scholarly journals Clinical Scenarios Emerging from Combined Immunophenotypic, Molecular and Morphologic Analysis of Pancreatic Cancer: the Good, the Bad and the Ugly Scenario

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 968 ◽  
Author(s):  
Karamitopoulou ◽  
Gloor
Keyword(s):  
Pancreatic Cancer ◽  
Immune Cell ◽  
Ductal Adenocarcinoma ◽  
Significant Heterogeneity ◽  
Dismal Prognosis ◽  
Clinical Scenarios ◽  
Novel Biomarkers ◽  
Morphologic Analysis ◽  
Dynamic Interplay ◽  
Immune Cell Infiltrates

: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with increasing incidence and dismal prognosis. The composition of the immune cell infiltrates in the tumor microenvironment (TME) and the dynamic interplay between cancer- and immune cells can influence and/or be influenced by tumor-intrinsic characteristics like molecular profiles and tumor cell morphology. The combined analyses of pancreatic cancer by using morphologic, genetic, and immunologic features help us understand the significant heterogeneity of the TME and recognize the different mechanisms of immune evasion. Moreover, this information may lead to the identification of novel biomarkers for more precise patient stratification and therapy guidance.

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.

scholarly journals CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response

2020 ◽  
Vol 117 (46) ◽  
pp. 28960-28970 ◽  
Author(s):  
Daniele Biasci ◽  
Martin Smoragiewicz ◽  
Claire M. Connell ◽  
Zhikai Wang ◽  
Ya Gao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Response ◽  
T Cell ◽  
Chemokine Receptors ◽  
Immune Cell ◽  
Antibody Therapy ◽  
Transcriptional Analysis ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Colorectal Cancers

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.

scholarly journals The Tumor Microenvironment of Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3076
Author(s):  
Eva Karamitopoulou
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Incidence Rates ◽  
Ductal Adenocarcinoma ◽  
Dismal Prognosis ◽  
The Future ◽  
Rising Incidence

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis along with rising incidence rates and will be responsible for many cancer deaths in the future [...]

scholarly journals Prognostic Significance and Immune Infiltration of Microenvironment‐related Signatures in Pancreatic Cancer

2020 ◽  
Author(s):  
Qian Lu ◽  
Yu Zhang ◽  
Weihong Gu ◽  
Xinrong Ji ◽  
Zhong Chen
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Immune Cell ◽  
Differential Expression Analysis ◽  
Prognostic Significance ◽  
Ductal Adenocarcinoma ◽  
Immune Infiltration ◽  
Protein Protein Interaction ◽  
Tumor Tissues ◽  
Cox Analysis

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal and most aggressive types of malignancies and accounts for the vast majority of Pancreatic Cancer (PC). Numerous studies have reported that the tumor microenvironment (TME) was significantly correlated with the oncogenesis, progress, and prognosis of various malignancies. Therefore, mining of TME-related genes is reasonably important to improve the overall survival (OS) of patients with PDAC. Methods: The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm was applied to identify differential expressed genes (DEGs). Functional and pathway enrichment analyses, protein–protein interaction (PPI) network construction and module analysis, overall survival analysis and tumor immune estimation resource (TIMER) database analysis were then performed on DEGs. Results: Data analysis indicated that higher immune scores were correlated with better overall survival (P = 0.033). Differential expression analysis obtained 90 intersection genes influencing both stromal and immune scores. Among these intersection genes, CA9, EBI3, SPOCK2, WDFY4, CD1D and CCL22 were significantly correlated with OS in PDAC patients. Moreover, multivariate Cox analysis revealed that CA9, SPOCK2 and CD1D were the most significant prognostic genes, and were closely correlated with immune infiltration in TCGA cohort. Further analysis indicated that CD1D were significantly related with immune cell biomarkers for PDAC patients. Conclusions: In summary, our findings provide a more comprehensive insight into TME and show a list of prognostic immune associated genes in PDAC. However, further studies on these genes need to be performed to gain additional understanding of the association between TME and prognosis in PDAC.

Pancreatic cancer survival trends overall, by stage, and histologic sub-type: An analysis of Surveillance, Epidemiology and End Results (SEER) population-based data (2000-2015).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15772-e15772 ◽  
Author(s):  
Parisa Karimi ◽  
Vanessa L Gordon-Dseagu ◽  
Pavel Chernyavskiy ◽  
Michael Goggins ◽  
Philip S. Rosenberg ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Metastatic Disease ◽  
Cancer Survival ◽  
Comprehensive Evaluation ◽  
Credible Interval ◽  
The United States ◽  
Population Based ◽  
Ductal Adenocarcinoma ◽  
Significant Heterogeneity ◽  
Not Otherwise Specified

e15772 Background: Pancreatic cancer (PC) is the third leading cause of cancer mortality in the United States, with an overall relative 5-year survival rate of 8.2%. We conducted a comprehensive evaluation of survival trends after PC diagnosis overall and by stage and histologic sub-type. Methods: We conducted a retrospective, population-based study of 91,234 PC cases using nationally representative data from the SEER program to evaluate 5-year survival trends by histologic sub-type from 2000 to 2015. Our model incorporated sub-type-specific random intercepts to effectively stabilize survival estimates by borrowing information across all sub-types. The estimation was performed in a fully Bayesian setting in R. Results: Adenocarcinoma, not otherwise specified (NOS) and ductal adenocarcinomas comprised 81% of PC. Cancer stage and histologic sub-type were both important factors in explaining variability in 5-year survival. We observed a consistent ordering of cancer stages within each histologic sub-type from highest to lowest survival for local, regional, and metastatic disease, respectively. Adenocarcinoma not otherwise specified, ductal adenocarcinoma, ductal specified as mucinous, and poorly specified type had the lowest 5-year survival with fitted ranges of 25-35% for localized, 5-19% for regional and < 4% for metastatic disease. Ductal arising from intraductal papillary mucinous neoplasm, ductal specified as cystic, acinar cell, other adenocarcinoma, and non-carcinomas had intermediate 5-year survival of 54-75%; while endocrine non-secretory or neuroendocrine, endocrine secretory, carcinoid, and solid pseudopapillary cancers had the best survival (87-98%). On average, across histologic sub-types, PC survival improved by 0.5% (90% credible interval 0.01%, 1.0%) per year, or 5.1% (0.1%, 10.0%) per decade. Some improvement in fitted survival occurred across all stages and histologic sub-types. Conclusions: Overall survival for patients with PC has improved by around 5% per decade from 2000 to 2015, with significant heterogeneity by histologic sub-type.

scholarly journals Local Ablative Strategies for Ductal Pancreatic Cancer (Radiofrequency Ablation, Irreversible Electroporation): A Review

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Salvatore Paiella ◽  
Roberto Salvia ◽  
Marco Ramera ◽  
Roberto Girelli ◽  
Isabella Frigerio ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Radiofrequency Ablation ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Locally Advanced ◽  
Irreversible Electroporation ◽  
Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Dismal Prognosis ◽  
Ablative Techniques

Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Locally advanced pancreatic cancer (LAPC) accounts for the 40% of the new diagnoses. Current treatment options are based on chemo- and radiotherapy regimens. Local ablative techniques seem to be the future therapeutic option for stage-III patients with PDAC. Radiofrequency Ablation (RFA) and Irreversible Electroporation (IRE) are actually the most emerging local ablative techniques used on LAPC. Initial clinical studies on the use of these techniques have already demonstrated encouraging results in terms of safety and feasibility. Unfortunately, few studies on their efficacy are currently available. Even though some reports on the overall survival are encouraging, randomized studies are still required to corroborate these findings. This study provides an up-to-date overview and a thematic summary of the current available evidence on the application of RFA and IRE on PDAC, together with a comparison of the two procedures.

scholarly journals Pancreatic Cancer Meets Human Microbiota: Close Encounters of the Third Kind

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1231
Author(s):  
Tatjana Arsenijevic ◽  
Remy Nicolle ◽  
Christelle Bouchart ◽  
Nicky D’Haene ◽  
Pieter Demetter ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Human Microbiome ◽  
Predictive Biomarker ◽  
Ductal Adenocarcinoma ◽  
Cancer Resistance ◽  
First Line ◽  
Resistance To Therapy ◽  
Dismal Prognosis ◽  
Over 40 Years ◽  
Potential Use

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer with a dismal prognosis. The five-year survival rate has not changed significantly in over 40 years. Current first-line treatments only offer a modest increase in overall survival in unselected populations, and there is an urgent need to personalize treatment in this aggressive disease and develop new therapeutic strategies. Evolving evidence suggests that the human microbiome impacts cancerogenesis and cancer resistance to therapy. The mechanism of action and interaction of microbiome and PDAC is still under investigation. Direct and indirect effects have been proposed, and the use of several microbiome signatures as predictive and prognostic biomarkers for pancreatic cancer are opening new therapeutic horizons. In this review, we provide an overview for the clinicians of studies describing the influence and associations of oral, gastrointestinal and intratumoral microbiota on PDAC development, progression and resistance to therapy and the potential use of microbiota as a diagnostic, prognostic and predictive biomarker for PDAC.

Effect of diferuloyl methane (curcumin) on radiation-induced inhibition of proliferation and cytotoxicity of pancreatic cancer cells.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 222-222 ◽  
Author(s):  
R. Tuli ◽  
A. Surmak ◽  
J. M. Herman
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Combined Treatment ◽  
Single Agent ◽  
Locally Advanced ◽  
Ductal Adenocarcinoma ◽  
Inhibition Of Proliferation ◽  
Pancreatic Cancer Cells ◽  
Dismal Prognosis

222 Background: Pancreatic ductal adenocarcinoma carries a dismal prognosis. Unfortunately, the majority of patients present with locally advanced or metastatic disease unamenable to resection, and the benefit of radiation therapy (RT) in this population is not well substantiated. Diferuloyl methane (curcumin) is a naturally occurring polyphenol derived from the spice turmeric. Although it has been shown to have anticancer properties, it has not been well studied with radiation, particularly for pancreatic cancer. Herein, we attempt to determine whether curcumin can sensitize pancreatic cancer cells to radiation. Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were utilized for studies. Cells were treated with curcumin (10 nM to 1 mM), RT (1 to 9 Gy), or combinations thereof and compared to untreated controls. Cells were irradiated using a 137-Cs GammaCell in a single fraction. If applicable, cells were pretreated with curcumin one hour prior to RT. Cell viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3 and -7 activities using a luminescent assay. Results: Treatment with curcumin alone led to minimal inhibition of proliferation until concentrations exceeded 10 uM. The half maximal inhibitory concentration (IC50) was 40 uM and the IC20 was 10 uM. Cells experienced a dose- dependent inhibition of proliferation with increasing RT doses (IC20 of 5 Gy). Combined treatment with IC20 of curcumin and RT led to a synergistic increase in inhibition of proliferation (70%). The RT dose enhancement factor was 2.5 with 100 uM curcumin and 5 Gy. Caspase 3/7 activity was not significantly enhanced by treatment with curcumin alone (10 uM), but increased significantly when RT was added (5 Gy; p<.01). Conclusions: Curcumin is a potent radiosensitizer of pancreatic cancer cells that synergistically enhances the effects of RT. It has minimal effects on proliferation and apoptosis when used as a single agent at lower doses. Curcumin also potentiates RT-induced cytotoxicity through induction of apoptosis. These data are currently being validated in an orthotopic pancreatic cancer model. No significant financial relationships to disclose.

scholarly journals The Role of Autophagy in Pancreatic Cancer—Recent Advances

Biology ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 7 ◽  
Author(s):  
Maria New ◽  
Sharon Tooze
Keyword(s):  
Pancreatic Cancer ◽  
Early Stage ◽  
Large Body ◽  
Ductal Adenocarcinoma ◽  
Improve Treatment ◽  
Recent Advances ◽  
Dismal Prognosis ◽  
Tumor Survival ◽  
Metastasis Development

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with a 5-year survival rate of only 9%, despite ongoing efforts to improve treatment. This dismal prognosis is due to the difficulty of early stage diagnosis, drug resistance, and likelihood of metastasis development. It is therefore of great importance to identify appropriate therapeutic targets and gain a greater understanding of PDAC biology. Autophagy is a membrane-mediated degradation and recycling mechanism, which is crucial for cell homeostasis. There is evidence for both a tumor-suppressive and a tumor-promoting role of autophagy in cancer, and this is likely context dependent. Within PDAC, a large body of evidence points towards autophagy being required for tumor survival and metabolism. In this review, we describe the recent advances in the understanding of the role and regulation of autophagy in PDAC.

scholarly journals Loss of Activating Transcription Factor 3 prevents KRAS-mediated pancreatic cancer

2020 ◽  
Author(s):  
Nawab Azizi ◽  
Jelena Toma ◽  
Mickenzie Martin ◽  
Muhammad Faran Khalid ◽  
Nina Steele ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Transcription Factor ◽  
Immune Cell ◽  
Germ Line ◽  
Intraepithelial Neoplasia ◽  
Initial Step ◽  
Ductal Adenocarcinoma ◽  
Activating Transcription Factor 3 ◽  
Activating Transcription Factor ◽  
Transcription Factor 3

AbstractThe unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, wxe examined Activating Transcription Factor 3 (ATF3), a mediator of the UPR which promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germ line mutation of Atf3 (Atf3-/-) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasLSL-G12D). Atf3-/- mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3-/- mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia formation and PDAC in Ptf1acreERT/+KrasLSL-G12D mice. In response to injury, KRASG12D bipassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. However, unlike Ptf1acreERT/+KrasLSL-G12D mice, APK mice exhibited a cachexia-like phenotype, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology.

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