scholarly journals Targeting HGF/c-MET Axis in Pancreatic Cancer

2020 ◽  
Vol 21 (23) ◽  
pp. 9170
Author(s):  
Srinivasa P. Pothula ◽  
Zhihong Xu ◽  
David Goldstein ◽  
Romano C. Pirola ◽  
Jeremy S. Wilson ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Tumour Progression ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Clinical Settings ◽  
Pancreatic Cancer Cells ◽  
Hepatocyte Growth

Pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC/PC)) has been an aggressive disease that is associated with early metastases. It is characterized by dense and collagenous desmoplasia/stroma, predominantly produced by pancreatic stellate cells (PSCs). PSCs interact with cancer cells as well as other stromal cells, facilitating disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells and endothelial cells. The current review discusses the role of the MET/HGF axis in tumour progression and dissemination of pancreatic cancer. Therapeutic approaches that were developed targeting either the ligand (HGF) or the receptor (c-MET) have not been shown to translate well into clinical settings. We discuss a two-pronged approach of targeting both the components of this pathway to interrupt the stromal–tumour interactions, which may represent a potential therapeutic strategy to improve outcomes in PC.

scholarly journals Analogs of the hepatocyte growth factor and macrophage-stimulating protein hinge regions act as Met and Ron dual inhibitors in pancreatic cancer cells

2016 ◽  
Vol 27 (8) ◽  
pp. 766-779 ◽  
Author(s):  
Kevin J. Church ◽  
Brett R. Vanderwerff ◽  
Rachelle R. Riggers ◽  
Michelle D. McMicheal ◽  
Beatriz Mateo-Victoriano ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cancer Cells ◽  
Macrophage Stimulating Protein ◽  
Pancreatic Cancer Cells ◽  
Dual Inhibitors ◽  
Hepatocyte Growth

scholarly journals Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Tim DD Somerville ◽  
Giulia Biffi ◽  
Juliane Daßler-Plenker ◽  
Stella K Hur ◽  
Xue-Yan He ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lineage ◽  
Pancreatic Stellate Cells ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Stromal Microenvironment ◽  
Pancreatic Cancer Cells ◽  
Human And Mouse

A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. Here, we investigated whether squamous trans-differentiation of human and mouse pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous pancreatic cancer cells secrete factors that recruit neutrophils and convert pancreatic stellate cells into cancer-associated fibroblasts (CAFs) that express inflammatory cytokines at high levels. We use gain- and loss-of-function approaches to show that squamous-subtype pancreatic tumor models become enriched with neutrophils and inflammatory CAFs in a p63-dependent manner. These effects occur, at least in part, through p63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A and CXCL1 as key targets. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.

scholarly journals Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts

2019 ◽  
Vol 27 (8) ◽  
pp. 945-956 ◽  
Author(s):  
Yosuke Mitsui ◽  
Nahoko Tomonobu ◽  
Masami Watanabe ◽  
Rie Kinoshita ◽  
I Wayan Sumardika ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Motility ◽  
Cancer Cells ◽  
Cellular Migration ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Mechanistic Investigation

S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11‐RAGE‐TPL2‐COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

Sa1717 Role of MicroRNAs in the Interactions Between Pancreatic Stellate Cells and Pancreatic Cancer Cells

2013 ◽  
Vol 144 (5) ◽  
pp. S-291
Author(s):  
Tetsuya Takikawa ◽  
Atsushi Masamune ◽  
Shin Hamada ◽  
Eriko Nakano ◽  
Tooru Shimosegawa
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Cancer Cells

scholarly journals The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives

2021 ◽  
Vol 10 ◽  
Author(s):  
Yang Wu ◽  
Chun Zhang ◽  
Kuirong Jiang ◽  
Jens Werner ◽  
Alexandr V. Bazhin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Gastrointestinal Malignancy ◽  
Desmoplastic Reaction ◽  
Pancreatic Cancer Cells ◽  
Promising Strategy

Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a dismal clinical outcome. Accumulating evidence suggests that activated pancreatic stellate cells (PSCs), the major producers of extracellular matrix (ECM), drive the severe stromal/desmoplastic reaction in PDAC. Furthermore, the crosstalk among PSCs, pancreatic cancer cells (PCCs) as well as other stroma cells can establish a growth-supportive tumor microenvironment (TME) of PDAC, thereby enhancing tumor growth, metastasis, and chemoresistance via various pathways. Recently, targeting stroma has emerged as a promising strategy for PDAC therapy, and several novel strategies have been proposed. The aim of our study is to give a profound review of the role of PSCs in PDAC progression and recent advances in stroma-targeting strategies.

scholarly journals HDGF supports anti-apoptosis and pro-fibrosis in pancreatic stellate cells of pancreatic cancer

2018 ◽  
Author(s):  
Yi-Ting Chen ◽  
Tso-Wen Wang ◽  
Tsung-Hao Chang ◽  
Teng-Po Hsu ◽  
Jhih-Ying Chi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Stellate Cells ◽  
Transforming Growth Factor Β1 ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Cancer Cells ◽  
Tgf Β1

ABSTRACTPancreatic cancer is refractory and characterized by extensively surrounding- and intra-tumor fibrotic reactions that are contributed by activated pancreatic stellate cells (PSCs). Activation of PSCs plays a pivotal role for developing fibrotic reactions to affect themselves or pancreatic cancer cells (PCCs). In the current study, we demonstrated that hepatoma-derived growth factor (HDGF) was secreted from transforming growth factor-β1 (TGF-β1)-treated PSCs. We found that HDGF contributed to anti-apoptosis of PSCs and led to synthesis and depositions of extracellular matrix proteins for stabilizing PSCs/PCCs tumor foci. CCAAT/enhancer binding protein δ (CEBPD) responds to TGF-β1 through a reciprocal loop regulation and further activated hypoxia inducible factor-1α (HIF-1α) contributed to up-regulation ofHDGFgene. It agrees with the observation that severe stromal growth positively correlated with stromal HDGF and CEBPD in pancreatic cancer specimens. Collectively, the identification of TGF-β1-activated CEBPD/HIF-1α/HDGF axis provides new insights for the novel discoveries of HDGF in anti-apoptosis and pro-fibrosis of PSCs and outgrowth of pancreatic cancer cells.

Sign in / Sign up

Export Citation Format

Share Document