scholarly journals Cancer-associated fibroblasts as a potential target in oncology therapy

2019 ◽  
Vol 73 ◽  
pp. 536-549
Author(s):  
Agnieszka Dominiak ◽  
Tomasz Nowicki ◽  
Dominika Łacheta ◽  
Grażyna Nowicka
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Early Stage ◽  
Normal Fibroblast ◽  
Cancer Associated Fibroblasts ◽  
Complex Environment ◽  
Reactive Stroma ◽  
Promising Therapeutic Target ◽  
Cell Groups ◽  
Phenotypic Transition

Tumors make up a complex environment that consists of intensive proliferating cancer cells surrounded by normal cells. Fibroblasts recruited by cancer termed CAFs, are one of the major cell groups within the reactive stroma of the most common tumors. Because of the crosstalk between quiescent fibroblasts and cancer cells, fibroblasts undergo phenotypic transition and acquire new functions that have been “forced by a tumor”. CAFs affect the development of the drug resistance and cancer progression as they are involved in the growth of cancers, neoangiogenesis, immune evasion and metastatic colonisation in distant organs. Fibroblast-directed therapy offers the opportunity to prevent initiation, progression and metastasis of many invasive tumors. The current studies on CAF-based therapy focus on two strategies. The first strategy leads to the elimination of CAFs and the neutralization of their released factors and the second aims at reverting the CAF-phenotype to a “normal” fibroblast-phenotype. Although the results of preclinical studies conducted on cell cultures and animal models indicate that therapy aimed at reversion or inhibition CAFs function seem to be a promising therapeutic target, available clinical studies have not yet confirmed this. Nevertheless, it is necessary to underline that until now CAF-based therapy has been used in patients with advanced cancer and there is no clinical study using such therapy in the early stage of cancer. The available data also indicates that CAF-based therapy could be used in combination with common anticancer drugs to increase their effectiveness. Therefore, further studies on the usefulness of the proposed CAF-based therapy are needed.

scholarly journals miR-338-3p Is Regulated by Estrogens through GPER in Breast Cancer Cells and Cancer-Associated Fibroblasts (CAFs)

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 203 ◽  
Author(s):  
Adele Vivacqua ◽  
Anna Sebastiani ◽  
Anna Miglietta ◽  
Damiano Rigiracciolo ◽  
Francesca Cirillo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancer Patients ◽  
Expression Of Genes ◽  
Taqman Array

Estrogens acting through the classic estrogen receptors (ERs) and the G protein estrogen receptor (GPER) regulate the expression of diverse miRNAs, small sequences of non-coding RNA involved in several pathophysiological conditions, including breast cancer. In order to provide novel insights on miRNAs regulation by estrogens in breast tumor, we evaluated the expression of 754 miRNAs by TaqMan Array in ER-negative and GPER-positive SkBr3 breast cancer cells and cancer-associated fibroblasts (CAFs) upon 17β-estradiol (E2) treatment. Various miRNAs were regulated by E2 in a peculiar manner in SkBr3 cancer cells and CAFs, while miR-338-3p displayed a similar regulation in both cell types. By METABRIC database analysis we ascertained that miR-338-3p positively correlates with overall survival in breast cancer patients, according to previous studies showing that miR-338-3p may suppress the growth and invasion of different cancer cells. Well-fitting with these data, a miR-338-3p mimic sequence decreased and a miR-338-3p inhibitor sequence rescued the expression of genes and the proliferative effects induced by E2 through GPER in SkBr3 cancer cells and CAFs. Altogether, our results provide novel evidence on the molecular mechanisms by which E2 may regulate miR-338-3p toward breast cancer progression.

scholarly journals Snail1-dependent cancer-associated fibroblasts induce epithelial-mesenchymal transition in lung cancer cells via exosomes

QJM ◽  
2019 ◽  
Vol 112 (8) ◽  
pp. 581-590 ◽  
Author(s):  
J You ◽  
M Li ◽  
L M Cao ◽  
Q H Gu ◽  
P B Deng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Conditioned Medium ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Negative Control ◽  
Lung Cancer Cells ◽  
Cancer Associated Fibroblasts ◽  
Mesenchymal Transition ◽  
E Cadherin

Abstract Background Epithelial-mesenchymal transition (EMT) is an essential component of metastasis. Our previous study demonstrated that cancer-associated fibroblasts (CAFs) induce EMT in lung cancer cells. In recent years, many studies have demonstrated that CAFs induce metastasis and drug resistance in cancer cells via exosomes. Aim We sought to discover the mechanism underlying how CAFs induce EMT in lung cancer cells, unveiling the role of exosomes in lung cancer progression. Design We cultured lung cancer cell (i) with control medium, normal fibroblasts (NFs) or CAFs; (ii) with SNAI1-transfected or NC (negative control)-transfected CAFs; (iii) with exosomes extracted from NF- or CAF-conditioned medium; (iv) with exosomes released by SNAI1 or NC-transfected CAFs; (v) with CAF-conditioned medium or exosome-depleted CAF-conditioned medium. Methods qRT-PCR was conducted to examine the expression of CDH1 (gene of E-cadherin) and VIM (gene of Vimentin), western blotting was conducted to examine E-cadherin and vimentin levels in lung cancer cells. Results Exosomes released by CAFs-promoted EMT in lung cancer cells. Interestingly, SNAI1 levels in exosomes secreted from CAFs were correlated with SNAI1 expression in CAFs. Furthermore, the level of SNAI1 in exosomes was crucial for inducing EMT in lung cancer cells. Finally, treatment of CAFs with GW4869, an inhibitor of exosome release, noticeably inhibited their EMT-inducing effect on recipient epithelial cells. Conclusions The molecular mechanism underlying how CAFs induce EMT in cancer cells may be that CAFs deliver SNAI1 to recipient cancer cells via exosomes.

scholarly journals Sensitivity to Cisplatin in Head and Neck Cancer Cells Is Significantly Affected by Patient-Derived Cancer-Associated Fibroblasts

2021 ◽  
Vol 22 (4) ◽  
pp. 1912
Author(s):  
Barbora Peltanova ◽  
Marketa Liskova ◽  
Jaromir Gumulec ◽  
Martina Raudenska ◽  
Hana Holcova Polanska ◽  
...  
Keyword(s):  
Head And Neck ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Treatment Resistance ◽  
Tumor Stroma ◽  
Cancer Associated Fibroblasts ◽  
Paracrine Effects ◽  
Expression Of Genes ◽  
Critical Components ◽  
Sensitizing Effect

Cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor stroma. CAFs can impact many important steps of cancerogenesis and may also influence treatment resistance. Some of these effects need the direct contact of CAFs and cancer cells, while some involve paracrine signals. In this study, we investigated the ability of head and neck squamous cell carcinomas (HNSCC) patient-derived CAFs to promote or inhibit the colony-forming ability of HNSCC cells. The effect of cisplatin on this promoting or inhibiting influence was also studied. The subsequent analysis focused on changes in the expression of genes associated with cancer progression. We found that cisplatin response in model HNSCC cancer cells was modified by coculture with CAFs, was CAF-specific, and different patient-derived CAFs had a different “sensitizing ratio”. Increased expression of VEGFA, PGE2S, COX2, EGFR, and NANOG in cancer cells was characteristic for the increase of resistance. On the other hand, CCL2 expression was associated with sensitizing effect. Significantly higher amounts of cisplatin were found in CAFs derived from patients who subsequently experienced a recurrence. In conclusion, our results showed that CAFs could promote and/or inhibit colony-forming capability and cisplatin resistance in HNSCC cells via paracrine effects and subsequent changes in gene expression of cancer-associated genes in cancer cells.

scholarly journals Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Fanglong Wu ◽  
Jin Yang ◽  
Junjiang Liu ◽  
Ye Wang ◽  
Jingtian Mu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Matrix Remodeling ◽  
Cancer Associated Fibroblasts

AbstractTo flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial–mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.

scholarly journals Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2896
Author(s):  
Naofumi Mukaida ◽  
Di Zhang ◽  
So-ichiro Sasaki
Keyword(s):  
Bone Marrow ◽  
Bone Metastasis ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cancer Associated Fibroblasts ◽  
Cancer Cell Growth ◽  
Lung Cancers ◽  
Osteoclast Activation

Bone metastasis is frequently complicated in patients with advanced solid cancers such as breast, prostate and lung cancers, and impairs patients’ quality of life and prognosis. At the first step of bone metastasis, cancer cells adhere to the endothelium in bone marrow and survive in a dormant state by utilizing hematopoietic niches present therein. Once a dormant stage is disturbed, cancer cells grow through the interaction with various bone marrow resident cells, particularly osteoclasts and osteoblasts. Consequently, osteoclast activation is a hallmark of bone metastasis. As a consequence, the drugs targeting osteoclast activation are frequently used to treat bone metastasis but are not effective to inhibit cancer cell growth in bone marrow. Thus, additional types of resident cells are presumed to contribute to cancer cell growth in bone metastasis sites. Cancer-associated fibroblasts (CAFs) are fibroblasts that accumulate in cancer tissues and can have diverse roles in cancer progression and metastasis. Given the presence of CAFs in bone metastasis sites, CAFs are emerging as an important cellular player in bone metastasis. Hence, in this review, we will discuss the potential roles of CAFs in tumor progression, particularly bone metastasis.

scholarly journals Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis

2017 ◽  
Vol 45 (1) ◽  
pp. 229-236 ◽  
Author(s):  
Begum Erdogan ◽  
Donna J. Webb
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
Matrix Remodeling ◽  
Growth Factor Signaling ◽  
Cancer Associated Fibroblasts ◽  
Cell Migration And Invasion ◽  
Tumor Cell Migration

Cancer-associated fibroblasts (CAFs) are major components of the surrounding stroma of carcinomas that emerge in the tumor microenvironment as a result of signals derived from the cancer cells. Biochemical cross-talk between cancer cells and CAFs as well as mechanical remodeling of the stromal extracellular matrix (ECM) by CAFs are important contributors to tumor cell migration and invasion, which are critical for cancer progression from a primary tumor to metastatic disease. In this review, we discuss key paracrine signaling pathways between CAFs and cancer cells that promote cancer cell migration and invasion. In addition, we discuss physical changes that CAFs exert on the stromal ECM to facilitate migration and invasion of cancer cells.

scholarly journals Determinants and Functions of CAFs Secretome During Cancer Progression and Therapy

2021 ◽  
Vol 8 ◽  
Author(s):  
Jenniffer Linares ◽  
Juan A. Marín-Jiménez ◽  
Jordi Badia-Ramentol ◽  
Alexandre Calon
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Diagnosis ◽  
Response To Treatment ◽  
Cancer Associated Fibroblasts ◽  
Epithelial Cancer ◽  
Diagnosis And Prognosis ◽  
Secreted Factors ◽  
Druggable Targets ◽  
Lines Of Evidence

Multiple lines of evidence are indicating that cancer development and malignant progression are not exclusively epithelial cancer cell-autonomous processes but may also depend on crosstalk with the surrounding tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are abundantly represented in the TME and are continuously interacting with cancer cells. CAFs are regulating key mechanisms during progression to metastasis and response to treatment by enhancing cancer cells survival and aggressiveness. The latest advances in CAFs biology are pointing to CAFs-secreted factors as druggable targets and companion tools for cancer diagnosis and prognosis. Especially, extensive research conducted in the recent years has underscored the potential of several cytokines as actionable biomarkers that are currently evaluated in the clinical setting. In this review, we explore the current understanding of CAFs secretome determinants and functions to discuss their clinical implication in oncology.

scholarly journals Cancer Associated Fibroblasts Promote Renal Cancer Progression Through a TDO/Kyn/AhR Dependent Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Li-bo Chen ◽  
Shun-ping Zhu ◽  
Tian-pei Liu ◽  
Heng Zhao ◽  
Ping-feng Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Renal Cancer ◽  
Cancer Progression ◽  
Cancer Associated Fibroblasts ◽  
Aromatic Hydrocarbon Receptor ◽  
Cancer Migration ◽  
Tumor Tissues ◽  
Enhanced Secretion

Cancer associated fibroblasts (CAFs) play crucial roles in cancer development, however, the specific mechanisms of CAFs associated renal cancer progression remain poorly understood. Our study observed enriched CAFs in high degree malignant tumor tissues from renal cancer patients. These CAFs isolated from tumor tissues are prone to facilitate drugs resistance and promote tumor progression in vitro and in vivo. Mechanistically, CAFs up-regulated tryptophan 2, 3-dioxygenase (TDO) expression, resulting in enhanced secretion of kynurenine (Kyn). Kyn produced from CAFs could up-regulated the expression of aromatic hydrocarbon receptor (AhR), eventually resulting in the AKT and STAT3 signaling pathways activation. Inhibition of AKT signal prevented cancer cells proliferation, while inhibition of the STAT3 signal reverted drugs resistance and cancer migration induced by kynurenine. Application of AhR inhibitor DMF could efficiently suppress distant metastasis of renal cancer cells, and improve anticancer effects of sorafenib (Sor)/sunitinib (Sun), which described a promising therapeutic strategy for clinical renal cancer.

scholarly journals Searching for Promoters to Drive Stable and Long-Term Transgene Expression in Fibroblasts for Syngeneic Mouse Tumor Models

2020 ◽  
Vol 21 (17) ◽  
pp. 6098
Author(s):  
Dina V. Antonova ◽  
Irina V. Alekseenko ◽  
Anastasiia K. Siniushina ◽  
Alexey I. Kuzmich ◽  
Victor V. Pleshkan
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transgene Expression ◽  
Close Contact ◽  
Mouse Tumor ◽  
Cancer Associated Fibroblasts

Tumor is a complex system of interactions between cancer cells and other cells of the tumor microenvironment. The cancer-associated fibroblasts (CAFs) of the tumor microenvironment remain in close contact with the cancer cells and play an important role in cancer progression. Genetically, CAFs are more stable than cancer cells, making them an attractive target for genetic modification in gene therapy. However, the efficiency of various promoters for transgene expression in fibroblasts is scarcely studied. We performed a comparative analysis of transgene long-term expression under the control of strong cytomegalovirus promoter (pCMV), constitutive cell promoter of the PCNA gene (pPCNA), and the potentially fibroblast-specific promoter of the IGFBP2 gene (pIGFBP2). In vitro expression of the transgene under the control of pCMV in fibroblasts was decreased soon after transduction, whereas the expression was more stable under the control of pIGFBP2 and pPCNA. The efficiency of transgene expression was higher under pPCNA than that under pIGFBP2. Additionally, in a mouse model, pPCNA provided more stable and increased transgene expression in fibroblasts as compared to that under pCMV. We conclude that PCNA promoter is the most efficient for long-term expression of transgenes in fibroblasts both in vitro and in vivo.

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