Novel role for tumor-induced expansion of myeloid-derived cells in cancer cachexia.
Cancer progression is associated with inflammation, increased metabolic demand, infection, cachexia, and eventually death. Myeloid-derived suppressor cells (MDSCs) commonly expand during cancer and are associated with adaptive immune suppression and inflammatory metabolite production. We propose that cancer-induced cachexia is driven at least in part by the expansion of MDSCs. MDSC expansion in 4T1 mammary carcinoma-bearing hosts is associated with induction of a hepatic acute-phase protein response and altered host energy and fat metabolism, and eventually reduced survival to polymicrobial sepsis and endotoxemia. Similar results are also seen in mice bearing a Lewis lung carcinoma and a C26 colon adenocarcinoma. However, a similar cachexia response is not seen with equivalent growth of the 66C4 subclone of 4T1, in which MDSC expansion does not occur. Importantly, reducing MDSC numbers in 4T1-bearing animals can ameliorate some of these late responses and reduce susceptibility to inflammation-induced organ injury and death. In addition, administering MDSCs from both tumor- and nontumor-bearing mice can produce an acute-phase response. Thus, we propose a previously undescribed mechanism for the development of cancer cachexia, whereby progressive MDSC expansion contributes to changes in host protein and energy metabolism and reduced resistance to infection.
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Alex G
AG
Cuenca
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Angela L
AL
Cuenca
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Robert D
RD
Winfield
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Dallas N
DN
Joiner
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Lori
L
Gentile
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Matthew J
MJ
Delano
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Kindra M
KM
Kelly-Scumpia
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Philip O
PO
Scumpia
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL 32610;
Michael K
MK
Matheny
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL 32610;
Philip J
PJ
Scarpace
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610; and.
Lizette
L
Vila
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Philip A
PA
Efron
Merck Research Laboratories (formerly DNAX Research Institute), Palo Alto, CA 94304.
Drake M
DM
LaFace
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610; moldawer@surgery.ufl.edu.
Lyle L
LL
Moldawer
D000818:Animals; D002100:Cachexia / Q000209:etiology / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology