The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities

Ho, Won Jin; Jaffee, Elizabeth M.; Li, Zheng

doi:10.1038/s41571-020-0363-5

Cited by 766 publications

(674 citation statements)

References 175 publications

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“…The ensuing hypoxic and nutrient-poor tumor microenvironment (TME) also serves as a cradle for highly resilient PDAC cells that are metabolically adapted to this inhospitable environment. 2 , 3 In addition, CAFs secrete various chemokines and cytokines that enhance tumor progression and therapeutic resistance. A critical pathophysiological process that associates PDAC cells with these feats is epithelial-mesenchymal transition (EMT).…”

Section: Introductionmentioning

confidence: 99%

“…Several excellent reviews were published in recent years on the underlying signaling mechanisms and role of EMT in cancer, 5 – 7 , 9 – 12 as well as the pathogenic role of stroma in PDAC. 2 , 3 , 13 However, a dedicated review on how stroma promotes EMT in PDAC is lacking. In this study we critically reviewed seminal and recent literature and provided a focused review on signaling mechanisms by which distinct elements of stroma, namely CAFs, ECM and hypoxia, promote EMT of PDAC cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bulle

Lim

2020

Sig Transduct Target Ther

122

123

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Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutics that target the driver mutations, especially the KRAS oncoprotein and its effector cascades, have been ineffective. It is increasing clear that the extensive fibro-inflammatory stroma (or desmoplasia) of PDAC plays an active role in the progression and therapeutic resistance of PDAC. The desmoplastic stroma is composed of dense extracellular matrix (ECM) deposited mainly by the cancer-associated-fibroblasts (CAFs) and infiltrated with various types of immune cells. The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells. In addition, mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms, particularly engagement of the epithelial-mesenchymal transition (EMT) program. Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapy-induced apoptosis. Here, we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC. We discussed the experimental models that are currently employed and best suited to study EMT in PDAC, which are instrumental in increasing the chance of successful clinical translation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bulle

Lim

2020

Sig Transduct Target Ther

122

123

View full text Add to dashboard Cite

show abstract

“…The PDAC tumor also exploits existing immune cells to promote an immunosuppresive environment [ 100 ]. The PDAC tumor microenvironment is typically infiltrated by suppressive immune cells such as regulatory T cells (T reg ), myeloid-derived suppressor cells (MDSCs), N2 neutrophils, and tumor-associated macrophages (TAMs) rather than anti-tumor promoting immune cells [ 98 , 101 ]. CD8 + T cells, natural killer (NK) cells, and dendritic cells, in contrast, are typically exhausted as the tumor progresses and are unable to exert anti-tumorigenic effects that they may been able to exert during early progression of PDAC [ 98 ].…”

Section: The Tumor Microenvironment and The Regulation Of Pdac Invmentioning

confidence: 99%

Pancreatic Adenocarcinoma Invasiveness and the Tumor Microenvironment: From Biology to Clinical Trials

et al. 2020

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Pancreatic adenocarcinoma (PDAC) originates in the glandular compartment of the exocrine pancreas. Histologically, PDAC tumors are characterized by a parenchyma that is embedded in a particularly prominent stromal component or desmoplastic stroma. The unique characteristics of the desmoplastic stroma shape the microenvironment of PDAC and modulate the reciprocal interactions between cancer and stromal cells in ways that have profound effects in the pathophysiology and treatment of this disease. Here, we review some of the most recent findings regarding the regulation of PDAC cell invasion by the unique microenvironment of this tumor, and how new knowledge is being translated into novel therapeutic approaches.

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“…cells, including B lymphocytes, T lymphocytes, neutrophils, macrophages, dendritic cells, and other immune cells that infiltrate tumor tissues (7,8). Previous studies have shown that the tumor microenvironment of pancreatic cancer is extremely complex (12,13). Tang et al (14) have reported that the level of CD8 + T lymphocyte infiltration in pancreatic tumor tissues is lower compared with that in adjacent normal tissues.…”

Section: Cxcl5 Expression In Tumor Tissues Is Associated With Poor Prmentioning

confidence: 99%

CXCL5 expression in tumor tissues is associated with poor prognosis in patients with pancreatic cancer

Wang

et al. 2020

Oncol Lett

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Immunotherapy based on the tumor microenvironment is a feasible method for treating cancer; therefore, it is necessary to investigate the immune microenvironment of pancreatic cancer and the influencing factors of the immune microenvironment. Chemokines are an important factor affecting the tumor immune microenvironment. In the present study, chemokines or chemokine receptors were screened to identify those differentially expressed in pancreatic cancer compared with normal controls and associated with patient prognosis. Chemokines or chemokine receptors that are differentially expressed in pancreatic cancer tumor tissues were initially screened using the Gene Expression Omnibus database. Next, survival analysis was performed using GEPIA, a website based on The Cancer Genome Atlas (TCGA) database. Immunohistochemical staining of CXCL5 was performed in tissue microarrays (TMAs) containing 119 cases of pancreatic cancer. Histochemistry score (H-SCORE) was used to evaluate the expression of CXCL5. Next, association analysis of the H-SCORE of CXCL5 and the clinical characteristics of patients was performed, as well as Kaplan-Meier survival and Cox multivariate regression analyses. The results of the bioinformatics analysis demonstrated that CXCL5 was highly expressed in pancreatic cancer tissues. High expression of CXCL5 in pancreatic cancer tissues was associated with a poor prognosis in patients in TCGA cohort. The expression level of CXCL5 in tumor tissues was significantly higher compared with that in adjacent peritumoral normal tissues in the immunohistochemical analysis. There was no significant association between CXCL5 expression in pancreatic cancer tumor tissues and clinicopathological factors. Patients with pancreatic cancer with high CXCL5 expression had a poor prognosis, as determined by Kaplan-Meier survival analysis based on the TMA dataset. The results of Cox multivariate regression analysis showed that CXCL5 was an independent factor for a poor prognosis in patients with pancreatic cancer. In conclusion, the results of the present study revealed that the chemokine CXCL5 was highly expressed in pancreatic cancer tissues; high CXCL5 expression was associated with a poor prognosis in patients with pancreatic cancer.

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The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities

Cited by 766 publications

References 175 publications

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Pancreatic Adenocarcinoma Invasiveness and the Tumor Microenvironment: From Biology to Clinical Trials

CXCL5 expression in tumor tissues is associated with poor prognosis in patients with pancreatic cancer

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