Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma

Qi, Weier; Tian, Ying; Zhang, Jingqiu; Zhang, Hongpeng; Gu, Fengming; Lu, Yongdie; Zou, Shengnan; Chen, Yuji; Sun, Pengxiang; Xu, Mingang; Sun, Xuemei; Xia, Chao; Chi, Hao; Zhu, A Ying; Tang, Dong; Wang, Daorong

doi:10.18632/oncotarget.21970

Cited by 44 publications

(43 citation statements)

References 154 publications

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“…Another hallmark of PDAC tumors is an extremely immunosuppressive microenvironment. Numerous studies have confirmed a major role for CAFs in generating factors, such as secreted cytokines and chemokines (Harper and Sainson, 2014;Wu et al, 2017), that contribute to this environment, as well as physically sequestering anti-tumor immune cells (Ene-Obong et al, 2013). Furthermore, compared to many other tumor types, PDAC has one of the lowest mutational burdens and display of neoantigens (Chalmers et al, 2017;Evans et al, 2016), which correlates directly with low response rates to immune checkpoint inhibitors, such as PD-1 (Yarchoan et al, 2017).…”

Section: Discussionmentioning

confidence: 98%

“…In addition to the metabolic roles, CAFs are also at the center of the immunosuppressive PDAC microenvironment (Basso et al, 2014;Clark et al, 2007;Fu et al, 2018;Harper and Sainson, 2014). CAFs exert immunosuppressive effects through direct modulation of immune cell function via cytokine secretion (Wu et al, 2017), exclusion of anti-tumor immune cells from the tumor (Ene-Obong et al, 2013), and/or recruitment of immunosuppressive immune cells to the tumor (Kumar et al, 2017). Intriguingly, recent studies have reported a functional link between metabolism and immune cell function, which has suggested that anti-tumor immune cells rely on a constant supply of nutrients to perform their functions (Buck et al, 2017;Kouidhi et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression

Francescone

Vendramini–Costa

Franco‐Barraza

et al. 2018

Preprint

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SummaryPancreatic ductal adenocarcinoma (PDAC) is a devastating disease lacking effective therapies. A major hallmark of PDAC is desmoplasia, characterized by the expansion of cancer-associated fibroblasts (CAFs) and their extracellular matrix, creating a unique microenvironment that limits blood-supplied nutrition and is highly immunosuppressive. Here, we uncovered the upregulation of NetrinG1 (NetG1) in CAFs and its binding partner NetrinG1 ligand (NGL-1) in PDAC cells and patient tissue samples. Using a three-dimensional culturing system, we observed that the NetG1/NGL-1 axis controls key pro-tumorigenic features of CAFs and PDAC cells, in cell autonomous and reciprocal manners. Results were confirmed in vivo using patient tissues and in a murine PDAC model in which NGL-1 ablation in PDAC cells significantly halted tumor growth. Thus, this study identifies two potential targets for PDAC, both tumoral and microenvironmental.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression

Francescone

Vendramini–Costa

Franco‐Barraza

et al. 2018

Preprint

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“…Activated PSCs are classified as a loss of cytoplastic lipid droplets, upregulation of MMP and ECM proteins [ 37 ], and activated PSCs acquire proliferative capacity. Additionally, activated PSCs play a vital role in the pancreatic cancer microenvironment by secreting molecules such as TGFβ, IL-6, stromal cell-derived factor-1 (SDF-1), hepatocyte growth factor (HGF) and galectin-1 to promote pancreatic cancer progression [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor microenvironment participates in metastasis of pancreatic cancer

et al. 2018

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Pancreatic cancer is a deadly disease with high mortality due to difficulties in its early diagnosis and metastasis. The tumor microenvironment induced by interactions between pancreatic epithelial/cancer cells and stromal cells is critical for pancreatic cancer progression and has been implicated in the failure of chemotherapy, radiation therapy and immunotherapy. Microenvironment formation requires interactions between pancreatic cancer cells and stromal cells. Components of the pancreatic cancer microenvironment that contribute to desmoplasia and immunosuppression are associated with poor patient prognosis. These components can facilitate desmoplasia and immunosuppression in primary and metastatic sites or can promote metastasis by stimulating angiogenesis/lymphangiogenesis, epithelial-mesenchymal transition, invasion/migration, and pre-metastatic niche formation. Some molecules participate in both microenvironment formation and metastasis. In this review, we focus on the mechanisms of pancreatic cancer microenvironment formation and discuss how the pancreatic cancer microenvironment participates in metastasis, representing a potential target for combination therapy to enhance overall survival.

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“…The study of the cellular interactions taking place between the cancer and stroma has recently emerged as an important topic in pancreatic cancer research [43][44][45]. Multiple new stromal targets of potential clinical importance in PDAC are currently being investigated [46].…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor

Amrutkar

Larsen

Aasrum

et al. 2020

Cells

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis, and its treatment remains a challenge. As the existing in vitro experimental models offer only a limited resemblance to human PDAC, there is a strong need for additional research tools to better understand PDAC tumor biology, particularly the impact of the tumor stroma. Here, we report for the first time the establishment and characterization of human PDAC-derived paired primary monolayer cultures of (epithelial) cancer cells (PCCs) and mesenchymal stellate cells (PSCs) derived from the same tumor by the outgrowth method. Characterization of cell morphology, cytostructural, and functional profiles and proteomics-based secretome analysis were performed. All PCCs harbored KRAS and TP53 mutations, and expressed cytokeratin 19, ki-67, and p53, while the expression of EpCAM and vimentin was variable. All PSCs expressed α-smooth muscle actin (α-SMA) and vimentin. PCCs showed a significantly higher growth rate and proliferation than PSCs. Secretome analysis confirmed the distinct nature of PCCs as compared to PSCs and allowed identification of potential molecular regulators of PSC-conditioned medium (PSC-CM)-induced migration of PCCs. Paired primary cultures of PCCs and PSCs derived from the same tumor specimen represent a novel experimental model for basic research in PDAC tumor biology.

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Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma

Cited by 44 publications

References 154 publications

Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression

Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression

Tumor microenvironment participates in metastasis of pancreatic cancer

Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor

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