Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches

Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient. The factors involved in chemoresistance include the development of a desmoplastic stroma which reprograms cellular metabolism, and both contribute to an impaired response to therapy. PDAC stroma is composed of immune cells, endothelial cells, and cancer-associated fibroblasts embedded in a prominent, dense extracellular matrix associated with areas of hypoxia and acidic extracellular pH. While multiple gene mutations are involved in PDAC initiation, this desmoplastic stroma plays an important role in driving progression, metastasis, and chemoresistance. Elucidating the mechanisms underlying PDAC resistance are a prerequisite for designing novel approaches to increase patient survival. In this review, we provide an overview of the stromal features and how they contribute to the chemoresistance in PDAC treatment. By highlighting new paradigms in the role of the stromal compartment in PDAC therapy, we hope to stimulate new concepts aimed at improving patient outcomes.

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The role of FDG PET/CT or PET/MRI in assessing response to neoadjuvant therapy for patients with borderline or resectable pancreatic cancer: a systematic literature review

Annals of Nuclear Medicine ◽

10.1007/s12149-021-01629-0 ◽

2021 ◽

Author(s):

Laura Evangelista ◽

Pietro Zucchetta ◽

Lucia Moletta ◽

Simone Serafini ◽

Gianluca Cassarino ◽

...

Keyword(s):

Neoadjuvant Therapy ◽

Fdg Pet ◽

Standardized Uptake Value ◽

Response To Therapy ◽

Ductal Adenocarcinoma ◽

Resectable Pancreatic Cancer ◽

Number Of Patients ◽

Pet Ct ◽

Fdg Pet Ct

AbstractThe aim of the present systematic review is to examine the role of fluorodeoxyglucose (FDG) positron emission tomography (PET) associated with computed tomography (CT) or magnetic resonance imaging (MRI) in assessing response to preoperative chemotherapy or chemoradiotherapy (CRT) for patients with borderline and resectable pancreatic ductal adenocarcinoma (PDAC). Three researchers ran a database query in PubMed, Web of Science and EMBASE. The total number of patients considered was 488. The most often used parameters of response to therapy were the reductions in the maximum standardized uptake value (SUVmax) or the peak standardized uptake lean mass (SULpeak). Patients whose SUVs were higher at the baseline (before CRT) were associated with a better response to therapy and a better overall survival. SUVs remaining high after neoadjuvant therapy correlated with a poor prognosis. Available data indicate that FDG PET/CT or PET/MRI can be useful for predicting and assessing response to CRT in patients with resectable or borderline PDAC.

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The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma

Biomedicines ◽

10.3390/biomedicines8120565 ◽

2020 ◽

Vol 8 (12) ◽

pp. 565

Author(s):

Sona Ciernikova ◽

Maria Novisedlakova ◽

Danka Cholujova ◽

Viola Stevurkova ◽

Michal Mego

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Malignant Tumors ◽

Current Knowledge ◽

Early Stage ◽

Poor Response ◽

Response To Therapy ◽

Oral Microbiome ◽

Ductal Adenocarcinoma ◽

The Impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant tumors due to the absence of biomarkers for early-stage detection and poor response to therapy. Since mounting evidence supports the role of microbiota composition in tumorigenesis and cancer treatment, the link between microbiome and PDAC has been described. In this review, we summarize the current knowledge regarding the impact of the gut and oral microbiome on the risk of PDAC development. Microenvironment-driven therapy and immune system interactions are also discussed. More importantly, we provide an overview of the clinical trials evaluating the microbiota role in the risk, prognosis, and treatment of patients suffering from PDAC and solid tumors. According to the research findings, immune tolerance might result from the microbiota-derived remodeling of pancreatic tumor microenvironment. Thus, microbiome profiling and targeting represent the potential trend to enhance antitumor immunity and improve the efficacy of PDAC treatment.

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Targeting Epithelial Mesenchymal Plasticity in Pancreatic Cancer: A Compendium of Preclinical Discovery in a Heterogeneous Disease

Cancers ◽

10.3390/cancers11111745 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1745

Author(s):

James H. Monkman ◽

Erik W. Thompson ◽

Shivashankar H. Nagaraj

Keyword(s):

Cellular Transformation ◽

Therapeutic Strategies ◽

Host Tissue ◽

Ductal Adenocarcinoma ◽

Stromal Compartment ◽

Aggressive Disease ◽

Intratumoural Heterogeneity ◽

Collective Interactions ◽

Significant Mortality

Pancreatic Ductal Adenocarcinoma (PDAC) is a particularly insidious and aggressive disease that causes significant mortality worldwide. The direct correlation between PDAC incidence, disease progression, and mortality highlights the critical need to understand the mechanisms by which PDAC cells rapidly progress to drive metastatic disease in order to identify actionable vulnerabilities. One such proposed vulnerability is epithelial mesenchymal plasticity (EMP), a process whereby neoplastic epithelial cells delaminate from their neighbours, either collectively or individually, allowing for their subsequent invasion into host tissue. This disruption of tissue homeostasis, particularly in PDAC, further promotes cellular transformation by inducing inflammatory interactions with the stromal compartment, which in turn contributes to intratumoural heterogeneity. This review describes the role of EMP in PDAC, and the preclinical target discovery that has been conducted to identify the molecular regulators and effectors of this EMP program. While inhibition of individual targets may provide therapeutic insights, a single ‘master-key’ remains elusive, making their collective interactions of greater importance in controlling the behaviours’ of heterogeneous tumour cell populations. Much work has been undertaken to understand key transcriptional programs that drive EMP in certain contexts, however, a collaborative appreciation for the subtle, context-dependent programs governing EMP regulation is needed in order to design therapeutic strategies to curb PDAC mortality.

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Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer

Cells ◽

10.3390/cells10040847 ◽

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.

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The Desmoplastic Stroma Plays an Essential Role in the Accumulation and Modulation of Infiltrated Immune Cells in Pancreatic Adenocarcinoma

Clinical and Developmental Immunology ◽

10.1155/2011/212810 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 47

Author(s):

Vegard Tjomsland ◽

Lina Niklasson ◽

Per Sandström ◽

Kurt Borch ◽

Henrik Druid ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Immune Cell ◽

Ductal Adenocarcinoma ◽

Inflammatory Factors ◽

Desmoplastic Stroma ◽

Chemotactic Factors ◽

Cox 2 ◽

Short Time

Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, which all work together and create an inflammatory environment favoring tumor progression. The present study aimed to investigate the role of the desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC) regarding expression of inflammatory factors and infiltration of immune cells and their impact on the clinical outcome. The PDAC tissues examined expressed significantly increased levels of immunomodulatory and chemotactic factors (IL-6, TGFβ, IDO, COX-2, CCL2, and CCL20) and immune cell-specific markers corresponding to macrophages, myeloid, and plasmacytoid dendritic cells (DCs) as compared to controls. Furthermore, short-time survivors had the lowest levels of DC markers. Immunostainings indicated that the different immune cells and inflammatory factors are mainly localized to the desmoplastic stroma. Therapies modulating the inflammatory tumor microenvironment to promote the attraction of DCs and differentiation of monocytes into functional DCs might improve the survival of PDAC patients.

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The prognostic role of desmoplastic stroma in pancreatic ductal adenocarcinoma

Oncotarget ◽

10.18632/oncotarget.6770 ◽

2015 ◽

Vol 7 (4) ◽

pp. 4183-4194 ◽

Cited By ~ 44

Author(s):

Lai Mun Wang ◽

Michael A. Silva ◽

Zenobia D’Costa ◽

Robin Bockelmann ◽

Zahir Soonawalla ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Prognostic Role ◽

Desmoplastic Stroma

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Adjuvant Treatment in Pancreatic Cancer: Shaping the Future of the Curative Setting

Frontiers in Oncology ◽

10.3389/fonc.2021.695627 ◽

2021 ◽

Vol 11 ◽

Author(s):

Annalisa Pappalardo ◽

Emilio Francesco Giunta ◽

Giuseppe Tirino ◽

Luca Pompella ◽

Piera Federico ◽

...

Keyword(s):

Early Stage ◽

Current Treatment ◽

Point Of View ◽

Ductal Adenocarcinoma ◽

Adjuvant Setting ◽

Therapeutic Approaches ◽

Treatment Scenario ◽

Clinical Point ◽

Localized Disease

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease even in the early stages, despite progresses in surgical and pharmacological treatment in recent years. High potential for metastases is the main cause of therapeutic failure in localized disease, highlighting the current limited knowledge of underlying pathological processes. However, nowadays research is focusing on the search for personalized approaches also in the adjuvant setting for PDAC, by implementing the use of biomarkers and investigating new therapeutic targets. In this context, the aim of this narrative review is to summarize the current treatment scenario and new potential therapeutic approaches in early stage PDAC, from both a preclinical and clinical point of view. Additionally, the review examines the role of target therapies in localized PDAC and the influence of neoadjuvant treatments on survival outcomes.

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PRMT5: An Emerging Target for Pancreatic Adenocarcinoma

Cancers ◽

10.3390/cancers13205136 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5136

Author(s):

Michael K. C. Lee ◽

Sean M. Grimmond ◽

Grant A. McArthur ◽

Karen E. Sheppard

Keyword(s):

Current Knowledge ◽

Tumour Microenvironment ◽

Inhibitory Response ◽

Response To Therapy ◽

Ductal Adenocarcinoma ◽

Therapeutic Approaches ◽

Growth Inhibitory ◽

Increased Sensitivity ◽

Novel Therapeutic ◽

Significant Bearing

The overall survival of pancreatic ductal adenocarcinoma (PDAC) remains poor and its incidence is rising. Targetable mutations in PDAC are rare, thus novel therapeutic approaches are needed. Protein arginine methyltransferase 5 (PRMT5) overexpression is associated with worse survival and inhibition of PRMT5 results in decreased cancer growth across multiple cancers, including PDAC. Emerging evidence also suggests that altered RNA processing is a driver in PDAC tumorigenesis and creates a partial dependency on this process. PRMT5 inhibition induces altered splicing and this vulnerability can be exploited as a novel therapeutic approach. Three possible biological pathways underpinning the action of PRMT5 inhibitors are discussed; c-Myc regulation appears central to its action in the PDAC setting. Whilst homozygous MTAP deletion and symmetrical dimethylation levels are associated with increased sensitivity to PRMT5 inhibition, neither measure robustly predicts its growth inhibitory response. The immunomodulatory effect of PRMT5 inhibitors on the tumour microenvironment will also be discussed, based on emerging evidence that PDAC stroma has a significant bearing on disease behaviour and response to therapy. Lastly, with the above caveats in mind, current knowledge gaps and the implications and rationales for PRMT5 inhibitor development in PDAC will be explored.

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The Role of miRNA in the Pathophysiology of Neuroendocrine Tumors

International Journal of Molecular Sciences ◽

10.3390/ijms22168569 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8569

Author(s):

Lukas Geisler ◽

Raphael Mohr ◽

Joeri Lambrecht ◽

Jana Knorr ◽

Henning Jann ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Response To Therapy ◽

Diagnostic Tools ◽

Therapeutic Approaches ◽

Future Directions ◽

Rna Molecules ◽

Tumor Group ◽

Tumor Stages ◽

Established Role

Neuroendocrine tumors (NETs) represent a tumor group that is both rare and heterogeneous. Prognosis is largely determined by the tumor grading and the site of the primary tumor and metastases. Despite intensive research efforts, only modest advances in diagnostic and therapeutic approaches have been achieved in recent years. For patients with non-respectable tumor stages, prognosis is poor. In this context, the development of novel diagnostic tools for early detection of NETs and prediction of tumor response to therapy as well as estimation of the overall prognosis would greatly improve the clinical management of NETs. However, identification of novel diagnostic molecules is hampered by an inadequate understanding of the pathophysiology of neuroendocrine malignancies. It has recently been demonstrated that microRNA (miRNA), a family of small RNA molecules with an established role in the pathophysiology of quite different cancer entities, may also play a role as a biomarker. Here, we summarize the available knowledge on the role of miRNAs in the development of NET and highlight their potential use as serum-based biomarkers in the context of this disease. We discuss important challenges currently preventing their use in clinical routine and give an outlook on future directions of miRNA research in NET.

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