scholarly journals The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4932
Author(s):  
Young Researchers in Inflammatory Carcinogenesis Group ◽  
Anna Wandmacher ◽  
Anne-Sophie Mehdorn ◽  
Susanne Sebens
Keyword(s):  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Therapy Response ◽  
Therapy Resistance ◽  
Ductal Adenocarcinoma ◽  
Cell Heterogeneity ◽  
Survival Times ◽  
Stromal Compartment ◽  
Therapeutic Concepts ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. As a result, PDAC is still one of the deadliest tumors. Tumor heterogeneity, manifesting at multiple levels, provides a conclusive explanation for divergent survival times and therapy responses of PDAC patients. Besides tumor cell heterogeneity, PDAC is characterized by a pronounced inflammatory stroma comprising various non-neoplastic cells such as myofibroblasts, endothelial cells and different leukocyte populations which enrich in the tumor microenvironment (TME) during pancreatic tumorigenesis. Thus, the stromal compartment also displays a high temporal and spatial heterogeneity accounting for diverse effects on the development, progression and therapy responses of PDAC. Adding to this heterogeneity and the impact of the TME, the microbiome of PDAC patients is considerably altered. Understanding this multi-level heterogeneity and considering it for the development of novel therapeutic concepts might finally improve the dismal situation of PDAC patients. Here, we outline the current knowledge on PDAC cell heterogeneity focusing on different stromal cell populations and outline their impact on PDAC progression and therapy resistance. Based on this information, we propose some novel concepts for treatment of PDAC patients.

scholarly journals Interactions between Cancer-Associated Fibroblasts and T Cells in the Pancreatic Tumor Microenvironment and the Role of Chemokines

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2995
Author(s):  
Laia Gorchs ◽  
Helen Kaipe
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Cell Trafficking ◽  
Cancer Associated Fibroblasts ◽  
Cell Axis ◽  
Combinational Treatment

Less than 10% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive 5 years or more, making it one of the most fatal cancers. Accumulation of T cells in pancreatic tumors is associated with better prognosis, but immunotherapies to enhance the anti-tumor activity of infiltrating T cells are failing in this devastating disease. Pancreatic tumors are characterized by a desmoplastic stroma, which mainly consists of activated cancer-associated fibroblasts (CAFs). Pancreatic CAFs have emerged as important regulators of the tumor microenvironment by contributing to immune evasion through the release of chemokines, cytokines, and growth factors, which alters T-cell migration, differentiation and cytotoxic activity. However, recent discoveries have also revealed that subsets of CAFs with diverse functions can either restrain or promote tumor progression. Here, we discuss our current knowledge about the interactions between CAFs and T cells in PDAC and summarize different therapy strategies targeting the CAF–T cell axis with focus on CAF-derived soluble immunosuppressive factors and chemokines. Identifying the functions of different CAF subsets and understanding their roles in T-cell trafficking within the tumor may be fundamental for the development of an effective combinational treatment for PDAC.

scholarly journals Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

2020 ◽  
Author(s):  
S. Mahnaz ◽  
L. Das Roy ◽  
M. Bose ◽  
C. De ◽  
S. Nath ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathways ◽  
Suppressor Cells ◽  
Ductal Adenocarcinoma ◽  
Myeloid Derived Suppressor Cells ◽  
Mucin 1 ◽  
Transmembrane Glycoprotein ◽  
The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

scholarly journals The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma

Biomedicines ◽  
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.

scholarly journals Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4318
Author(s):  
Brittany P. Rickard ◽  
Christina Conrad ◽  
Aaron J. Sorrin ◽  
Mustafa Kemal Ruhi ◽  
Jocelyn C. Reader ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Biology ◽  
Metastatic Cancer ◽  
Treatment Options ◽  
Therapy Response ◽  
Therapy Resistance ◽  
Malignant Ascites ◽  
Molecular Characteristics ◽  
The Impact

Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology.

scholarly journals The Impact of Biomarkers in Pancreatic Ductal Adenocarcinoma on Diagnosis, Surveillance and Therapy

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 217
Author(s):  
Niklas Sturm ◽  
Thomas J. Ettrich ◽  
Lukas Perkhofer
Keyword(s):  
Early Detection ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Early Stage ◽  
Therapy Response ◽  
Ductal Adenocarcinoma ◽  
Current State ◽  
Novel Biomarkers ◽  
State Of Research ◽  
Noninvasive Biomarkers ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer.

The Impact of the Activated Stroma on Pancreatic Ductal Adenocarcinoma Biology and Therapy Resistance

2012 ◽  
Vol 12 (3) ◽  
pp. 288-303 ◽  
Author(s):  
Mert Erkan ◽  
Carolin Reiser-Erkan ◽  
Christoph W. Michalski ◽  
Bo Kong ◽  
Irene Esposito ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapy Resistance ◽  
Ductal Adenocarcinoma ◽  
The Impact

scholarly journals Role of Hypoxic Stress in Regulating Tumor Immunogenicity, Resistance and Plasticity

2018 ◽  
Vol 19 (10) ◽  
pp. 3044 ◽  
Author(s):  
Stéphane Terry ◽  
Rania Faouzi Zaarour ◽  
Goutham Hassan Venkatesh ◽  
Amirtharaj Francis ◽  
Walid El-Sayed ◽  
...  
Keyword(s):  
Cell Biology ◽  
Tumor Heterogeneity ◽  
Current Knowledge ◽  
Therapy Resistance ◽  
Strong Impact ◽  
Hypoxic Stress ◽  
Tumor Microenvironments ◽  
Immune Resistance ◽  
Tumor Immunogenicity ◽  
The Impact

Hypoxia, or gradients of hypoxia, occurs in most growing solid tumors and may result in pleotropic effects contributing significantly to tumor aggressiveness and therapy resistance. Indeed, the generated hypoxic stress has a strong impact on tumor cell biology. For example, it may contribute to increasing tumor heterogeneity, help cells gain new functional properties and/or select certain cell subpopulations, facilitating the emergence of therapeutic resistant cancer clones, including cancer stem cells coincident with tumor relapse and progression. It controls tumor immunogenicity, immune plasticity, and promotes the differentiation and expansion of immune-suppressive stromal cells. In this context, manipulation of the hypoxic microenvironment may be considered for preventing or reverting the malignant transformation. Here, we review the current knowledge on how hypoxic stress in tumor microenvironments impacts on tumor heterogeneity, plasticity and resistance, with a special interest in the impact on immune resistance and tumor immunogenicity.

scholarly journals Genomic Heterogeneity of Pancreatic Ductal Adenocarcinoma and Its Clinical Impact

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4451
Author(s):  
María Laura Gutiérrez ◽  
Luis Muñoz-Bellvís ◽  
Alberto Orfao
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Patient Outcomes ◽  
Current Knowledge ◽  
Genomic Data ◽  
Response To Therapy ◽  
Ductal Adenocarcinoma ◽  
Tumor Resistance ◽  
Driver Genes ◽  
Genetic Traits ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death due to limited advances in recent years in early diagnosis and personalized therapy capable of overcoming tumor resistance to chemotherapy. In the last decades, significant advances have been achieved in the identification of recurrent genetic and molecular alterations of PDAC including those involving the KRAS, CDKN2A, SMAD4, and TP53 driver genes. Despite these common genetic traits, PDAC are highly heterogeneous tumors at both the inter- and intra-tumoral genomic level, which might contribute to distinct tumor behavior and response to therapy, with variable patient outcomes. Despite this, genetic and genomic data on PDAC has had a limited impact on the clinical management of patients. Integration of genomic data for classification of PDAC into clinically defined entities—i.e., classical vs. squamous subtypes of PDAC—leading to different treatment approaches has the potential for significantly improving patient outcomes. In this review, we summarize current knowledge about the most relevant genomic subtypes of PDAC including the impact of distinct patterns of intra-tumoral genomic heterogeneity on the classification and clinical and therapeutic management of PDAC.

scholarly journals TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting

2019 ◽  
Vol 69 (2) ◽  
pp. 237-244 ◽  
Author(s):  
Marlies J. W. Peeters ◽  
Anne Rahbech ◽  
Per thor Straten
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Protein S ◽  
Cell Types ◽  
Therapy Resistance ◽  
Activated T Cells ◽  
Tam Receptors ◽  
Antigen Presenting ◽  
Different Cell Types

Abstract The TAM receptors—TYRO3, AXL, MERTK—are pleiotropically expressed receptors in both healthy and diseased tissue. A complex of the ligands Protein S (PROS1) or Growth Arrest-Specific 6 (GAS6) with apoptotic phosphatidylserine activates the TAM receptors. Hence, this receptor family is essential for the efferocytosis of apoptotic material by antigen-presenting cells. In addition, TAM receptors are expressed by virtually all cells of the tumor microenvironment. They are also potent oncogenes, frequently overexpressed in cancer and involved in survival and therapy resistance. Due to their pro-oncogenic and immune-inhibitory traits, TAM receptors have emerged as promising targets for cancer therapy. Recently, TAM receptors have been described to function as costimulatory molecules on human T cells. TAM receptors’ ambivalent functions on many different cell types therefore make therapeutic targeting not straight-forward. In this review we summarize our current knowledge of the function of TAM receptors in the tumor microenvironment. We place particular focus on TAM receptors and the recently unraveled role of MERTK in activated T cells and potential consequences for anti-tumor immunity.

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