regulatory mechanisms is essential to improve the outcome of this devastating disease.
去分化脂肪肉瘤（DDLPS）的分子特征是野生型p53和MDM2基因扩增，导致MDM2蛋白过度产生，这是DDLPS中的关键致癌过程。DDLPS通常位于有脂肪的腹膜后区域，近60%的DDLPS患者会发生多灶性复发，通常仅适合姑息治疗，偶尔会发生远处转移。这些因素导致10年总生存率低至10%。肿瘤细胞衍生的细胞外囊泡（EVs）可通过沉积参与肿瘤细胞植入和生长的前转移微环境形成的分子因子，促进局部区域恶性肿瘤的扩散。在DDLPS患者血清的EVs（ROC与正常对照；0.95）以及DDLPS细胞系的EVs中均鉴定出大量MDM2 DNA分子。这种MDM2 DNA可转移至前脂肪细胞（P-a），P-a是DDLPS肿瘤微环境（TME）的主要且普遍存在的细胞成分，随后P-a会产生基质金属蛋白酶2（MMP2），这是转移级联反应中的关键成分。由此提出假说，即DDLPS微环境（特别是P-a细胞）可能参与DDLPS的复发事件。由于多灶性局部区域DDLPS扩散是该疾病高致死率的主要原因，更好地了解潜在的致癌过程及其调控机制对于改善这种毁灭性疾病的治疗结果至关重要。
