scholarly journals Nerve Fibers in the Tumor Microenvironment Are Co-Localized with Lymphoid Aggregates in Pancreatic Cancer

2021 ◽  
Vol 10 (3) ◽  
pp. 490
Author(s):  
Lara R. Heij ◽  
Xiuxiang Tan ◽  
Jakob N. Kather ◽  
Jan M. Niehues ◽  
Shivan Sivakumar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Clinical Outcome ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Treatment Resistance ◽  
Nerve Fibers ◽  
Cellular Interactions ◽  
Improve Clinical Outcome ◽  
Lymphoid Aggregates

B cells and tertiary lymphoid structures (TLS) are reported to be important in survival in cancer. Pancreatic Cancer (PDAC) is one of the most lethal cancer types, and currently, it is the seventh leading cause of cancer-related death worldwide. A better understanding of tumor biology is pivotal to improve clinical outcome. The desmoplastic stroma is a complex system in which crosstalk takes place between cancer-associated fibroblasts, immune cells and cancer cells. Indirect and direct cellular interactions within the tumor microenvironment (TME) drive key processes such as tumor progression, metastasis formation and treatment resistance. In order to understand the aggressiveness of PDAC and its resistance to therapeutics, the TME needs to be further unraveled. There are some limited data about the influence of nerve fibers on cancer progression. Here we show that small nerve fibers are located at lymphoid aggregates in PDAC. This unravels future pathways and has potential to improve clinical outcome by a rational development of new therapeutic strategies.

scholarly journals Computational STAT3 activity inference reveals its roles in the pancreatic tumor microenvironment

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Evelien Schaafsma ◽  
Yiwei Yuan ◽  
Yanding Zhao ◽  
Chao Cheng
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Copy Number Variation ◽  
Cancer Progression ◽  
Copy Number ◽  
Dominant Role ◽  
Tumor Biology ◽  
Systematic Analysis ◽  
Number Variation

AbstractTranscription factor (TF) STAT3 contributes to pancreatic cancer progression through its regulatory roles in both tumor cells and the tumor microenvironment (TME). In this study, we performed a systematic analysis of all TFs in patient-derived gene expression datasets and confirmed STAT3 as a critical regulator in the pancreatic TME. Importantly, we developed a novel framework that is based on TF target gene expression to distinguish between environmental- and tumor-specific STAT3 activities in gene expression studies. Using this framework, our results novelly showed that compartment-specific STAT3 activities, but not STAT3 mRNA, have prognostications towards clinical values within pancreatic cancer datasets. In addition, high TME-derived STAT3 activity correlates with an immunosuppressive TME in pancreatic cancer, characterized by CD4 T cell and monocyte infiltration and high copy number variation burden. Where environmental-STAT3 seemed to play a dominant role at primary pancreatic sites, tumor-specific STAT3 seemed dominant at metastatic sites where its high activity persisted. In conclusion, by combining compartment-specific inference with other tumor characteristics, including copy number variation and immune-related gene expression, we demonstrate our method’s utility as a tool to generate novel hypotheses about TFs in tumor biology.

scholarly journals Diet, Obesity, and Cancer Progression: Are Adipocytes the Link?

2013 ◽  
Vol 6 ◽  
pp. LPI.S10871 ◽  
Author(s):  
Paul Toren ◽  
Benjamin C. Mora ◽  
Vasundara Venkateswaran
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Model Systems ◽  
In Vivo Model ◽  
Diet Induced Obesity ◽  
Breast And Prostate Cancer ◽  
Obesity And Cancer

Obesity has been linked to more aggressive characteristics of several cancers, including breast and prostate cancer. Adipose tissue appears to contribute to paracrine interactions in the tumor microenvironment. In particular, cancer-associated adipocytes interact reciprocally with cancer cells and influence cancer progression. Adipokines secreted from adipocytes likely form a key component of the paracrine signaling in the tumor microenvironment. In vitro coculture models allow for the assessment of specific adipokines in this interaction. Furthermore, micronutrients and macronutrients present in the diet may alter the secretion of adipokines from adipocytes. The effect of dietary fat and specific fatty acids on cancer progression in several in vivo model systems and cancer types is reviewed. The more common approaches of caloric restriction or diet-induced obesity in animal models establish that such dietary changes modulate tumor biology. This review seeks to explore available evidence regarding how diet may modulate tumor characteristics through changes in the role of adipocytes in the tumor microenvironment.

scholarly journals Advance in Pancreatic Cancer Diagnosis and Therapy

2020 ◽  
Author(s):  
Xiaojie Cai ◽  
Jie Gao ◽  
Yanfang Liu ◽  
Ming Wang ◽  
Qiulian Ma ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Survival Rate ◽  
Tumor Microenvironment ◽  
Cancer Diagnosis ◽  
Treatment Resistance ◽  
Serum Markers ◽  
Molecular Probes ◽  
Cancer Death ◽  
Cancer Diagnosis And Therapy

Pancreatic carcinoma is the fourth leading cause of cancer death in the word wild. Although the advance in treatment this disease, the 5-years survival rate is still rather low. In the recent year, many new therapy and treatment avenues have been developed for pancreatic cancer. In this chapter, we mainly focus on the following aspect: 1) the treatment modality in pancreatic cancer, including chemotherapy, radiotherapy, and immunotherapy; 2) the mechanism of pancreatic cancer treatment resistance, especially in cancer stem cells and tumor microenvironment; 3) the diagnosis tools in pancreatic cancer, including serum markers, imaging methods and endoscopic ultrasonography. Novel molecular probes based on the nanotechnology in the diagnosis of pancreatic cancer are also discussed.

scholarly journals Metabolic Alterations in Pancreatic Cancer Progression

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 2 ◽  
Author(s):  
Enza Vernucci ◽  
Jaime Abrego ◽  
Venugopal Gunda ◽  
Surendra K. Shukla ◽  
Aneesha Dasgupta ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Precancerous Lesions ◽  
Genetically Engineered ◽  
Metabolic Reprogramming ◽  
Pancreatic Tumors ◽  
Metabolic Alterations ◽  
Genetically Engineered Mice

Pancreatic cancer is the third leading cause of cancer-related deaths in the USA. Pancreatic tumors are characterized by enhanced glycolytic metabolism promoted by a hypoxic tumor microenvironment and a resultant acidic milieu. The metabolic reprogramming allows cancer cells to survive hostile microenvironments. Through the analysis of the principal metabolic pathways, we identified the specific metabolites that are altered during pancreatic cancer progression in the spontaneous progression (KPC) mouse model. Genetically engineered mice exhibited metabolic alterations during PanINs formation, even before the tumor development. To account for other cells in the tumor microenvironment and to focus on metabolic adaptations concerning tumorigenic cells only, we compared the metabolic profile of KPC and orthotopic tumors with those obtained from KPC-tumor derived cell lines. We observed significant upregulation of glycolysis and the pentose phosphate pathway metabolites even at the early stages of pathogenesis. Other biosynthetic pathways also demonstrated a few common perturbations. While some of the metabolic changes in tumor cells are not detectable in orthotopic and spontaneous tumors, a significant number of tumor cell-intrinsic metabolic alterations are readily detectable in the animal models. Overall, we identified that metabolic alterations in precancerous lesions are maintained during cancer development and are largely mirrored by cancer cells in culture conditions.

scholarly journals The clinical implication of CD45RA+ naive T cells and CD45RO+ memory T cells in advanced pancreatic cancer: A proxy for tumor biology and outcome prediction.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 196-196
Author(s):  
Junjie Hang ◽  
Lixia Wu ◽  
Kequn Xu
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Cancer Progression ◽  
Cox Regression ◽  
Memory T Cells ◽  
Tumor Biology ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Prognostic Impact ◽  
Student’S T

196 Background: Naive and memory T cells play a pivotal role in solid tumor pathogenesis but their role in pancreatic cancer progression remains elusive. Thus, we aimed to investigate their clinical potential in advanced pancreatic cancer (APC). Methods: Flow cytometry was performed to evaluate the level of peripheral naive and memory T cells from APC patients. Interrelationships between naive, memory T cells and clinicopathological variables were evaluated using pearson’s correlation. The prognostic impact of naive and memory T cells were assessed by Kaplan-Meier analysis and Cox regression. The correlation between naive/memory T cells and tumor progression was investigated by Student’s t test. Results: CD4+ naive/memory ratio showed close correlations with hemoglobin, red blood cell (RBC), absolute neutrophil count (ANC) and platelet while CD8+ naive/memory ratio was correlated with hemoglobin, RBC and CEA. Higher baseline lever of CD4+CD45RO+/CD4+ was correlated with better overall survival (OS) (P = 0.036). Patients with CD4+ naive/memory ratio ≥ 0.36 had a poorer OS than those with CD4+ naive/memory ratio < 0.36 (P = 0.021). In addition, CD4+ naive/memory ratio showed independent prognostic impact (HR 1.427, 95%CI 1.033-1.973, P = 0.031). Furthermore, poorer clinical response was correlated with higher level of CD8+ naive/memory ratio after the third cycle of chemotherapy (P = 0.01). Besides, patients with an low level of CD8+ naive/memory ratio had longer progression-free survival (PFS) (P = 0.028). Conclusions: We propose CD4+ naive/memory ratio as a novel prognostic biomarker for APC. In addition, CD8+ naive/memory ratio can be a candidate marker for predicting PFS and the change of its level may reflect the progression of APC.

scholarly journals The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 96
Author(s):  
Ana S. Leal ◽  
Phillip Liu ◽  
Teresa Krieger-Burke ◽  
Bruce Ruggeri ◽  
Karen T. Liby
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Immune Cell ◽  
Cell Populations ◽  
Control Group ◽  
Immune Recognition ◽  
Transcriptional Initiation ◽  
Bet Inhibitor ◽  
Kpc Mice

In pancreatic cancer the tumor microenvironment (TME) can account for up to 90% of the tumor mass. The TME drives essential functions in disease progression, invasion and metastasis. Tumor cells can use epigenetic modulation to evade immune recognition and shape the TME toward an immunosuppressive phenotype. Bromodomain inhibitors are a class of drugs that target BET (bromodomain and extra-terminal) proteins, impairing their ability to bind to acetylated lysines and therefore interfering with transcriptional initiation and elongation. INCB057643 is a new generation, orally bioavailable BET inhibitor that was developed for treating patients with advanced malignancies. KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mice mimic human disease, with similar progression and incidence of metastasis. Treatment of established tumors in KPC mice with INCB057643 increased survival by an average of 55 days, compared to the control group. Moreover, INCB057643 reduced metastatic burden in these mice. KPC mice treated with INCB057643, starting at 4 weeks of age, showed beneficial changes in immune cell populations in the pancreas and liver. Similarly, INCB057643 modified immune cell populations in the pancreas of KrasG12D/+; Pdx-1-Cre (KC) mice with pancreatitis, an inflammatory process known to promote pancreatic cancer progression. The data presented here suggest that the bromodomain inhibitor INCB057643 modulates the TME, reducing disease burden in two mouse models of pancreatic cancer. Furthermore, this work suggests that BRD4 may play a role in establishing the TME in the liver, a primary metastatic site for pancreatic cancer.

scholarly journals Abstract 5902: Roles of tumor microenvironment in pancreatic cancer progression

2017 ◽  
Author(s):  
Kei Takahashi ◽  
Shogo Ehata ◽  
Daizo Koinuma ◽  
Kohei Miyazono
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression

scholarly journals ANXA1 Contained in EVs Regulates Macrophage Polarization in Tumor Microenvironment and Promotes Pancreatic Cancer Progression and Metastasis

2021 ◽  
Vol 22 (20) ◽  
pp. 11018
Author(s):  
Nunzia Novizio ◽  
Raffaella Belvedere ◽  
Emanuela Pessolano ◽  
Silvana Morello ◽  
Alessandra Tosco ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Wild Type ◽  
Soluble Factors ◽  
Knock Out ◽  
Orthotopic Xenografts ◽  
M2 Phenotype

The tumor microenvironment (TME) is a dynamic system where nontumor and cancer cells intercommunicate through soluble factors and extracellular vesicles (EVs). The TME in pancreatic cancer (PC) is critical for its aggressiveness and the annexin A1 (ANXA1) has been identified as one of the oncogenic elements. Previously, we demonstrated that the autocrine/paracrine activities of extracellular ANXA1 depend on its presence in EVs. Here, we show that the complex ANXA1/EVs modulates the macrophage polarization further contributing to cancer progression. The EVs isolated from wild type (WT) and ANXA1 knock-out MIA PaCa-2 cells have been administrated to THP-1 macrophages finding that ANXA1 is crucial for the acquisition of a protumor M2 phenotype. The M2 macrophages activate endothelial cells and fibroblasts to induce angiogenesis and matrix degradation, respectively. We have also found a significantly increased presence of M2 macrophage in mice tumor and liver metastasis sections previously obtained by orthotopic xenografts with WT cells. Taken together, our data interestingly suggest the relevance of ANXA1 as potential diagnostic/prognostic and/or therapeutic PC marker.

scholarly journals P03.04 Applying multispectral unmixing and spatial analyses to explore tumor heterogeneity with a pre-optimized 7-color immuno-oncology workflow

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A23.2-A24
Author(s):  
V Goubert
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Multispectral Imaging ◽  
Dynamic Range ◽  
Tumor Biology ◽  
Cellular Interactions ◽  
Spatial Analyses ◽  
Spatial Interactions ◽  
Priority Rules ◽  
End To End

BackgroundThe tumor microenvironment hosts a myriad of cellular interactions that influence tumor biology and patient outcomes. Multiplex immunofluorescence (mIF) provides the ability to investigate a large number of these interactions in a single tissue section, and has been shown to outperform other testing modalities for predicting response to immunotherapies.1 Multispectral imaging (MSI) improves the capabilities of mIF by providing the ability to spectrally unmix fluorescence signals. This increases the number of markers that can be probed in the same scan and allows for separation of true immunofluorescence signals from tissue autofluorescence background. Here, we apply MSI to explore spatial interactions observed in lung cancer samples using an end-to-end translational workflow based on the PhenopticsTM platform. The workflow includes a pre-optimized 7-color staining panel kit along with a pre-configured analysis algorithm for cell phenotyping. Using tissue microarrays (TMA), we demonstrate the heterogeneity of spatial interactions observed among different lung cancer samples and the improved sensitivity of detection afforded by unmixing multispectral scans.Materials and MethodsFormalin-fixed paraffin-embedded (FFPE) lung cancer TMA contained 120 cores (1.5 mm diameter, US Biomax, Inc., Derwood, MD). The TMA was stained using the MOTiFTM PD-1/PD-L1 Panel: Auto Lung Cancer Kit and pre-optimized protocol for the Leica BOND RXTM. Whole slide 7-color MOTiF multispectral scan was acquired on Vectra Polaris® using pre-defined parameters. PhenochartTM software was used to identify cores for analysis. Scans were unmixed and analyzed with inForm® software using a pre-configured algorithm tailored to the MOTiFTM PD-1/PD-L1 Panel kit. With this algorithm, cells are assigned phenotypes using intensity thresholds for CD8, PD-1, FoxP3, CD68, and PanCK signal levels, subject to pre-defined marker priority rules. The rules limit co-positivity to any combination of CD8, FoxP3, and PD-1, but no combinations of those markers with CD68 or PanCK, and no combination of CD68 with PanCK. When threshold levels generate excluded combinations, priority is given to calls for CD8/FoxP3/PD-1 over CD68, which in turn has priority over PanCK. To explore the dynamic range of PD-L1, it was assessed via expression level (signal intensity), not phenotyping. Spatial analyses and visualizations were performed in R 2 using the phenoptr and phenoptrReports packages3, and custom scripts.ResultsThe pre-optimized Opal Polaris 7-Color PD-1/PD-L1 Lung Cancer Panel Kit was able to visualize the panel targets (PD-L1, PD-1, CD8, CD68, FoxP3, and Cytokeratin) across the variety of lung cancer samples in the TMA. Cell phenotyping and spatial analyses revealed core-to-core variations in cell densities and proximities among different markers. Measurement of the dynamic range of PD-L1 expression across different cores also revealed the improved sensitivity in PD-L1 detection provided by unmixing.ConclusionsThe end-to-end Phenoptics staining, imaging, unmixing, and spatial analysis workflow described here provides a robust and sensitive platform for exploring the immune landscape within the tumor microenvironment.Disclosure InformationV. Goubert: None.

scholarly journals Cancer-associated adipocytes: key players in breast cancer progression

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Qi Wu ◽  
Bei Li ◽  
Zhiyu Li ◽  
Juanjuan Li ◽  
Si Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Active Role ◽  
Cell Types ◽  
Functional Changes ◽  
Cell Crosstalk

Abstract Adipocytes are one of the primary stromal cells in many tissues, and they are considered to play an active role in the tumor microenvironment. Cancer-associated adipocytes (CAAs) are not only found adjacent to cancer cells, but also communicate with cancer cells through releasing various factors that can mediate local and systemic effects. The adipocyte-cancer cell crosstalk leads to phenotypical and functional changes of both cell types, which can further enhance tumor progression. Indeed, obesity, which is associated with an increase in adipose mass and an alteration of adipose tissue, is becoming pandemic in some countries and it is now considered to be an independent risk factor for cancer progression. In this review, we focus on the potential mechanisms involved with special attention to the adipocyte-cancer cell circle in breast cancer. We envisage that besides having a direct impact on tumor cells, CAAs systemically preconditions the tumor microenvironment by favoring anti-tumor immunity. A better understanding of cancer-associated adipocytes and the key molecular events in the adipocyte-cancer cell crosstalk will provide insights into tumor biology and permit the optimization of therapeutic strategies.

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