Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival

Özdemir, Berna C.; Pentcheva-Hoang, Tsvetelina; Carstens, Julienne L.; Zheng, Xiaofeng; Wu, Chia Chin; Simpson, Tyler R.; Laklai, Hanane; Sugimoto, Hikaru; Kahlert, Christoph; Novitskiy, Sergey V.; Jesus-Acosta, Ana De; Sharma, Padmanee; Heidari, Pedram; Mahmood, Umar; Chin, Lynda; Moses, Harold L.; Weaver, Valerie M.; Maitra, Anirban; Allison, James P.; LeBleu, Valerie S.; Kalluri, Raghu

doi:10.1016/j.ccell.2015.11.002

Cited by 277 publications

(254 citation statements)

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“…Our results demonstrate that CYR61 promotes resistance to gemcitabine predominantly by modulating the levels of the nucleoside transporters that mediate cellular uptake of gemcitabine. The role of the stroma in therapy resistance is an emerging area of interest in PDAC with recent genetic mouse models and clinical trials that target PSCs having conflicting results, with both positive and negative effects on cancer progression and response to gemcitabine (49)(50)(51)(52). Understanding what aspects of PSCs promote therapy resistance and identifying signaling mechanisms that regulate this are important to effectively target the stroma.…”

Section: Discussionmentioning

confidence: 99%

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

Hesler¹,

Huang²,

Starr³

et al. 2016

CARCIN

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61. We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.

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Section: Discussionmentioning

confidence: 99%

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

Hesler¹,

Huang²,

Starr³

et al. 2016

CARCIN

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“…However, none of the efforts targeting stromal components and pathways have yet led to effective therapies in patients, reducing the impact of tests in GEMMs models. This might be at least partially explained by two recent studies revealing that depletion of stromal cells can prompt a more biologically aggressive form of PDAC with poorly differentiated histology, increased vascularity and proliferation, while depletion of carcinoma-associated fibroblasts induces immunosuppression, associated to epithelial-to-mesenchymal transition [23][24][25] . Most recently, Hidalgo and collaborators used "avatar" models as an in vivo platform to test treatment strategies suggested by parallel whole-exome sequencing analysis of 25 patients with advanced solid tumors, including seven PDAC patients 22 .…”

Section: Discussionmentioning

confidence: 99%

Development of bioluminescent chick chorioallantoic membrane (CAM) models from primary pancreatic cancer cells: A platform for drug testing

León

Rovithi

Avan³

et al. 2017

Pancreatology

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The aim of the present study was to develop chick-embryo chorioallantoic membrane (CAM) bioluminescent tumor models employing low passage cell cultures obtained from primary pancreatic ductal adenocarcinoma (PDAC) cells. Primary PDAC cells transduced with lentivirus expressingFirefly-luciferase (Fluc) were established and inoculated onto the CAM membrane, with >80% engraftment. Fluc signal reliably correlated with tumor growth. Tumor features were evaluated by immunohistochemistry and genetic analyses, including analysis of mutations and mRNA expression of PDAC pivotal genes, as well as microRNA (miRNA) profiling. These studies showed that CAM tumors had histopathological and genetic characteristic comparable to the original tumors. We subsequently tested the modulation of key miRNAs and the activity of gemcitabine and crizotinib on CAM tumors, showing that combination treatment resulted in 63% inhibition of tumor growth as compared to control (p < 0.01). These results were associated with reduced expression of miR-21 and increased expression of miR-155. Our study provides the first evidence that transduced primary PDAC cells can form tumors on the CAM, retaining several histopathological and (epi)genetic characteristics of original tumors. Moreover, our results support the use of these models for drug testing, providing insights on molecular mechanisms underlying antitumor activity of new drugs/combinations.With less than 7% of patients alive five years after diagnosis, pancreatic ductal adenocarcinoma (PDAC) exhibits one of the poorest prognoses of all solid tumors. Despite extensive clinical efforts, the outcome of this malignancy has not improved in the last decade, and PDAC is expected to become the second deadliest cancer, after lung cancer, by 2030 1,2 .Gaining more insight into the mechanisms that delineate tumor progression in PDAC could ultimately provide more successful therapeutic approaches. To this end, genetically engineered mouse models (GEMMs) have provided a powerful tool, developing tumors that recapitulate both the underlying biology and the dense desmoplastic reaction of PDACs. This stromal reaction has been considered for years as one of the mediators of resistance to chemotherapy 3 . However, experimental and clinical evidence demonstrated that anti-stromal approaches may favour PDAC aggressiveness, reinforcing the need to critically revisit the complexity of cancer-stroma interactions for translational and pharmacological implications 4 . Recent studies suggested that early passages of primary PDAC cells and "avatar" mice can mimic the genetic diversity that characterizes the human disease and might be better predictors of drug activity, including the standard treatment with gemcitabine 5,6 .Despite several studies used such in vivo models in order to promote drug development and selection, their costs and complexity impaired the translation of these results in the clinical setting. Novel, cost-effective models that similarly mimic tumor biology and provide faster information on the activ...

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Section: Strategies To Improve Drug Deliverymentioning

confidence: 99%

“…Similarly, pharmacologic depletion of CAFs has shown to reduce intratumoral stresses, improving perfusion, drug delivery and overall survival in pancreatic and breast tumor models [19,20]. However, genetic deletion of CAFs might enhance tumor progression [21,22].The vascular normalization strategy on the other hand, which has been used in the clinic during the last 10 years [9,23], is based on the notion that the tumor vasculature needs to be brought closer to a more "normal" state to be functional. Vascular normalization is achieved with judicious doses of anti-angiogenic drugs, targeting mainly Vascular Endothelial Growth Factor (VEGF) or its receptors.…”

mentioning

confidence: 99%

Targeting Inflammation to Improve Tumor Drug Delivery

2017

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Inefficient delivery of drugs is a main cause of chemotherapy failure in hypo-perfused tumors. To enhance perfusion and drug delivery in these tumors, two strategies have been developed: vascular normalization, aiming at normalizing tumor vasculature and blood vessel leakiness; and stress alleviation, aiming at decompressing tumor vessels. Vascular normalization is based on antiangiogenic drugs, whereas stress alleviation on stroma-depleting agents. Here, an alternatively approach to normalize vessels is presented, considering that malignant tumors tend to develop at chronic inflammation sites. Similarly to tumor vessel leakiness, inflammation is also characterized by vascular hyper-permeability. Therefore, testing the ability of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs or inflammation resolution mediators, as an alternative way to increase tumor drug delivery, might prove promising.Keywords stress alleviation; vascular normalization; tumor perfusion; anti-inflammatory agents; inflammation resolution The Tumor microenvironment and drug deliveryTumors are complex tissues consisting of cancer cells and their microenvironment [1,2], which includes structural and cellular components. Structural components of the tumor microenvironment comprise tumor blood and lymphatic vessels, and the extracellular matrix (ECM) (see Glossary); while the stromal cell constituents [3] include angiogenic vascular cells (endothelial cells and pericytes), infiltrating immune cells, and cancer-associated fibroblasts (CAFs). Naturally, interactions between cancer cells and the various components of tumor microenvironment affect fundamental cancer cell properties such as proliferation, apoptosis, migration and invasion.It has been postulated that components and features of the tumor microenvironment may also set certain barriers with regard to the effective delivery of therapeutic agents, resulting in compromised therapeutic outcomes and decreased survival [4]. Chemotherapeutic drugs are, without a doubt, potent cytotoxic agents. However, they often fail to cure cancer due to the fact that they are unable to reach cancer cells within the tumor in sufficient amounts [5,6]. Hence, the discovery of more efficient approaches to enhance tumor drug delivery is imperative. Here, the main obstacles in drug delivery to the tumor are presented along with the approaches currently used to overcome them. Furthermore, the use of anti-inflammatory agents is proposed as a promising alternative approach to normalize vessels and improve therapy. Europe PMC Funders Group Causes of insufficient drug delivery to tumorsInefficient drug delivery may arise due to barriers posed by abnormal structure and function of tumor stroma, known as desmoplasia. Desmoplastic tumors are characterized by a dense ECM, containing increased levels of total fibrillar collagen, hyaluronan, fibronectin, proteoglycans and tenascin C [4], which also provides the tumor with a reservoir of growth factors eventually promoting its growth. The dense ...

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Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival

Cited by 277 publications

References 0 publications

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

Development of bioluminescent chick chorioallantoic membrane (CAM) models from primary pancreatic cancer cells: A platform for drug testing

Targeting Inflammation to Improve Tumor Drug Delivery

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