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pancreatic cancer PSCs

Yaojie Fu, Shanshan Liu, Shan Zeng, Hong Shen
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases worldwide. It is refractory to conventional treatments, and consequently has a documented 5-year survival rate as low as 7%. Increasing evidence indicates that activated pancreatic stellate cells (PSCs), one of the stromal components in tumor microenvironment (TME), play a crucial part in the desmoplasia, carcinogenesis, aggressiveness, metastasis associated with PDAC. Despite the current understanding of PSCs as a "partner in crime" to PDAC, detailed regulatory roles of PSCs and related microenvironment remain obscure...
February 19, 2018: Molecular Cancer
Divya Chakravarthy, Amanda R Muñoz, Angel Su, Rosa F Hwang, Brian R Keppler, Daniel E Chan, Glenn Halff, Rita Ghosh, Addanki P Kumar
Reciprocal interaction between pancreatic stellate cells (PSCs) and cancer cells (PCCs) in the tumor microenvironment (TME) promotes tumor cell survival and progression to lethal, therapeutically resistant pancreatic cancer. The goal of this study was to test the ability of Palmatine (PMT) to disrupt this reciprocal interaction in vitro and examine the underlying mechanism of interaction. We show that PSCs secrete glutamine into the extracellular environment under nutrient deprivation. PMT suppresses glutamine-mediated changes in GLI signaling in PCCs resulting in the inhibition of growth and migration while inducing apoptosis by inhibition of survivin...
January 31, 2018: Cancer Letters
Jonas Schnittert, Marcel A Heinrich, Praneeth R Kuninty, Gert Storm, Jai Prakash
Pancreatic stellate cells (PSCs) are the precursors of cancer-associated fibroblasts (CAFs), which potentiate pancreatic tumor growth and progression. In this study, we investigated whether Lipoxin A4 (LXA4), an endogenous bioactive lipid, can inhibit the differentiation of human PSCs (hPSCs) into CAF-like myofibroblasts and thereby hPSC-induced pro-tumorigenic effects. LXA4 significantly inhibited TGF-β-mediated differentiation of hPSCs by inhibiting pSmad2/3 signalling. Furthermore, treatment with LXA4 abolished the paracrine effects (proliferation and migration of Panc-1 tumor cells) of hPSCs in vitro...
February 2, 2018: Cancer Letters
Amanda R Muñoz, Divya Chakravarthy, Jingjing Gong, Glenn A Halff, Rita Ghosh, Addanki P Kumar
Purpose of the review: The 5-year survival rate of patients with pancreatic cancer (PanCA) has remained stagnant. Unfortunately, the incidence is almost equal to mortality rates. These facts underscore the importance of concerted efforts to understand the pathology of this disease. Deregulation of multiple signaling pathways involved in a wide variety of cellular processes including proliferation, apoptosis, invasion, and metastasis contribute not only to cancer development but also to therapeutic resistance...
December 2017: Current Pharmacology Reports
Ji-Hyun Lee, Seul-Ki Kim, Iftikhar Ali Khawar, Su-Yeong Jeong, Seok Chung, Hyo-Jeong Kuh
BACKGROUND: Pancreatic stellate cells (PSCs), a major component of the tumor microenvironment in pancreatic cancer, play roles in cancer progression as well as drug resistance. Culturing various cells in microfluidic (microchannel) devices has proven to be a useful in studying cellular interactions and drug sensitivity. Here we present a microchannel plate-based co-culture model that integrates tumor spheroids with PSCs in a three-dimensional (3D) collagen matrix to mimic the tumor microenvironment in vivo by recapitulating epithelial-mesenchymal transition and chemoresistance...
January 12, 2018: Journal of Experimental & Clinical Cancer Research: CR
Dong Tang, Qi Wu, Jingqiu Zhang, Hongpeng Zhang, Zhongxu Yuan, Jiaming Xu, Yang Chong, Yuqin Huang, Qingquan Xiong, Sen Wang, Ying Tian, Yongdie Lu, Xiao Ge, Wenjing Shen, Daorong Wang
Chronic pancreatitis/pancreatic cancer (CP/PC) is characterized by fibrous connective tissue proliferation induced by activated pancreatic stellate cells (PSCs). Galectin-1 is upregulated in activated PSCs and is important for the continuing activation of PSCs. The aim of this study was to evaluate the effect of galectin-1 derived from activated PSCs on the progression of fibrosis in CP/PC. To this end, the expression of desmin, α-SMA, galectin-1, fibronectin and collagen type I in normal pancreatic, CP and PC tissues, as well as quiescent/activated PSCs, was investigated...
January 9, 2018: Oncology Reports
Maya Saison-Ridinger, Kathleen E DelGiorno, Tejia Zhang, Annabelle Kraus, Randall French, Dawn Jaquish, Crystal Tsui, Galina Erikson, Benjamin T Spike, Maxim N Shokhirev, Christopher Liddle, Ruth T Yu, Michael Downes, Ronald M Evans, Alan Saghatelian, Andrew M Lowy, Geoffrey M Wahl
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense fibrotic stroma, which contributes to tumor growth, metastasis, and drug resistance. During tumorigenesis, quiescent pancreatic stellate cells (PSCs) are activated and become major contributors to fibrosis, by increasing growth factor signaling and extracellular matrix deposition. The p53 tumor suppressor is known to restrict tumor initiation and progression through cell autonomous mechanisms including apoptosis, cell cycle arrest, and senescence...
2017: PloS One
Yang Liu, Fan Li, Feng Gao, Lingxi Xing, Peng Qin, Xingxin Liang, Jiajie Zhang, Xiaohui Qiao, Lizhou Lin, Qian Zhao, Lianfang Du
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic reaction. Pancreatic stellate cells (PSCs) are the principal effector cells responsible for stroma production. Aberrant up-regulation of periostin expression has been reported in activated PSCs. In this study, we investigated the role of periostin and the mechanisms underlying its aberrant upregulation in PDAC. We used lentiviral shRNA and human recombinant periostin protein to down and up regulate periostin expression in vitro ...
October 27, 2017: Oncotarget
Dong Tang, Jingqiu Zhang, Zhongxu Yuan, Hongpeng Zhang, Yang Chong, Yuqin Huang, Jie Wang, Qingquan Xiong, Sen Wang, Qi Wu, Ying Tian, Yongdie Lu, Xiao Ge, Wenjing Shen, Daorong Wang
Galectin-1 has previously been shown to be strongly expressed in activated pancreatic stellate cells (PSCs) and promote the development and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms by which Galectin-1 promotes the malignant behavior of pancreatic cancer cells remain unclear. In this study, we examined the effects of Galectin-1 knockdown or overexpression in PSCs co-cultured with pancreatic cancer (PANC-1) cells. Immunohistochemical analysis showed expression of epithelial-mesenchymal transition (EMT) markers and MMP9 were positively associated with the expression of Galectin-1 in 66 human PDAC tissues...
October 17, 2017: Oncotarget
Atsushi Masamune, Naoki Yoshida, Shin Hamada, Tetsuya Takikawa, Tatsuhide Nabeshima, Tooru Shimosegawa
Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer-conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell-to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC-derived exosomes...
October 27, 2017: Biochemical and Biophysical Research Communications
Srinivasa P Pothula, Zhihong Xu, David Goldstein, Neil Merrett, Romano C Pirola, Jeremy S Wilson, Minoti V Apte
Stromal-tumor interactions in pancreatic cancer (PC) impact on treatment outcomes. Pancreatic stellate cells (PSCs) produce the collagenous stroma of PC and interact with cancer cells to facilitate 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. We studied the effects on PC progression of inhibiting the HGF/c-MET pathway in the presence and absence of a representative chemotherapeutic agent, gemcitabine...
September 29, 2017: Oncotarget
Shu Z Wiley, Krishna Sriram, Wenjing Liang, Sarah E Chang, Randall French, Thalia McCann, Jason Sicklick, Hiroshi Nishihara, Andrew M Lowy, Paul A Insel
The microenvironment of pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma (desmoplasia) generated by pancreatic cancer-associated fibroblasts (CAFs) derived from pancreatic stellate cells (PSCs) and pancreatic fibroblasts (PFs). Using an unbiased GPCRomic array approach, we identified 82 G-protein-coupled receptors (GPCRs) commonly expressed by CAFs derived from 5 primary PDAC tumors. Compared with PSCs and PFs, CAFs have increased expression of GPR68 (a proton-sensing GPCR), with the results confirmed by immunoblotting, The Cancer Genome Atlas data, and immunohistochemistry of PDAC tumors...
November 1, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Vegard Tjomsland, Monica Aasrum, Thoralf Christoffersen, Ivar P Gladhaug
The pancreatic stellate cell (PSC) is the principal cell type of the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC). PSCs interact with cancer cells and influence the progression of the disease through a complex network of signaling molecules including hepatocyte growth factor (HGF). Functional heterogeneity of PSCs within a tumor might conceivably influence tumor progression. We investigated PSC populations isolated from different human PDACs and examined the effects of PSC-conditioned medium on BxPC-3 and AsPC-1 pancreatic cancer cells...
September 22, 2017: Oncotarget
Kazuhiro Koikawa, Kenoki Ohuchida, Shin Takesue, Yohei Ando, Shin Kibe, Hiromichi Nakayama, Sho Endo, Toshiya Abe, Takashi Okumura, Kohei Horioka, Masafumi Sada, Chika Iwamoto, Taiki Moriyama, Kohei Nakata, Yoshihiro Miyasaka, Riichi Ohuchida, Tatsuya Manabe, Takao Ohtsuka, Eishi Nagai, Kazuhiro Mizumoto, Makoto Hashizume, Masafumi Nakamura
Specific cell populations leading the local invasion of cancer are called "leading cells". However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs...
January 1, 2018: Cancer Letters
Tomoki Hata, Koichi Kawamoto, Hidetoshi Eguchi, Yoshihiro Kamada, Shinji Takamatsu, Tomohiro Maekawa, Satoshi Nagaoka, Daisaku Yamada, Yoshifumi Iwagami, Tadafumi Asaoka, Takehiro Noda, Hiroshi Wada, Kunihito Gotoh, Atsushi Masamune, Eiji Miyoshi, Masaki Mori, Yuichiro Doki
OBJECTIVES: Pancreatic ductal adenocarcinoma is one of the deadliest diseases worldwide. Fatty acids (FAs) have properties that affect both cancer cells and tumor environment. We assessed the effects of FAs on malignant characteristics in a pancreatic cancer and pancreatic stellate cell (PSC) coculture model. This study aimed to clarify the FA signature of PSC-derived inflammation and fibrosis in vitro and in a clinicopathological analysis. METHODS: The in vitro model involved coculture of the human pancreatic cancer cell lines PANC-1 and MIA PaCa-2 with human PSCs...
November 2017: Pancreas
Liying Wang, Xiangrui Liu, Quan Zhou, Meihua Sui, Zipeng Lu, Zhuxian Zhou, Jianbin Tang, Yi Miao, Min Zheng, Weilin Wang, Youqing Shen
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a dismal overall prognosis mainly unchanged over the past decades. PDAC is generally refractory to conventional treatments, and thus novel therapies are urgently needed. Recently, accumulating evidence has indicated that human pancreatic stellate cells (PSCs) facilitate PDAC development and drug resistance through paracrine activation of hedgehog pathway. Here, we report that smart SN38 (active metabolite of irinotecan) polymeric prodrug-based nanoparticles effectively encapsulate the commercial hedgehog pathway inhibitor GDC-0449 for co-delivery...
August 2, 2017: Biomaterials
Tianjiao Ji, Jiayan Lang, Jing Wang, Rong Cai, Yinlong Zhang, Feifei Qi, Lijing Zhang, Xiao Zhao, Wenjing Wu, Jihui Hao, Zhihai Qin, Ying Zhao, Guangjun Nie
During pancreatic tumor development, pancreatic stellate cells (PSCs) proliferate exuberantly to secrete extracellular matrix (ECM) in the tumor stroma, which presents major barriers for drug delivery and penetration in tumor tissue. Thus, down-regulating ECM levels via regulation of the PSCs may allow enhanced penetration of therapeutic drugs and thereby enhancing their therapeutic efficacy. To regulate the PSCs, a matrix metalloproteinase-2 (MMP-2) responsive peptide-hybrid liposome (MRPL) was constructed via coassembly of a tailor-designed MMP-2 responsive amphiphilic peptide and phospholipids...
September 26, 2017: ACS Nano
Yan Wei, Yuxi Wang, Dengning Xia, Shiyan Guo, Feng Wang, Xinxin Zhang, Yong Gan
Fibrotic stroma and tumor-promoting pancreatic stellate cells (PSCs), critical characters in the pancreatic ductal adenocarcinoma (PDA) microenvironment, promote a tumor-facilitating environment that simultaneously prevents drug penetration into tumor foci and stimulates tumor growth. Nab-PTX, a human serum albumin (HSA) nanoparticle of paclitaxel (PTX), indicates enhanced matrix penetration in PDA probably due to its small size in vivo and high affinity of HSA with secreted protein acidic and rich in cysteine (SPARC), overexpressed in the PDA stroma...
July 24, 2017: ACS Applied Materials & Interfaces
Tony C Y Pang, Jeremy S Wilson, Minoti V Apte
PURPOSE OF REVIEW: Pancreatic stellate cells (PSCs) play an integral role in the pathogenesis of pancreatitis and pancreatic cancer. With the developing knowledge of this important cell type, we are at the cusp of developing effective therapies for the above diseases based upon targeting the PSC and modulating its function. RECENT FINDINGS: The major themes of the recent PSC literature include: PSC interactions with the extracellular matrix and other stromal components; intracellular calcium physiology as drivers of mechanical interactions and necrosis; the relationship between proinflammatory, protumoural, angiogenic, and metabolic pathways in pancreatic necrosis, fibrosis, and carcinogenesis; and targeting of the stroma for antitumoural and antifibrotic effects...
September 2017: Current Opinion in Gastroenterology
J V Gerasimenko, S Peng, T Tsugorka, O V Gerasimenko
In spite of significant scientific progress in recent years, acute pancreatitis (AP) is still a dangerous and in up to 5% of cases deadly disease with no specific cure. It is self-resolved in the majority of cases, but could result in chronic pancreatitis (CP) and increased risk of pancreatic cancer (PC). One of the early events in AP is premature activation of digestive pro-enzymes, including trypsinogen, inside pancreatic acinar cells (PACs) due to an excessive rise in the cytosolic Ca(2+) concentration, which is the result of Ca(2+) release from internal stores followed by Ca(2+) entry through the store operated Ca(2+) channels in the plasma membrane...
May 18, 2017: Cell Calcium
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