scholarly journals Targeting and Reprograming Cancer-Associated Fibroblasts and the Tumor Microenvironment in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 697
Author(s):  
Yoshiaki Sunami ◽  
Viktoria Böker ◽  
Jörg Kleeff
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
The United States ◽  
Surrounding Tissue ◽  
Cancer Associated Fibroblasts ◽  
Cancer Associated Fibroblast ◽  
Clinical Investigations ◽  
Cellular Mediators ◽  
Activated Fibroblasts ◽  
Pancreatic Cancer Therapy

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States both in female and male, and is projected to become the second deadliest cancer by 2030. The overall five-year survival rate remains at around 10%. Pancreatic cancer exhibits a remarkable resistance to established therapeutic options such as chemotherapy and radiotherapy, due to dense stromal tumor microenvironment. Cancer-associated fibroblasts are the major stromal cell type and source of extracellular matrix proteins shaping a physical and metabolic barrier thereby reducing therapeutic efficacy. Targeting cancer-associated fibroblasts has been considered a promising therapeutic strategy. However, depleting cancer-associated fibroblasts may also have tumor-promoting effects due to their functional heterogeneity. Several subtypes of cancer-associated fibroblasts have been suggested to exhibit tumor-restraining function. This review article summarizes recent preclinical and clinical investigations addressing pancreatic cancer therapy through targeting specific subtypes of cancer-associated fibroblasts, deprogramming activated fibroblasts, administration of mesenchymal stem cells, as well as reprogramming tumor-promoting cancer-associated fibroblasts to tumor-restraining cancer-associated fibroblasts. Further, inter-cellular mediators between cancer-associated fibroblasts and the surrounding tissue microenvironment are discussed. It is important to increase our understanding of cancer-associated fibroblast heterogeneity and the tumor microenvironment for more specific and personalized therapies for pancreatic cancer patients in the future.

scholarly journals Visualization Analysis of Publication Trends and Research Hotspots on the Tumor Microenvironment of Pancreatic Cancer Between 2010 and 2020: a Bibliometric Study

2021 ◽  
Author(s):  
Kaiwen Wu ◽  
Ye Liu ◽  
Lei Liu ◽  
Yunlan Peng ◽  
Honglin Pang ◽  
...  
Keyword(s):  
United States ◽  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
The United States ◽  
Future Research ◽  
Cancer Associated Fibroblasts ◽  
Serious Disease ◽  
Number Of Publications ◽  
Number Of Citations ◽  
Research Hotspots

Abstract Background: Pancreatic cancer (PC) is a serious disease with high mortality. The tumor microenvironment plays a key role in the occurrence and development of PC. The purpose of this study is to analyze the trends by year, country, institution, journal, and keywords in publications on the PC microenvironment and to predict the future hotspots.Methods: The Web of Science Core Collection was used to search for and download publications. We analyzed the contributions of various countries/regions, institutes, and authors and discerned the research hotspots and promising future trends by using the CiteSpace and VOSviewer programs. We also summarized relevant completed clinical trials.Results: A total of 1,766 papers on the PC microenvironment published between 2010 and 2020 were included in the study. The average number of citations per article was 28.7. The United States had the most publications, followed by China, and a total of five influential articles were identified through co-citation analysis. Clustering analysis revealed three clusters of keywords: carcinogenesis of PC, stroma of PC, and therapy of PC. The research hotspots included cancer-associated fibroblasts, exosomes, FOLFIRINOX [FOL – folinic acid (also called leucovorin, calcium folinate, or FA), F – fluorouracil (also called 5-FU), Irin – irinotecan, Ox – oxaliplatin], and immunotherapy.Conclusion: The number of publications and the research enthusiasm generally showed an upward trend, and the United States has made prominent contributions to the field of the tumor microenvironment of PC. The current research hotspots are mainly cancer-associated fibroblasts, exosomes, and the treatment of pancreatic cancer, which might be the directions of future research.

scholarly journals Nanoparticle-based delivery systems modulate the tumor microenvironment in pancreatic cancer for enhanced therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ming Jia ◽  
Dan Zhang ◽  
Chunxiang Zhang ◽  
Chunhong Li
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Malignant Tumors ◽  
Treatment Strategies ◽  
Delivery Systems ◽  
Cancer Microenvironment ◽  
Cancer Associated Fibroblasts ◽  
Hypoxic Environment ◽  
Promising Therapeutic Approach

AbstractPancreatic cancer is one of the most lethal malignant tumors with a low survival rate, partly because the tumor microenvironment (TME), which consists of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), immune cells, and vascular systems, prevents effective drug delivery and chemoradiotherapy. Thus, modulating the microenvironment of pancreatic cancer is considered a promising therapeutic approach. Since nanoparticles are one of the most effective cancer treatment strategies, several nano-delivery platforms have been developed to regulate the TME and enhance treatment. Here, we summarize the latest advances in nano-delivery systems that alter the TME in pancreatic cancer by depleting ECM, inhibiting CAFs, reversing immunosuppression, promoting angiogenesis, or improving the hypoxic environment. We also discuss promising new targets for such systems. This review is expected to improve our understanding of how to modulate the pancreatic cancer microenvironment and guide the development of new therapies. Graphical Abstract

scholarly journals Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

2021 ◽  
Vol 12 ◽  
Author(s):  
Pei-Yu Chen ◽  
Wen-Fei Wei ◽  
Hong-Zhen Wu ◽  
Liang-Sheng Fan ◽  
Wei Wang
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Regulation ◽  
Stromal Cells ◽  
Cancer Associated Fibroblasts ◽  
Immune Microenvironment ◽  
Cancer Associated Fibroblast ◽  
Different Origins ◽  
Fibroblast Heterogeneity

Cancer-associated fibroblasts (CAFs) are important, highly heterogeneous components of the tumor extracellular matrix that have different origins and express a diverse set of biomarkers. Different subtypes of CAFs participate in the immune regulation of the tumor microenvironment (TME). In addition to their role in supporting stromal cells, CAFs have multiple immunosuppressive functions, via membrane and secretory patterns, against anti-tumor immunity. The inhibition of CAFs function and anti-TME therapy targeting CAFs provides new adjuvant means for immunotherapy. In this review, we outline the emerging understanding of CAFs with a particular emphasis on their origin and heterogeneity, different mechanisms of their regulation, as well as their direct or indirect effect on immune cells that leads to immunosuppression.

scholarly journals Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1347 ◽  
Author(s):  
Jeffrey Norton ◽  
Deshka Foster ◽  
Malini Chinta ◽  
Ashley Titan ◽  
Michael Longaker
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Parenchymal Cell ◽  
Surgical Techniques ◽  
Treatment Strategies ◽  
The United States ◽  
Cancer Associated Fibroblasts ◽  
Cancer Cell Growth

Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer.

scholarly journals NetrinG1+ cancer-associated fibroblasts generate unique extracellular vesicles that support the survival of pancreatic cancer cells under nutritional stress

2021 ◽  
Author(s):  
Kristopher S Raghavan ◽  
Ralph Francescone ◽  
Janusz Franco-Barraza ◽  
Jaye C Gardiner ◽  
Débora B Vendramini-Costa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Vesicles ◽  
Tumor Stroma ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Cancer Associated Fibroblasts ◽  
Fibrous Stroma ◽  
Pancreatic Cancer Cells ◽  
Α5β1 Integrin

It is projected that, in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). This fibrous stroma, known as desmoplasia, causes the collapse of local blood vessels rendering a nutrient-deprived milieu. Hence, PDAC cells are nurtured by local CAF-secreted products, which include, among others, CAF-generated small extracellular vesicles (sEVs). It is well-accepted that upon culturing functionally tumor-promoting CAFs under pathophysiological-relevant conditions (e.g., within self-produced ECM), these cells express NetrinG1 (NetG1) and sustain endosomal pools rich in active α5β1-integrin, traits indicative of poor patient survival. We herein report that NetG1+ CAFs generate sEVs that rescue PDAC cells from nutrient-deprived induced apoptosis. Two unique sEVs, NetG1+ and α5β1-integrin+, were uncovered. The former constitutes cargo of CAF-generated exomeres, and the latter is detected in classic exosomes. Proteomic and metabolomic analyses showed that the sEV-dependent PDAC survival is, at least in part, dictated by the cargo packaged within sEVs in a NetG1-dependent manner. Indeed, despite producing a similar number of vesicles, selected key proteins and metabolites (e.g., glutamine) were incorporated within the unique sEVs. Finally, we found that NetG1 and α5β1-integrin were detected in sEVs collected from plasma of PDAC patients, while their concomitant levels were significantly lower in plasma of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF sEVs opens a new investigative avenue in tumor-stroma interactions and stroma staging detection.

scholarly journals Gemcitabine Combination Nano Therapies for Pancreatic Cancer

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 574 ◽  
Author(s):  
Kamalika Samanta ◽  
Saini Setua ◽  
Sonam Kumari ◽  
Meena Jaggi ◽  
Murali M. Yallapu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
The United States ◽  
Chemotherapeutic Agents ◽  
Medical Attention ◽  
Experimental Investigations ◽  
Chemotherapeutic Drugs ◽  
First Line ◽  
Chemotherapy Agent ◽  
Therapeutic Benefits ◽  
Pancreatic Cancer Therapy

Pancreatic cancer is one of the deadliest causes of cancer-related death in the United States, with a 5-year overall survival rate of 6 to 8%. These statistics suggest that immediate medical attention is needed. Gemcitabine (GEM) is the gold standard first-line single chemotherapy agent for pancreatic cancer but, after a few months, cells develop chemoresistance. Multiple clinical and experimental investigations have demonstrated that a combination or co-administration of other drugs as chemotherapies with GEM lead to superior therapeutic benefits. However, such combination therapies often induce severe systemic toxicities. Thus, developing strategies to deliver a combination of chemotherapeutic agents more securely to patients is needed. Nanoparticle-mediated delivery can offer to load a cocktail of drugs, increase stability and availability, on-demand and tumor-specific delivery while minimizing chemotherapy-associated adverse effects. This review discusses the available drugs being co-administered with GEM and the limitations associated during the process of co-administration. This review also helps in providing knowledge of the significant number of delivery platforms being used to overcome problems related to gemcitabine-based co-delivery of other chemotherapeutic drugs, thereby focusing on how nanocarriers have been fabricated, considering the modes of action, targeting receptors, pharmacology of chemo drugs incorporated with GEM, and the differences in the physiological environment where the targeting is to be done. This review also documents the focus on novel mucin-targeted nanotechnology which is under development for pancreatic cancer therapy.

Regulation of tumor microenvironment for pancreatic cancer therapy

Biomaterials ◽  
2021 ◽  
Vol 270 ◽  
pp. 120680
Author(s):  
Xu Huang ◽  
Lei Ding ◽  
Xingkai Liu ◽  
Rongsheng Tong ◽  
Jianxun Ding ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Pancreatic Cancer Therapy

scholarly journals Pancreatic Adenocarcinoma Therapeutics Targeting RTK and TGF Beta Receptor

2021 ◽  
Vol 22 (15) ◽  
pp. 8125
Author(s):  
Hsin-Han Yang ◽  
Jen-Wei Liu ◽  
Jui-Hao Lee ◽  
Horng-Jyh Harn ◽  
Tzyy-Wen Chiou
Keyword(s):  
Pancreatic Cancer ◽  
Tyrosine Kinases ◽  
Pancreatic Cancer Cell ◽  
Survival Rates ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Tgf Beta ◽  
Beta Receptor ◽  
Pancreatic Cancer Therapy ◽  
Cycle Regulation

Despite the improved overall survival rates in most cancers, pancreatic cancer remains one of the deadliest cancers in this decade. The rigid microenvironment, which majorly comprises cancer-associated fibroblasts (CAFs), plays an important role in the obstruction of pancreatic cancer therapy. To overcome this predicament, the signaling of receptor tyrosine kinases (RTKs) and TGF beta receptor (TGFβR) in both pancreatic cancer cell and supporting CAF should be considered as the therapeutic target. The activation of receptors has been reported to be aberrant to cell cycle regulation, and signal transduction pathways, such as growth-factor induced proliferation, and can also influence the apoptotic sensitivity of tumor cells. In this article, the regulation of RTKs/TGFβR between pancreatic ductal adenocarcinoma (PDAC) and CAFs, as well as the RTKs/TGFβR inhibitor-based clinical trials on pancreatic cancer are reviewed.

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