Adipose-Induced Retroperitoneal Soft Tissue Sarcoma Tumorigenesis: A Potential Crosstalk between Sarcoma and Fat Cells.
Previous data demonstrated that high retroperitoneal visceral fat content increases retroperitoneal soft-tissue sarcoma (RSTS) local recurrence and patients' mortality. Most RSTS tumors initiate and recur within visceral fat. The objective of the current study was to evaluate potential paracrine effects of visceral fat on RSTS. A xenograft model was used to evaluate in vivo effects of human visceral fat on STS growth. Tissue explants were prepared from visceral fat, and their conditioned medium (CM) was utilized for various in vitro experiments designed to evaluate growth, survival, migration, and invasion of STS and endothelial cells. Visceral fat-secreted protumorigenic factors were identified by mass spectrometry. The in vivo experiments demonstrated a significant increase in STS tumor growth rate when SK-LMS-1 leiomyosarcoma cells were colocalized with human visceral fat compared with subcutaneous injection of cancer cells only. The in vitro model demonstrated that visceral fat CM increased STS cellular growth and reduced doxorubicin-induced apoptosis. Visceral fat also enhanced STS cellular migration and invasion. In addition, visceral fat CM significantly increased endothelial cell tube formation, suggesting its role as a proangiogenic factor in the STS tumor microenvironment (TME). Using a robust proteomic approach, liquid chromatography and tandem mass spectrometry resolved various molecules within the visceral fat CM, of which a subset was associated with protumorigenic biologic processes. These results suggest that visceral fat directly interacts with STS cells by secreting specific adipokines into the TME, thus augmenting STS tumor cell proliferation and invasiveness. Fat-induced STS molecular deregulations should be studied to identify new potential prognostic and therapeutic targets.



Visceral fat induces protumorigenic effects, in STS, through various secreted factors that should be investigated to improve our understanding of adipose-cancer cell interactions. Mol Cancer Res; 14(12); 1254-65. ©2016 AACR.
Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel.
Shelly
S
Loewenstein
Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel.
Nir
N
Lubezky
Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel.
Eran
E
Nizri
Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel.
Meir
M
Zemel
de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Israel.
Yishai
Y
Levin
de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Israel.
Alon
A
Savidor
Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Osnat
O
Sher
Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel.
Joseph M
JM
Klausner
Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. guyla@tlvmc.gov.il.|Sackler School of Medicine, The Nicholas and Elizabeth Cathedra of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel.
Guy
G
Lahat
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D054392:Adipokines / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002853:Chromatography, Liquid; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D007890:Leiomyosarcoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009374:Neoplasms, Experimental; D019899:Paracrine Communication; D040901:Proteomics / Q000379:methods*; D012186:Retroperitoneal Neoplasms / Q000378:metabolism / Q000473:pathology*; D053719:Tandem Mass Spectrometry; D046509:Tissue Culture Techniques; D059016:Tumor Microenvironment
D054392:Adipokines; D017077:Culture Media, Conditioned