scholarly journals The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

2021 ◽  
Vol 9 ◽  
Author(s):  
Paul Manoukian ◽  
Maarten Bijlsma ◽  
Hanneke van Laarhoven
Keyword(s):  
Pancreatic Cancer ◽  
Stromal Cells ◽  
Ex Vivo ◽  
Tumor Stroma ◽  
Cell Types ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Tumors ◽  
Cancer Associated Fibroblasts ◽  
Homogeneous Population ◽  
Different Origins

Pancreatic tumors are known to harbor an abundant and highly desmoplastic stroma. Among the various cell types that reside within tumor stroma, cancer-associated fibroblasts (CAFs) have gained a lot of attention in the cancer field due to their contributions to carcinogenesis and tumor architecture. These cells are not a homogeneous population, but have been shown to have different origins, phenotypes, and contributions. In pancreatic tumors, CAFs generally emerge through the activation and/or recruitment of various cell types, most notably resident fibroblasts, pancreatic stellate cells (PSCs), and tumor-infiltrating mesenchymal stem cells (MSCs). In recent years, single cell transcriptomic studies allowed the identification of distinct CAF populations in pancreatic tumors. Nonetheless, the exact sources and functions of those different CAF phenotypes remain to be fully understood. Considering the importance of stromal cells in pancreatic cancer, many novel approaches have aimed at targeting the stroma but current stroma-targeting therapies have yielded subpar results, which may be attributed to heterogeneity in the fibroblast population. Thus, fully understanding the roles of different subsets of CAFs within the stroma, and the cellular dynamics at play that contribute to heterogeneity in CAF subsets may be essential for the design of novel therapies and improving clinical outcomes. Fortunately, recent advances in technologies such as microfluidics and bio-printing have made it possible to establish more advanced ex vivo models that will likely prove useful. In this review, we will present the different roles of stromal cells in pancreatic cancer, focusing on CAF origin as a source of heterogeneity, and the role this may play in therapy failure. We will discuss preclinical models that could be of benefit to the field and that may contribute to further clinical development.

scholarly journals Derivation and Validation of the Potential Core Genes in Pancreatic Cancer for Tumor-Stroma Crosstalk

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Ran Xue ◽  
Lin Hua ◽  
Wenbin Xu ◽  
Yan Gao ◽  
Yanhua Pang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Principal Component Analysis ◽  
Cancer Progression ◽  
Principal Component ◽  
Tumor Stroma ◽  
Component Analysis ◽  
Gene Expression Omnibus ◽  
Pancreatic Stellate Cells ◽  
Potential Core ◽  
Core Genes

Background. Pancreatic cancer is a fatal malignancy with a poor prognosis. The interactions between tumor cells and stromal cells contribute to cancer progression. Pancreatic stellate cells (PSCs) play a key role in tumor-stroma crosstalk of pancreatic cancer. The in-depth exploration for tumor-stroma crosstalk is helpful to develop novel therapeutic strategies. Our aim was to identify the potential core genes and pathways in tumor-stroma crosstalk.Methods. 3 microarray datasets were from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were screened through bioinformatics analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network were used to obtain the biological roles of DEGs. The top 15 DEGs were explored by principal component analysis. We validated the top 15 DEGs expression in the tumor-stroma crosstalk model in which PSCs were treated with the mixture of Aspc-1 and Panc-1 supernatant.Results. A total of 221 genes were filtered as DEGs for tumor-stroma crosstalk. The results of principal component analysis for the top 15 DEGs can distinguish three groups. According to the KEGG enrichment, there were 8, 7, and 7 DEGs enriched in cancer related pathway, PI3K-Akt signaling pathway, and microRNAs, respectively. In the tumor-stroma crosstalk model, significant differences can be validated in the AKAP12, CLDN1, CP, FKBP1A, LAMB3, LSM4, MTMR3, PRKARIA, YWHAZ, and JUND expressions.Conclusions. These results identified the potential core genes and pathways in pancreatic cancer for tumor-stroma crosstalk, which could provide potential targets for the treatment of pancreatic cancer.

Vitamin D modulates migration and activation of pancreatic stellate cells and tumor-stroma crosstalk in pancreatic cancer

Pancreatology ◽  
2019 ◽  
Vol 19 ◽  
pp. S162
Author(s):  
Yang Wu ◽  
Quan Li ◽  
Chun Zhang ◽  
Maximilian Weniger ◽  
Matthias Ilmer ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Vitamin D ◽  
Tumor Stroma ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells

Tumor-Host Interactions: A Far-Reaching Relationship

2010 ◽  
Vol 28 (26) ◽  
pp. 4022-4028 ◽  
Author(s):  
Sandra S. McAllister ◽  
Robert A. Weinberg
Keyword(s):  
Cancer Progression ◽  
Stromal Cells ◽  
Tumor Biology ◽  
Mesenchymal Cell ◽  
Tumor Stroma ◽  
Cell Types ◽  
Host Interactions ◽  
Recent Advances ◽  
Extracellular Matrix Components ◽  
Heterotypic Interactions

Carcinomas are composed of neoplastic epithelial cells, which form the heart of the tumor, as well as a variety of mesenchymal cell types and extracellular matrix components that comprise the tumor stroma, often termed its microenvironment. The normal counterparts of some stromal cells are thought to limit tumor growth, while tumor-associated stromal cells have been convincingly shown to actively promote tumor progression via complex heterotypic interactions with the nearby carcinoma cells. More recent advances have revealed that tumor-host interactions extend well beyond the local tissue microenvironment (ie, interactions between the neoplastic cells and the nearby stroma) and that tumors not only respond to, but actively perturb host organs at distant anatomic sites. This indicates that many aspects of tumor biology can only be explained by a detailed understanding of both local and systemic interactions, yet we currently have only a fragmentary understanding of both processes. In this review, we address the recent advances in our understanding of the contributions of local and systemic environments to cancer progression, the ability of tumors to actively perturb the host environment, and current therapeutic approaches that are designed to disrupt tumor-host relationships.

scholarly journals Cancer-Associated Fibroblasts in Pancreatic Cancer: Should They Be Deleted or Reeducated?

2018 ◽  
Vol 17 (4) ◽  
pp. 1016-1019 ◽  
Author(s):  
Chao Qu ◽  
Qing Wang ◽  
Zhiqiang Meng ◽  
Peng Wang
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Cancer Associated Fibroblasts

Pancreatic ductal adenocarcinoma is characterized by an extensive stromal response called desmoplasia. Within the tumor stroma, cancer-associated fibroblasts (CAFs) are the primary cell type. CAFs have been shown to play a role in pancreatic cancer progression; they secrete growth factors, inflammatory cytokines, and chemokines that stimulate signaling pathways in cancer cells and modulate the cancer biology toward increased aggressiveness. Therefore, targeting CAFs may serve as a powerful weapon against pancreatic cancer and improve therapeutic effects. However, a previous study aiming to deplete CAFs by inhibiting sonic Hedgehog signaling failed to show any benefit in survival time of pancreatic cancer patients. We reported that the natural product curcumin reeducated CAFs in pancreatic cancer treatment. A low concentration of curcumin reversed the activation of fibroblasts without exhibiting growth suppression effects. In addition, curcumin suppressed CAF-induced pancreatic cancer cell migration and invasion in vitro and lung metastasis in vivo. The results of our study suggest that active CAFs can be inactivated by certain natural products such as curcumin. Reeducation of CAFs back to their normal state, rather than their indiscriminate depletion, may broaden our view in the development of therapeutic options for the treatment of pancreatic cancer.

scholarly journals MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3

Oncogene ◽  
2021 ◽  
Author(s):  
Sunil Kumar Singh ◽  
Sandeep Kumar ◽  
Navin Viswakarma ◽  
Daniel R. Principe ◽  
Subhasis Das ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Pancreatic Cancer Cell ◽  
Tumor Stroma ◽  
Tumor Burden ◽  
Pancreatic Tumors ◽  
Cancer Cell Growth ◽  
Downstream Target

AbstractMAP4K4 is a Ste20 member and reported to play important roles in various pathologies, including in cancer. However, the mechanism by which MAP4K4 promotes pancreatic cancer is not fully understood. It is suggested that MAP4K4 might function as a cancer promoter via specific downstream target(s) in an organ-specific manner. Here we identified MLK3 as a direct downstream target of MAP4K4. The MAP4K4 and MLK3 associates with each other, and MAP4K4 phosphorylates MLK3 on Thr738 and increases MLK3 kinase activity and downstream signaling. The phosphorylation of MLK3 by MAP4K4 promotes pancreatic cancer cell proliferation, migration, and colony formation. Moreover, MAP4K4 is overexpressed in human pancreatic tumors and directly correlates with the disease progression. The MAP4K4-specific pharmacological inhibitor, GNE-495, impedes pancreatic cancer cell growth, migration, induces cell death, and arrests cell cycle progression. Additionally, the GNE-495 reduced the tumor burden and extended survival of the KPC mice with pancreatic cancer. The MAP4K4 inhibitor also reduced MAP4K4 protein expression, tumor stroma, and induced cell death in murine pancreatic tumors. These findings collectively suggest that MLK3 phosphorylation by MAP4K4 promotes pancreatic cancer, and therefore therapies targeting MAP4K4 might alleviate the pancreatic cancer tumor burden in patients.

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 Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma

2020 ◽  
Author(s):  
Allison N. Lau ◽  
Zhaoqi Li ◽  
Laura V. Danai ◽  
Anna M. Westermark ◽  
Alicia M. Darnell ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Heterogeneous Systems ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Specific Cell ◽  
Isolated Cells ◽  
Pancreatic Cancer Cells ◽  
Turn Over

AbstractTumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between various cell types within a mixed population can be limited by the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in pancreatic cancer organoid-fibroblast co-cultures and in pancreatic tumors. In these contexts, we find pancreatic cancer cells exhibit increased pyruvate carboxylation relative to fibroblasts, and that this flux depends on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells is necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tumor tissue.

scholarly journals Cancer-associated Fibroblasts: Origins, Heterogeneity and Functions in Tumor Microenvironment

2020 ◽  
Author(s):  
Kevin Dzobo
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Tumor Stroma ◽  
Bioinformatic Analysis ◽  
Therapy Resistance ◽  
Response To Therapy ◽  
The Cancer Genome Atlas ◽  
Cancer Associated Fibroblasts

Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases was used. Bioinformatic analysis reveals differential expression of CAF markers in several cancer types, underscoring the need for further multiomics and biochemical studies on CAFs, CAF subsets and markers. Differences in CAF markers’ expression could be due to different cellular origins as well as the effect of cancer-specific tumor microenvironmental effect on CAFs. Lastly, I present recent advances in therapeutic targeting of CAFs and the success of such endeavours or its lack thereof. It is recommended that for patients’ outcomes to improve, cancer treatment be combinatorial in nature, targeting both cancer cells and stromal cells and interactions.

Extracellular Vesicles Isolated from Mesenchymal Stromal Cells Primed with Hypoxia: Novel strategy in Regenerative Medicine

2020 ◽  
Vol 15 ◽  
Author(s):  
Shalmali Pendse ◽  
Vaijayanti Kale ◽  
Anuradha Vaidya
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Cell Types ◽  
Molecular Profile ◽  
Cell Contact ◽  
Hematopoietic Stem

: Mesenchymal stromal cells (MSCs) regulate other cell types through a strong paracrine component called the secretome, comprising of several bioactive entities. The composition of the MSCs’ secretome is dependent upon the microenvironment in which they thrive, and hence, it could be altered by pre-conditioning the MSCs during in vitro culture. The primary aim of this review is to discuss various strategies that are being used for pre-conditioning of MSCs, also known as “priming of MSCs”, in the context of improving their therapeutic potential. Several studies have underscored the importance of extracellular vesicles (EVs) derived from primed MSCs in improving their efficacy in the treatment of various diseases. We have previously shown that co-culturing hematopoietic stem cells (HSCs) with hypoxiaprimed MSCs improves their engraftment potential. Now the question we pose is would priming of MSCs with hypoxiafavorably alter theirsecretome and would this altered secretome work as effectively as the cell to cell contact did? Here we review the current strategies of using the secretome, specifically the EVs (microvesicles and exosomes), collected from the primed MSCs with the intention of expanding HSCs ex vivo. We speculate that an effective priming of MSCs in vitrocould modulate the molecular profile of their secretome, which could eventually be used as a cell-free biologic in clinical settings.

scholarly journals The Effects of Chemotherapeutics on the Ovarian Cancer Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3136
Author(s):  
Mark A. Eckert ◽  
Carlos Orozco ◽  
Jason Xiao ◽  
Melissa Javellana ◽  
Ernst Lengyel
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Tumor Stroma ◽  
Cell Types ◽  
Parp Inhibitors ◽  
Chemotherapeutic Agents ◽  
Cancer Types ◽  
Cellular Components ◽  
Target Cancer

High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor–stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics.

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