Oncoscience

Cracking the riddle of dedifferentiated liposarcoma: is EV-MDM2 a key?

Lucia Casadei1,2, Raphael E. Pollock1,2

1 The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA

2 Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio

Correspondence to:

Lucia Casadei, email:lucia.casadei@osumc.edu

Raphael E. Pollock, email:raphael.Pollock@osumc.edu

Keywords: dedifferentiated liposarcoma; extracellular vesicles; MDM2; MMP2; tumor microenvironment

Received: December 11, 2019 Accepted: January 09, 2020 Published: February 01, 2020

Abstract

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.


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