Role of mononuclear cells and inflammatory cytokines in pancreatic cancer-related cachexia.
OBJECTIVE
The mechanism behind aggressive development of cachexia in patients suffering from pancreatic cancer is not well understood. In this study, we investigated which factors are associated with the cachectic status of the patients and evaluated cachexia-promoting capacity of cancer and inflammatory cells.


METHODS
DNA microarray analysis and quantitative reverse transcription-PCR were used to screen for cachexia-associated factors in pancreatic specimens obtained from noncachectic and cachetic patients diagnosed with pancreatic ductal adenocarcinoma. The expression pattern of the most prominently altered cachexia-associated factor, interleukin-6 (IL-6), was further analyzed in patients sera by ELISA, in pancreatic specimens by immunohistochemistry, and in a coculture system by quantitative reverse transcription-PCR using pancreatic cancer cell lines T3M4 (IL-6 positive) and Panc-1 (IL-6 negative) and peripheral blood mononuclear cells (PBMC) obtained from donors and noncachectic and cachectic patients.


RESULTS
Among numerous analyzed factors, IL-6 was significantly overexpressed in pancreatic specimens and elevated in serum of cachectic patients. The coculture system revealed that pancreatic cancer T3M4 cells but not Panc-1 cells were able to stimulate IL-6 exclusively in cachectic PBMC (by 14-fold) and this triggering was reduced by half in the presence of IL-6-neutralizing antibodies.


CONCLUSIONS
IL-6 represents a prominent cachexia-associated factor in pancreatic cancer. IL-6 overexpression in cachectic patients is related to the ability of certain tumors to sensitize PBMC and induce cytokine expression in cachectic PBMC.
Martignoni
Marc E
ME
Department of General Surgery, University of Heidelberg, Germany.
Kunze
Phillipp
P
Hildebrandt
Wulf
W
Künzli
Beat
B
Berberat
Pascal
P
Giese
Thomas
T
Klöters
Oliver
O
Hammer
Jürgen
J
Büchler
Markus W
MW
Giese
Nathalia A
NA
Friess
Helmut
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002100:Cachexia / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002908:Chronic Disease; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015850:Interleukin-6; D012333:RNA, Messenger