scholarly journals Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

2017 ◽  
Vol 214 (3) ◽  
pp. 579-596 ◽  
Author(s):  
Daniel Öhlund ◽  
Abram Handly-Santana ◽  
Giulia Biffi ◽  
Ela Elyada ◽  
Ana S. Almeida ◽  
...  
Keyword(s):  
Direct Evidence ◽  
Smooth Muscle Actin ◽  
Tumor Biology ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Neoplastic Cells ◽  
Disease Etiology ◽  
Elevated Expression ◽  
Therapeutic Development ◽  
Desmoplastic Stroma

Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.

scholarly journals ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer

2019 ◽  
Vol 5 (9) ◽  
pp. eaax2770 ◽  
Author(s):  
Praneeth R. Kuninty ◽  
Ruchi Bansal ◽  
Susanna W. L. De Geus ◽  
Deby F. Mardhian ◽  
Jonas Schnittert ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Tumor Stroma ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Tumor Penetration ◽  
Desmoplastic Stroma ◽  
Integrin Α5

Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.

scholarly journals CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 86
Author(s):  
Shivani Malik ◽  
Jill M. Westcott ◽  
Rolf A. Brekken ◽  
Francis J. Burrows
Keyword(s):  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Drug ◽  
Cancer Associated Fibroblasts ◽  
Term Survival ◽  
Farnesyl Transferase ◽  
Chemokine Cxcl12 ◽  
Tumor Environment ◽  
Desmoplastic Stroma ◽  
Activated Fibroblasts

Pancreatic ductal adenocarcinoma (PDAC) is a disease with limited therapeutic options and dismal long-term survival. The unique tumor environment of PDAC, consisting of desmoplastic stroma, immune suppressive cells, and activated fibroblasts, contributes to its resistance to therapy. Activated fibroblasts (cancer-associated fibroblasts and pancreatic stellate cells) secrete chemokines and growth factors that support PDAC growth, spread, chemoresistance, and immune evasion. In this review, we focus on one such chemokine, CXCL12, secreted by the cancer-associated fibroblasts and discuss its contribution to several of the classical hallmarks of PDAC and other tumors. We review the various therapeutic approaches in development to target CXCL12 signaling in PDAC. Finally, we propose an unconventional use of tipifarnib, a farnesyl transferase inhibitor, to inhibit CXCL12 production in PDAC.

The prognostic value of stroma desmoplasia in pancreatic ductal adenocarcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 211-211
Author(s):  
Emmanouil Fokas ◽  
Michael A Silva ◽  
Zenobia D'Costa ◽  
Robin Bockelmann ◽  
Zahir Soonawalla ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Adjuvant Chemotherapy ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Prognostic Value ◽  
Smooth Muscle Actin ◽  
Progression Free Survival ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Free Survival ◽  
Local Progression

211 Background: Pancreatic ductal adenocarcinoma (PDAC) often presents an abundant desmoplastic stroma. We assessed the prognostic value of stroma density and activity in patients with resectable PDAC treated with surgery and adjuvant gemcitabine-based chemotherapy. Methods: FFPE-tissue originating from the pancreatectomy of 145 patients was immunohistochemicallystained for haematoxylin-eosin and Masson’s trichrome to assess stroma density, and alpha-smooth muscle actin (αSMA) expression for activated pancreatic stellate cells. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS). Results: After a mean follow-up of 20 months (range, 2-69 months), the median OS was 21 months and the 3-year OS was 35.7 %. In multivariate analysis, highly-dense stroma was an independent prognostic parameter for OS (p = 0.001), PFS (p = 0.007), LPFS (p = 0.001) and DMFS (p = 0.002), while αSMA expression lacked significance. Interestingly, highly-dense stroma retained significance for the four clinical endpoints only in early (pT1-2) but not late (pT3-4) stage tumors. Additionally, late pT-stage (pT3-4), the presence of lymph node metastases (pN+ vs pN0), perineural/neural invasion PNI and adjuvant chemotherapy also correlated with prognosis in multivariate analysis. Conclusions: In summary, stroma density represents an independent prognostic marker in PDAC patients treated with adjuvant chemotherapy. Our findings highlight the complexity of desmoplasia and indicate that highly-dense stroma is associated with better outcome. Further validation of the prognostic value of stroma as a biomarker and its role in PDAC biology is warranted and will be performed in a prospective study.

scholarly journals Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Michelle R. Goulart ◽  
Jennifer Watt ◽  
Imran Siddiqui ◽  
Rita T. Lawlor ◽  
Ahmet Imrali ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ex Vivo ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Biomarkers ◽  
All Trans Retinoic Acid ◽  
Desmoplastic Stroma ◽  
Predictive Role

AbstractPancreatic ductal adenocarcinoma (PDAC), characterized by dense desmoplastic stroma laid down by pancreatic stellate cells (PSC), has no reliable diagnostic biomarkers for timely detection. A multi-center cohort of PDAC patients and controls (chronic pancreatitis, intra-ductal papillary neoplasms, gallstones and otherwise healthy) donated serum in an ethically approved manner. Serum PTX3 above 4.34 ng/mL has a higher sensitivity (86%, 95% confidence interval (CI): 65–97%) and specificity (86%, 95% CI: 79–91%), positive predictive value (97%) and likelihood ratio (6.05), and is superior when compared to serum CA19-9 and CEA for detection of PDAC. In vitro and ex vivo analyses of PTX3, in human PDAC samples, PSCs, cell lines and transgenic mouse model for PDAC, suggest that PTX3 originates from stromal cells, mainly PSC. In activated PSC, PTX3 secretion could be downregulated by rendering PSC quiescent using all-trans-retinoic acid (ATRA). PTX3 organizes hyaluronan in conjunction with tumor necrosis factor-stimulated gene 6 (TSG-6) and facilitates stellate and cancer cell invasion. In SCALOP clinical trial (ISRCTN96169987) testing chemo-radiotherapy without stromal targeting, PTX3 had no prognostic or predictive role. However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.

scholarly journals Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours

Gut ◽  
2021 ◽  
pp. gutjnl-2021-325180
Author(s):  
Hsi-Chien Huang ◽  
Yun-Chieh Sung ◽  
Chung-Pin Li ◽  
Dehui Wan ◽  
Po-Han Chao ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Phage Display ◽  
Tumour Microenvironment ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Tumour Stroma ◽  
Desmoplastic Stroma ◽  
Trail Resistance

ObjectiveStromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC.DesignNitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an in vitro–in vivo combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures in vitro and in orthotopic PDAC models in vivo.ResultsThe delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy.ConclusionThe co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.

scholarly journals IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer

Gut ◽  
2016 ◽  
Vol 67 (2) ◽  
pp. 320-332 ◽  
Author(s):  
Thomas A Mace ◽  
Reena Shakya ◽  
Jason R Pitarresi ◽  
Benjamin Swanson ◽  
Christopher W McQuinn ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Checkpoint Inhibitors ◽  
Tumour Progression ◽  
Antitumour Activity ◽  
Smooth Muscle Actin ◽  
Immunohistochemical Analysis ◽  
Genetically Engineered ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma

ObjectiveLimited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy.DesignTranscription profiles and IL-6 secretion from primary patient-derived pancreatic stellate cells (PSCs) were analyzed via Nanostring and immunohistochemistry, respectively. In vivo efficacy and mechanistic studies were conducted with antibodies (Abs) targeting IL-6, PD-L1, CD4 or CD8 in subcutaneous or orthotopic models using Panc02, MT5 or KPC-luc cell lines; and the aggressive, genetically engineered PDAC model (KrasLSL−G12D, Trp53LSL−R270H, Pdx1-cre, Brca2F/F (KPC-Brca2 mice)). Systemic and local changes in immunophenotype were measured by flow cytometry or immunohistochemical analysis.ResultsPSCs (n=12) demonstrated prominent IL-6 expression, which was localised to stroma of tumours. Combined IL-6 and PD-L1 blockade elicited efficacy in mice bearing subcutaneous MT5 (p<0.02) and Panc02 tumours (p=0.046), which was accompanied by increased intratumoural effector T lymphocytes (CD62L−CD44−). CD8-depleting but not CD4-depleting Abs abrogated the efficacy of combined IL-6 and PD-L1 blockade in mice bearing Panc02 tumours (p=0.0016). This treatment combination also elicited significant antitumour activity in mice bearing orthotopic KPC-luc tumours and limited tumour progression in KPC-Brca2 mice (p<0.001). Histological analysis revealed increased T-cell infiltration and reduced α-smooth muscle actin cells in tumours from multiple models. Finally, IL-6 and PD-L1 blockade increased overall survival in KPC-Brca2 mice compared with isotype controls (p=0.0012).ConclusionsThese preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.

α-Smooth Muscle Actin Expressing Stroma Promotes an Aggressive Tumor Biology in Pancreatic Ductal Adenocarcinoma

Pancreas ◽  
2010 ◽  
Vol 39 (8) ◽  
pp. 1254-1262 ◽  
Author(s):  
Hayato Fujita ◽  
Kenoki Ohuchida ◽  
Kazuhiro Mizumoto ◽  
Kohei Nakata ◽  
Jun Yu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Smooth Muscle Actin ◽  
Tumor Biology ◽  
Ductal Adenocarcinoma ◽  
Muscle Actin ◽  
Aggressive Tumor

scholarly journals Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 847
Author(s):  
Edward P. Carter ◽  
Abigail S. Coetzee ◽  
Elena Tomas Bort ◽  
Qiaoying Wang ◽  
Hemant M. Kocher ◽  
...  
Keyword(s):  
Critical Role ◽  
Growth Factor Receptor ◽  
Tumour Microenvironment ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Approaches ◽  
Desmoplastic Stroma ◽  
Fgf Signalling ◽  
Late Detection ◽  
Proliferation And Invasion

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5 year survival rate of less than 8%, and is predicted to become the second leading cause of cancer-related death by 2030. Alongside late detection, which impacts upon surgical treatment, PDAC tumours are challenging to treat due to their desmoplastic stroma and hypovascular nature, which limits the effectiveness of chemotherapy and radiotherapy. Pancreatic stellate cells (PSCs), which form a key part of this stroma, become activated in response to tumour development, entering into cross-talk with cancer cells to induce tumour cell proliferation and invasion, leading to metastatic spread. We and others have shown that Fibroblast Growth Factor Receptor (FGFR) signalling can play a critical role in the interactions between PDAC cells and the tumour microenvironment, but it is clear that the FGFR signalling pathway is not acting in isolation. Here we describe our current understanding of the mechanisms by which FGFR signalling contributes to PDAC progression, focusing on its interaction with other pathways in signalling networks and discussing the therapeutic approaches that are being developed to try and improve prognosis for this terrible disease.

scholarly journals Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Xuexiang Han ◽  
Yiye Li ◽  
Ying Xu ◽  
Xiao Zhao ◽  
Yinlong Zhang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Stromal Cells ◽  
Stellate Cells ◽  
Tumour Microenvironment ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Combination Strategy ◽  
Therapeutic Modalities ◽  
Wide Range ◽  
Desmoplastic Stroma

AbstractPancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.

scholarly journals Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 901
Author(s):  
Ramiz S. Ahmad ◽  
Timothy D. Eubank ◽  
Slawomir Lukomski ◽  
Brian A. Boone
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cellular Mechanisms ◽  
Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

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