Local and Systemic Cytokine Profiling for Pancreatic Ductal Adenocarcinoma to Study Cancer Cachexia in an Era of Precision Medicine

International Journal of Molecular Sciences

ShannonM. Wallet¹  BayliB. DiVita²  RachelL. Nosacka³  AndrewR. Judge³  SarahM. Judge³  AndreaE. Delitto³  PatrickW. Underwood⁴  JoseG. Trevino⁴  StevenJ. Hughes⁴  Daniel Delitto⁴  RyanM. Thomas⁴  MichaelH. Gerber⁴  JenniferB. Permuth⁵ 

[1] Department of Foundational Sciences, School of Dental Medicine, East Carolina University, Greenville, NC 27834, USA;Department of Neurosurgery, College of Medicine, University of Florida Health Science Center, Gainesville, FL 32610, USA;Department of Physical Therapy, University of Florida Health Science Center, Gainesville, FL 32610, USA;Department of Surgery, College of Medicine, University of Florida Health Science Center, Gainesville, FL 32610, USA;Departments of Cancer Epidemiology and Gastroinestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA;

关键词: pancreatic cancer;    cachexia;    cytokines;    innate immune system;   

DOI  :  10.3390/ijms19123836

来源: DOAJ

【 摘 要 】

Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P < 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1; P < 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P < 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P < 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy.

【 授权许可】

Unknown