Targeted destruction of the orchestration of the pancreatic stroma and tumor cells in pancreatic cancer cases: Molecular basis for therapeutic implications

Kong, Xiangyu; Li, Lei; Li, Zhao‐Shen; Xie, Keping

doi:10.1016/j.cytogfr.2012.06.006

Cited by 38 publications

(41 citation statements)

References 142 publications

(135 reference statements)

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“…A key histopathological feature of PDAC that is associated with its innate clinical and biological aggressiveness is its pronounced desmoplastic (stromal) reaction, which is now considered a potential therapeutic target in PDAC 44 . Stroma production is stimulated by cancer-cell derived growth factors including transforming growth factor- β (TGF β ), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), insulin-like growth factor 1 (IGF-1) and epidermal growth factor (EGF) 45 .The desmoplastic reaction is composed of ECM proteins, primarily type I and III collagen, fibronectin and proteoglycans; small endothelium lined vessels; and a diverse population of cells including inflammatory cells, fibroblasts and stellate cells 46 .…”

Section: Discussionmentioning

confidence: 99%

Generation of an in vitro 3D PDAC stroma rich spheroid model

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic/stromal reaction, which contributes to the poor clinical outcome of this disease. Therefore, greater understanding of the stroma development and tumor-stroma interactions is highly required. Pancreatic stellate cells (PSC) are myofibroblast-like cells that located in exocrine areas of the pancreas, which as a result of inflammation produced by PDAC migrate and accumulate in the tumor mass, secreting extracellular matrix components and producing the dense PDAC stroma. Currently, only a few orthotopic or ectopic animal tumor models, where PDAC cells are injected into the pancreas or subcutaneous tissue layer, or genetically engineered animals offer tumors that encompass some stromal component. Herein, we report generation of a simple 3D PDAC in vitro micro-tumor model without an addition of external extracellular matrix, which encompasses a rich, dense and active stromal compartment. We have achieved this in vitro model by incorporating PSCs into 3D PDAC cell culture using a modified hanging drop method. It is now known that PSCs are the principal source of fibrosis in the stroma and interact closely with cancer cells to create a tumor facilitatory environment that stimulates local and distant tumor growth. The 3D micro-stroma models are highly reproducible with excellent uniformity, which can be used for PDAC-stroma interaction analysis and high throughput automated drug-screening assays. Additionally, the increased expression of collagenous regions means that molecular based perfusion and cytostaticity of gemcitabine is decreased in our Pancreatic adenocarcinoma stroma spheroids (PDAC-SS) model when compared to spheroids grown without PSCs. We believe this model will allow an improved knowledge of PDAC biology and has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in PDAC and interrupting PSCPDAC cell interactions so as to inhibit cancer progression.

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Section: Discussionmentioning

confidence: 99%

Generation of an in vitro 3D PDAC stroma rich spheroid model

et al. 2016

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“…The in vitro cytotoxic effects of DSF on ha-PSCs and HapT1 cancer cells were ROS-dependent and -independent, respectively (Figures 5D and 5E). The origin of cancer-associated fibroblast cells (CAFs) is potentially from different sources and constitutes a heterogeneous population [6]. Therefore, to rule out the possibility that DSF is ineffective against cancer-associated fibroblast cells, we isolated these cells from HapT1 orthotopic tumor tissues and treated them with DSF or DSF+Cu (Supplementary Figure S6).…”

Section: Discussionmentioning

confidence: 99%

“…Although PSCs remain quiescent normally, it has been shown that pancreatic cancer cells (PCCs) activate PSCs in a paracrine fashion and as a result PSCs differentiate into α-SMA positive myofibroblast-like cells that produce high amounts of extracellular matrix (ECM) proteins, particularly collgen-I and fibronectin [5]. The crosstalk between PCCs and PSCs has been associated with tumor progression and metastasis [6]. Desmoplasia in PDAC contributes to chemoresistance which in turn results in poor prognosis [3].…”

Section: Introductionmentioning

confidence: 99%

Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia

Suklabaidya

Das

Ali³

et al. 2016

Oncotarget

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Desmoplasia in human pancreatic cancer (PC) promotes cancer progression and hinders effective drug delivery. The objectives of this study were to characterize a homologous orthotopic model of PC in Syrian golden hamster and investigate the effect of anti-fibrotic (pirfenidone), antioxidant (N-acetyl cysteine, NAC) and anti-addiction (disulfiram, DSF) drugs on desmoplasia and tumor growth in this model. The HapT1 PC cells when implanted orthotopically into hamsters formed tumors with morphological, cellular and molecular similarities to human PC. Protein profiling of activated hamster pancreatic stellate cells (ha-PSCs) revealed expression of proteins involved in fibrosis, cancer cells growth and metastasis. Pirfenidone, suppressed growth of HapT1 cells and the desmoplastic response in vivo; these effects were enhanced by co-administration of NAC. Disulfiram alone or in combination with copper (Cu) was toxic to HapT1 cells and PSCs in vitro; but co-administration of DSF and Cu accelerated growth of HapT1 cells in vivo. Moreover, DSF had no effect on tumor-associated desmoplasia. Overall, this study identifies HapT1-derived orthotopic tumors as a useful model to study desmoplasia and tumor-directed therapeutics in PC. Pirfenidone in combination with NAC could be a novel combination therapy for PC and warrants investigation in human subjects.

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“…Экспрессия поверхностного FGFR3 в эпителиальных тканях и его активация соответствующими лигандами, в основном FGF2 и FGF9, ассоциирована с активацией сигнального пути STAT1, подавлением деления и, в некоторых случаях, с инициацией апоптоза. Поэтому активация сигнального пути FGFR3 блокирует рост опухолей, происходящих из эпителиальных и эпителио-подобных клеток [5,41]. Рост таких опухолей происходит или при подавлении FGFR3, или при потере гетерозиготности по локусу 4p16.3.…”

Section: Fgfr3unclassified

“…К характерным особенностям опухолей поджелудочной железы относится образование опухолевой стромы (микроокружение опухоли, МО), окружающей раковые клетки. Опухолевая строма PDAC -неоднородное фиброзное формирование, включающее белки внеклеточного матрикса (ВКМ), активированные фибробласты, стеллатные клетки, лимфоциты, эндотелиальные клетки, перициты и нервные волокна [5,6].…”

Section: Introductionunclassified

Role of fibroblast growth factors in pancreatic cancer

Gnatenko

Копанцев

2016

BIOMED KHIM

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Факторы роста фибробластов (FGF) -сигнальные молекулы c широким спектром действия, вовлечённые во многие клеточные процессы. FGF играют важную роль не только в органогенезе, но и в канцерогенезе поджелудочной железы. Они относятся к тем факторам, посредством которых происходит потенцирующее взаимодействие между опухолью и окружающей её стромой -ключевым компонентом развития рака поджелудочной железы. Нарушения сигнального пути FGF/FGFR -комплексный процесс, в котором важную роль играют тип и изоформа рецепторов, регулирующих ремоделирующий эффект FGF и последующую активацию данными факторами пролиферации клеток рака поджелудочной железы. Факторы FGF и их рецепторы рассматриваются как потенциальные специфические маркеры и возможные мишени для терапии рака поджелудочной железы.Ключевые слова: ростовые факторы, рак, поджелудочная железа, мастер-гены

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Targeted destruction of the orchestration of the pancreatic stroma and tumor cells in pancreatic cancer cases: Molecular basis for therapeutic implications

Cited by 38 publications

References 142 publications

Generation of an in vitro 3D PDAC stroma rich spheroid model

Generation of an in vitro 3D PDAC stroma rich spheroid model

Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia

Role of fibroblast growth factors in pancreatic cancer

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