Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells.
Pancreatic ductal adenocarcinoma (PDAC) is a dynamic tumor supported by several stromal elements such as pancreatic stellate cells (PSC). Significant crosstalk exists between PSCs and tumor cells to stimulate oncogenic signaling and malignant progression of PDAC. However, how PSCs activate intercellular signaling in PDAC cells remains to be elucidated. We have previously shown that activated signal transducer and activator of transcription 3 (STAT3) signaling is a key component in the progression of pancreatic neoplasia. We hypothesize that PSC secreted IL-6 activates STAT3 signaling to promote PanIN progression to PDAC. Human PDAC and mouse PanIN cells were treated with PSC-conditioned media (PSC-CM), and phospho- and total-STAT3 levels by immunoblot analysis were determined. IL-6 was quantified in PSC-CM and cell invasion and colony formation assays were performed in the presence or absence of a neutralizing IL-6 antibody and the JAK/STAT3 inhibitor AZD1480. Serum from Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) and LSL-KrasG12D/+; Trp53R172H/+; Pdx1Cre/+ (KPC) mice demonstrated increased levels of IL-6 compared to serum from non-PDAC bearing KC and PK mice. PSC secreted IL-6 activated STAT3 signaling in noninvasive, precursor PanIN cells as well as PDAC cells, resulting in enhanced cell invasion and colony formation in both cell types. There was a significant positive linear correlation between IL-6 concentration and the ratio of phosphorylated STAT3/total STAT3. IL-6 neutralization or STAT3 inhibition attenuated PSC-CM induced activation of STAT3 signaling and tumorigenicity. These data provide evidence that PSCs are directly involved in promoting the progression of PanINs towards invasive carcinoma. This study demonstrates a novel role of PSC secreted IL-6 in transitioning noninvasive pancreatic precursor cells into invasive PDAC through the activation of STAT3 signaling.
Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
Nagaraj S
NS
Nagathihalli
Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Jason A
JA
Castellanos
Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
Michael N
MN
VanSaun
Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
Xizi
X
Dai
Meharry Medical College, Nashville, Tennessee, USA.
Mahogany
M
Ambrose
Yale School of Medicine, New Haven, Connecticut, USA.
Qiaozhi
Q
Guo
Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Yanhua
Y
Xiong
Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
Nipun B
NB
Merchant
D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002278:Carcinoma in Situ / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D015850:Interleukin-6; D050796:STAT3 Transcription Factor
IL-6; PanIN; STAT3; pancreatic cancer; pancreatic stellate cells