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1.
J Biochem Mol Toxicol ; 38(9): e23778, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39252517

RESUMO

Hepatocellular carcinoma (HCC) is a lethal form of liver cancer, and the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays a critical role in its progression. This study aimed to elucidate the mechanism by which CAF-derived exosomes regulate the development of HCC. The study employed quantitative real-time polymerase chain reaction for mRNA expression analysis and western blot analysis for protein expression detection. Chromatin immunoprecipitation assay and dual-luciferase reporter assay were performed to investigate the relationship between zinc finger protein 250 (ZNF250) and programmed cell death 1 ligand 1 (PD-L1). Transmission electron microscopy and western blot analysis were used to characterize the isolated exosomes. The transferability of CAF-derived exosomes and normal fibroblasts (NFs)-derived exosomes into HCC cells was analyzed using a green fluorescent labeling dye PKH67. Cell proliferation was assessed via a 5-Ethynyl-2'-deoxyuridine assay, while Transwell assays were conducted to evaluate cell migration and invasion. Flow cytometry was performed to measure cell apoptosis, while enzyme-linked immunosorbent assays were used to assess the levels of tumor necrosis factor-α and perforin. Finally, a xenograft mouse model was constructed to examine the effects of exosomes derived from ZNF250-deficient CAFs on the tumor properties of HCC cells. The study revealed increased expression of ZNF250 in HCC tissues and cells, with ZNF250 transcriptionally activating PD-L1 in HCC cells. ZNF250 expression was associated with HbsAg, clinical stage and tumor size of HCC patients. CAF-derived exosomal ZNF250 can regulate PD-L1 expression in HCC cells. Furthermore, exosomes derived from ZNF250-deficient CAFs inhibited the proliferation, migration, invasion, and immune escape of HCC cells by downregulating PD-L1 expression. Moreover, CAF-derived exosomal ZNF250 promoted tumor formation in vivo. These findings provide insights into the role of CAF-derived exosomes in the suppression of HCC development, highlighting the significance of ZNF250 and PD-L1 regulation in tumor progression.


Assuntos
Antígeno B7-H1 , Fibroblastos Associados a Câncer , Carcinoma Hepatocelular , Movimento Celular , Proliferação de Células , Exossomos , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/genética , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Humanos , Exossomos/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Animais , Camundongos , Invasividade Neoplásica , Linhagem Celular Tumoral , Evasão Tumoral , Camundongos Nus , Masculino , Ativação Transcricional , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica
2.
Front Immunol ; 15: 1427124, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39238647

RESUMO

Background: Ferroptosis, as a novel form of programmed cell death, plays a crucial role in the occurrence and development of bladder cancer (BCa). However, the regulatory mechanisms of ferroptosis in the tumor microenvironment (TME) of BCa remain to be elucidated. Methods: Based on single-cell RNA (scRNA) transcriptomic data of BCa, we employed non-negative matrix factorization (NMF) dimensionality reduction clustering to identify novel ferroptosis-related cell subtypes within the BCa TME, aiming to explore the biological characteristics of these TME cell subtypes. Subsequently, we conducted survival analysis and univariate Cox regression analysis to explore the prognostic significance of these cell subtypes. We investigated the relationship between specific subtypes and immune infiltration, as well as their implications for immunotherapy. Finally, we discovered a valuable and novel biomarker for BCa, supported by a series of in vitro experiments. Results: We subdivided cancer-associated fibroblasts (CAFs), macrophages, and T cells into 3-5 small subpopulations through NMF and further explored the biological features. We found that ferroptosis played an important role in the BCa TME. Through bulk RNA-seq analysis, we further verified that ferroptosis affected the progression, prognosis, and immunotherapy response of BCa by regulating the TME. Especially ACSL4+CAFs, we found that high-level infiltration of this CAF subtype predicted worse prognosis, more complex immune infiltration, and less response for immunotherapy. Additionally, we found that this type of CAF was associated with cancer cells through the PTN-SDC1 axis, suggesting that SDC1 may be crucial in regulating CAFs in cancer cells. A series of in vitro experiments confirmed these inferences: SDC1 promoted the progression of BCa. Interestingly, we also discovered FTH1+ macrophages, which were closely related to SPP1+ macrophages and may also be involved in the regulation of BCa TME. Conclusion: This study revealed the significant impact of ferroptosis on bladder cancer TME and identified novel ferroptosis-related TME cell subpopulations, ACSL4+CAFs, and important BCa biomarker SDC1.


Assuntos
Progressão da Doença , Ferroptose , Imunoterapia , Análise de Célula Única , Transcriptoma , Microambiente Tumoral , Neoplasias da Bexiga Urinária , Ferroptose/genética , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/patologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Imunoterapia/métodos , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Prognóstico , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia
3.
Theranostics ; 14(12): 4822-4843, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39239526

RESUMO

Background: Cancer-associated fibroblasts (CAFs) are the key components of the immune barrier in liver cancer. Therefore, gaining a deeper understanding of the heterogeneity and intercellular communication of CAFs holds utmost importance in boosting immunotherapy effectiveness and improving clinical outcomes. Methods: A comprehensive analysis by combing single-cell, bulk, and spatial transcriptome profiling with multiplexed immunofluorescence was conducted to unravel the complexities of CAFs in liver cancer. Results: Through an integrated approach involving 235 liver cancer scRNA-seq samples encompassing over 1.2 million cells, we found that CAFs were particularly increased in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). FAP + fibroblasts were identified as the dominant subtype of CAFs, and which were mainly involved in extracellular matrix organization and angiogenesis. These CAFs were enriched in the tumor boundary of HCC, but diffusely scattered within ICC. The DAB2 + and SPP1 + tumor-associated macrophages (TAMs) reinforce the function of FAP + CAFs through signals such as TGF-ß, PDGF, and ADM. Notably, the interaction between DAB2 + TAMs and FAP + CAFs promoted the formation of immune barrier and correlated with poorer patient survival, non-response to immunotherapy in HCC. High FAP and DAB2 immunohistochemical scores predicted shorter survival and higher serum AFP concentration in a local clinical cohort of 90 HCC patients. Furthermore, this communication pattern might be applicable to other solid malignancies as well. Conclusions: The interaction between DAB2 + TAMs and FAP + CAFs appears crucial in shaping the immune barrier. Strategies aimed at disrupting this communication or inhibiting the functions of FAP + CAFs could potentially enhance immunotherapy effectiveness and improve clinical outcomes.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/imunologia , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/imunologia , Microambiente Tumoral/imunologia , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Colangiocarcinoma/terapia , Colangiocarcinoma/patologia , Colangiocarcinoma/imunologia , Colangiocarcinoma/metabolismo , Imunoterapia/métodos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Masculino , Feminino , Endopeptidases
4.
Mol Cancer ; 23(1): 191, 2024 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-39244548

RESUMO

Cancer-associated fibroblasts (CAFs) are a diverse stromal cell population within the tumour microenvironment, where they play fundamental roles in cancer progression and patient prognosis. Multiple lines of evidence have identified that CAFs are critically involved in shaping the structure and function of the tumour microenvironment with numerous functions in regulating tumour behaviours, such as metastasis, invasion, and epithelial-mesenchymal transition (EMT). CAFs can interact extensively with cancer cells by producing extracellular vesicles (EVs), multiple secreted factors, and metabolites. Notably, CAF-derived EVs have been identified as critical mediators of cancer therapy resistance, and constitute novel therapy targets and biomarkers in cancer management. This review aimed to summarize the biological roles and detailed molecular mechanisms of CAF-derived EVs in mediating cancer resistance to chemotherapy, targeted therapy agents, radiotherapy, and immunotherapy. We also discussed the therapeutic potential of CAF-derived EVs as novel targets and clinical biomarkers in cancer clinical management, thereby providing a novel therapeutic strategy for enhancing cancer therapy efficacy and improving patient prognosis.


Assuntos
Fibroblastos Associados a Câncer , Resistencia a Medicamentos Antineoplásicos , Vesículas Extracelulares , Neoplasias , Microambiente Tumoral , Humanos , Vesículas Extracelulares/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Biomarcadores Tumorais/metabolismo , Animais , Transição Epitelial-Mesenquimal , Relevância Clínica
5.
Pathol Res Pract ; 262: 155576, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39232286

RESUMO

Cancer-associated fibroblasts are the most important cellular component of the tumor microenvironment, controlling cancer progression and therapeutic response. These cells in the tumor microenvironment regulate tumor progression and development as oncogenic or tumor suppressor agents. However, the mechanisms by which CAFs communicate with cancer cells remain to investigate. Here, we review evidence that extracellular vesicles, particularly exosomes, serve as vehicles for the intercellular transfer of bioactive cargos, notably microRNAs and long non-coding RNAs, from CAFs to cancer cells. We try to highlight molecular pathways of non-coding RNAs and the interaction among these molecules. Together, these findings elucidate a critical exosome-based communication axis by which CAFs create mostly a supportive pro-tumorigenic microenvironment and highlight therapeutic opportunities for disrupting this intercellular crosstalk.


Assuntos
Fibroblastos Associados a Câncer , Progressão da Doença , Exossomos , Neoplasias , Microambiente Tumoral , Humanos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Exossomos/metabolismo , Exossomos/genética , Neoplasias/patologia , Neoplasias/genética , Neoplasias/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Comunicação Celular , MicroRNAs/genética , MicroRNAs/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismo
6.
Sci Rep ; 14(1): 20698, 2024 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-39237667

RESUMO

Interactions between tumor and stromal cells are well known to play prominent roles in progression of pancreatic ductal adenocarcinoma (PDAC). As knowledge of stromal crosstalk in PDAC has evolved, it has become clear that cancer associated fibroblasts can play both tumor promoting and tumor suppressive roles through a combination of paracrine crosstalk and juxtacrine interactions involving direct physical contact. Another major contributor to dismal survival statistics for PDAC is development of resistance to chemotherapy drugs, though less is known about how the acquisition of chemoresistance impacts upon tumor-stromal crosstalk. Here, we use time lapse imaging and image analysis to study how co-culture geometry impacts interactions between epithelial and stromal cells. We show that extracellular matrix (ECM) overlay cultures in which stromal cells (pancreatic stellate cells, or normal human fibroblasts) are placed adjacent to PDAC cells (PANC1) result in direct heterotypic cell adhesions accompanied by dramatic fibroblast contractility. We analyze these interactions in co-cultures using particle image velocimetry (PIV) analysis to quantify cell velocities over the course of time lapse movie sequences. We further contrast co-cultures of PANC1 with those containing a drug resistant subline (PANC1-OR) previously established in our lab and find that heterotypic cell-cell interactions are suppressed in the latter relative to the parental line. We use RNA-seq and bioinformatics analysis to identify differential gene expression in PANC1 and PANC1-OR, which shows that negative regulation of cell adhesion molecules, consistent with increased epithelial mesenchymal transition (EMT), is also correlated with reduction in the hetrotypic cell-cell contact necessary for the contractile behavior observed in drug naïve cultures. Overall these findings elucidate the role of drug-resistance in inhibiting an avenue of stromal crosstalk which is associated with tumor suppression and also help to establish cell culture conditions useful for further mechanistic investigation.


Assuntos
Carcinoma Ductal Pancreático , Comunicação Celular , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos , Fibroblastos , Neoplasias Pancreáticas , Células Estromais , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Células Estromais/metabolismo , Fibroblastos/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Microambiente Tumoral , Células Estreladas do Pâncreas/metabolismo , Células Estreladas do Pâncreas/efeitos dos fármacos , Matriz Extracelular/metabolismo
7.
Cancer Res ; 84(18): 2938-2940, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39279382

RESUMO

Our knowledge of the origins, heterogeneity, and functions of cancer-associated fibroblasts (CAF) in pancreatic ductal adenocarcinoma (PDAC) has exponentially increased over the last two decades. This has been facilitated by the implementation of new models and single-cell technologies. However, a few key studies preceded the current exciting times in CAF research and were fundamental in initiating the investigation of CAFs and of their roles in PDAC. With their study published in Cancer Research in 2008, Hwang and colleagues have been first to successfully isolate and immortalize human pancreatic stellate cells (HPSC) from PDAC tissues. This new tool allowed them to probe the roles of CAFs in PDAC as never done before. By performing complementary in vitro and in vivo analyses, the authors demonstrated the involvement of HPSCs in PDAC malignant cell proliferation, invasion, and therapy resistance. Here, we leverage that seminal study as a framework to discuss the advances made over the last 16 years in understanding the complexity and central roles of CAFs in PDAC progression. See related article by Hwang and colleagues, Cancer Res 2008;68:918-26.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma Ductal Pancreático , Progressão da Doença , Neoplasias Pancreáticas , Humanos , Fibroblastos Associados a Câncer/patologia , Fibroblastos Associados a Câncer/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Animais , Células Estreladas do Pâncreas/patologia , Células Estreladas do Pâncreas/metabolismo , Proliferação de Células
8.
Int J Biol Sci ; 20(11): 4128-4145, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39247832

RESUMO

The occurrence of metastasis is a major factor contributing to poor prognosis in colorectal cancer. Different stages of the disease play a crucial role in distant metastasis. Furthermore, m6A has been demonstrated to play a significant role in regulating tumor metastasis. Therefore, we conducted an analysis of transcriptome data from high-stage and low-stage colorectal cancer patients in The Cancer Genome Atlas (TCGA) to identify genes associated with m6A-related regulation. We identified SYNPO2L as a core gene regulated by m6A, and it is correlated with adverse prognosis and metastasis in patients. Additionally, we demonstrated that the m6A writer gene Mettl16 can regulate the stability of SYNPO2L through interaction with YTHDC1. Subsequently, using Weighted Gene Co-expression Network Analysis (WGCNA), we discovered that SYNPO2L can regulate COL10A1, mediating the actions of Cancer-Associated Fibroblasts. SYNPO2L promotes the secretion of COL10A1 and the infiltration of tumor-associated fibroblasts, thereby facilitating Epithelial-Mesenchymal Transition (EMT) in tumor cells and making them more prone to distant metastasis.


Assuntos
Fibroblastos Associados a Câncer , Colágeno Tipo X , Neoplasias Pulmonares , Metiltransferases , RNA Mensageiro , Animais , Humanos , Camundongos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Colágeno Tipo X/metabolismo , Colágeno Tipo X/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metiltransferases/metabolismo , Metiltransferases/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética
9.
Nat Commun ; 15(1): 7984, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39266569

RESUMO

Alterations in nuclear structure and function are hallmarks of cancer cells. Little is known about these changes in Cancer-Associated Fibroblasts (CAFs), crucial components of the tumor microenvironment. Loss of the androgen receptor (AR) in human dermal fibroblasts (HDFs), which triggers early steps of CAF activation, leads to nuclear membrane changes and micronuclei formation, independent of cellular senescence. Similar changes occur in established CAFs and are reversed by restoring AR activity. AR associates with nuclear lamin A/C, and its loss causes lamin A/C nucleoplasmic redistribution. AR serves as a bridge between lamin A/C and the protein phosphatase PPP1. Loss of AR decreases lamin-PPP1 association and increases lamin A/C phosphorylation at Ser 301, a characteristic of CAFs. Phosphorylated lamin A/C at Ser 301 binds to the regulatory region of CAF effector genes of the myofibroblast subtype. Expression of a lamin A/C Ser301 phosphomimetic mutant alone can transform normal fibroblasts into tumor-promoting CAFs.


Assuntos
Fibroblastos Associados a Câncer , Núcleo Celular , Lamina Tipo A , Receptores Androgênicos , Humanos , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Lamina Tipo A/metabolismo , Lamina Tipo A/genética , Fosforilação , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Núcleo Celular/metabolismo , Proteína Fosfatase 1/metabolismo , Proteína Fosfatase 1/genética , Fibroblastos/metabolismo , Membrana Nuclear/metabolismo , Masculino , Microambiente Tumoral
10.
Cells ; 13(17)2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39272978

RESUMO

The role of periostin (POSTN) in remodeling the microenvironment surrounding solid tumors and its effect on the tumor cells in non-small-cell lung carcinoma (NSCLC) have not yet been fully understood. The aim of this study was to determine the relationship between POSTN expression (in tumor cells [NSCLC cells] and the tumor stroma) and pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and microvascular density (MVD) in NSCLC. In addition, these associations were analyzed in individual histological subtypes of NSCLC (SCC, AC, and LCC) and their correlations with clinicopathological factors and prognosis were examined. Immunohistochemistry using tissue microarrays (TMAs) was used to assess the expression of POSTN (in tumor cells and cancer-associated fibroblasts [CAFs]) and the pro-angiogenic factors. A significant positive correlation was found between the expression of POSTN (in cancer cells/CAFs) and the expression of the analyzed pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and MVD in the entire population of patients with NSCLC and individual histological subtypes (AC, SCC). In addition, this study found that POSTN expression (in tumor cells/CAFs) increased with tumor size (pT), histopathological grade (G), and lymph-node involvement (pN). In addition, a high expression of POSTN (in tumor cells and CAFs) was associated with shorter survival among patients with NSCLC. In conclusion, a high expression of POSTN (in cancer cells and CAFs) may be crucial for angiogenesis and NSCLC progression and can constitute an independent prognostic factor for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Moléculas de Adesão Celular , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Moléculas de Adesão Celular/metabolismo , Feminino , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Idoso , Neovascularização Patológica/metabolismo , Prognóstico , Indutores da Angiogênese/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Periostina
11.
Int J Mol Sci ; 25(17)2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39273225

RESUMO

Cancer-associated fibroblast (CAF)s in the tumour microenvironment (TME) modulate the extracellular matrix, interact with cancer cells, and facilitate communication with infiltrating leukocytes, significantly contributing to cancer progression and therapeutic response. In prostate cancer (PCa), CAFs promote malignancy through metabolic rewiring, cancer stem cell regulation, and therapy resistance. Pre-clinical studies indicate that targeting amino acid metabolism, particularly glutamine (Gln) metabolism, reduces cancer proliferation and stemness. However, most studies lack the context of CAF-cancer interaction, focusing on monocultures. This study assesses the influence of CAFs on PCa growth by manipulating Gln metabolism using colour-labelled PCa cell lines (red) and fibroblast (green) in a co-culture system to evaluate CAFs' effects on PCa cell proliferation and clonogenic potential. CAFs increased the proliferation of hormone-sensitive LNCaP cells, whereas the castration-resistant C4-2 cells were unaffected. However, clonogenic growth increased in both cell lines. Gln deprivation and GLS1 inhibition experiments revealed that the increased growth rate of LNCAP cells was associated with increased dependence on Gln, which was confirmed by proteomic analyses. Tissue analysis of PCa patients revealed elevated GLS1 levels in both the PCa epithelium and stroma, suggesting that GLS1 is a therapeutic target. Moreover, the median overall survival analysis of GLS1 expression in the PCa epithelium and stroma identified a "high-risk" patient group that may benefit from GLS1-targeted therapies. Therefore, GLS1 targeting appears promising in castration-resistant PCa patients with high GLS1 epithelium and low GLS1 stromal expression.


Assuntos
Fibroblastos Associados a Câncer , Proliferação de Células , Técnicas de Cocultura , Glutamina , Neoplasias da Próstata , Microambiente Tumoral , Humanos , Glutamina/metabolismo , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Glutaminase/metabolismo , Fibroblastos/metabolismo
12.
Int J Mol Sci ; 25(17)2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39273316

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is almost entirely resistant to conventional chemotherapy and radiation therapy. A significant factor in this resistance appears to be the dense desmoplastic stroma, which contains various cancer-associated fibroblast (CAF) populations. However, our understanding of the communication between tumor cells and CAFs that contributes to this aggressive malignancy is still developing. Recently, we used an advanced three-dimensional heterospecies, heterospheroid co-culture model to investigate the signaling between human pancreatic tumor Panc1 cells and mouse pancreatic stellate cells (mPSCs) through global expression profiling. Upon discovering that CCN1 was significantly upregulated in Panc1 cells during co-culture, we decided to explore the role of CCN1 using CRISPR-Cas9 knockout technology. Panc1 cells lacking CCN1 showed reduced differentiation and decreased sensitivity to gemcitabine, primarily due to lower expression of genes involved in gemcitabine transport and metabolism. Additionally, we observed that stimulation with TGF-ß1 and lysophosphatidic acid increased CCN1 expression in Panc1 cells and induced a shift in mPSCs towards a more myofibroblastic CAF-like phenotype.


Assuntos
Técnicas de Cocultura , Proteína Rica em Cisteína 61 , Desoxicitidina , Gencitabina , Neoplasias Pancreáticas , Células Estreladas do Pâncreas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Proteína Rica em Cisteína 61/metabolismo , Proteína Rica em Cisteína 61/genética , Humanos , Células Estreladas do Pâncreas/metabolismo , Células Estreladas do Pâncreas/efeitos dos fármacos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Camundongos , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lisofosfolipídeos/metabolismo , Lisofosfolipídeos/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos
13.
J Transl Med ; 22(1): 840, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39267037

RESUMO

BACKGROUND: The tumor microenvironment (TME) exerts profound effects on tumor progression and therapeutic efficacy. In hepatocellular carcinoma (HCC), the TME is enriched with cancer-associated fibroblasts (CAFs), which secrete a plethora of cytokines, chemokines, and growth factors that facilitate tumor cell proliferation and invasion. However, the intricate architecture of the TME in HCC, as well as the mechanisms driving interactions between tumor cells and CAFs, remains largely enigmatic. METHODS: We analyzed 10 spatial transcriptomics and 12 single-cell transcriptomics samples sourced from public databases, complemented by 20 tumor tissue samples from liver cancer patients obtained in a clinical setting. RESULTS: Our findings reveal that tumor cells exhibiting high levels of SPP1 are preferentially localized adjacent to hepatic stellate cells (HSCs). The SPP1 secreted by these tumor cells interacts with the CD44 receptor on HSCs, thereby activating the PI3K/AKT signaling pathway, which promotes the differentiation of HSCs into CAFs. Notably, blockade of the CD44 receptor effectively abrogates this interaction. Furthermore, in vivo studies demonstrate that silencing SPP1 expression in tumor cells significantly impairs HSC differentiation into CAFs, leading to a reduction in tumor volume and collagen deposition within the tumor stroma. CONCLUSIONS: This study delineates the SPP1-CD44 signaling axis as a pivotal mechanism underpinning the interaction between tumor cells and CAFs. Targeting this pathway holds potential to mitigate liver fibrosis and offers novel therapeutic perspectives for liver cancer management.


Assuntos
Carcinoma Hepatocelular , Quimiotaxia , Células Estreladas do Fígado , Neoplasias Hepáticas , Transcriptoma , Microambiente Tumoral , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Humanos , Transcriptoma/genética , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Animais , Quimiotaxia/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Linhagem Celular Tumoral , Transdução de Sinais , Receptores de Hialuronatos/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Diferenciação Celular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Regulação Neoplásica da Expressão Gênica
14.
Int J Nanomedicine ; 19: 9121-9143, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39258004

RESUMO

Purpose: Erythrocytes and fibroblasts in the pancreatic cancer tumor microenvironment promote tumor cell growth and invasion by providing nutrients and promoting immunosuppression. Additionally, they form a barrier against the penetration of chemotherapeutic drugs. Therefore, the search for diversified tumor-targeting materials plays an essential role in solving the above problems. Methods: Physicochemical characterization of Graphene fluorescent nanoparticles (GFNPs) and nanomedicines were analyzed by transmission electron microscopy (TEM), elemental analyzers and ultraviolet fluorescence (UV/FL) spectrophotometer. Localization of GFNPs in cell and tissue sections imaged with laser confocal microscope, fluorescence scanner and small animal in vivo imager. Qualitative detection and quantitative detection of GFNPs and GFNPs-GEM were performed using High performance liquid chromatography (HPLC). Results: Based on the 3 nm average dimensions, GFNPs penetrate vascular endothelial cells and smooth muscle cells, achieve up to label 30% tumor cells and 60% cancer-associated fibroblasts (CAFs) cells, and accurately label mature red blood cells in the tumor microenvironment. In orthotopic transplanted pancreatic cancer models, the fluorescence intensity of GFNPs in tumors showed a positive correlation with the cycle size of tumor development. The differential spatial distribution of GFNPs in three typical clinical pancreatic cancer samples demonstrated their diagnostic potential. To mediate the excellent targeting properties of GFNPs, we synthesized a series of nanomedicines using popular chemotherapeutic drugs, in which complex of GFNPs and gemcitabine (GFNPs-GEM) possessed stability in vivo and exhibited effective reduction of tumor volume and fewer side effects. Conclusion: GFNPs with multiple targeting tumor microenvironments in pancreatic cancer possess diagnostic efficiency and therapeutic potential.


Assuntos
Desoxicitidina , Gencitabina , Grafite , Nanopartículas , Neoplasias Pancreáticas , Microambiente Tumoral , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Nanopartículas/química , Linhagem Celular Tumoral , Humanos , Camundongos , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacologia , Desoxicitidina/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Grafite/química , Nanomedicina , Fibroblastos Associados a Câncer/efeitos dos fármacos , Modelos Animais de Doenças
15.
J Immunother Cancer ; 12(9)2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39260826

RESUMO

BACKGROUND AND AIMS: Endosialin, also known as tumor endothelial marker1 or CD248, is a transmembrane glycoprotein that is mainly expressed in cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC). Our previous study has found that endosialin-positive CAFs could recruit and induce the M2 polarization of macrophages in HCC. However, whether they may regulate other types of immune cells to promoting HCC progression is not known. APPROACH AND RESULTS: The growth of both subcutaneous and orthotopic HCC tumors was significantly inhibited in endosialin knockout (ENKO) mice. Single-cell sequencing and flow cytometry analysis showed that tumor tissues from ENKO mice had increased CD8+ T cell infiltration. Mixed HCC tumor with Hepa1-6 cells and endosialin knockdown fibroblasts also showed inhibited growth and increased CD8+ T cell infiltration. Data from in vitro co-culture assay, chemokine array and antibody blocking assay, RNA-seq and validation experiments showed that endosialin inhibits the phosphorylation and nuclear translocation of STAT1 in CAFs. This inhibition leads to a decrease in CXCL9/10 expression and secretion, resulting in the suppression of CD8+ T cell infiltration. High level of endosialin protein expression was correlated with low CD8+ T infiltration in the tumor tissue of HCC patients. The combination therapy of endosialin antibody and PD-1 antibody showed synergistic antitumor effect compared with either antibody used individually. CONCLUSIONS: Endosialin could inhibit CD8+ T cell infiltration by inhibiting the expression and secretion of CXCL9/10 in CAFs, thus promote HCC progression. Combination therapy with endosialin antibody could increase the antitumor effect of PD-1 antibody in HCC, which may overcome the resistance to PD-1 blockade.


Assuntos
Linfócitos T CD8-Positivos , Fibroblastos Associados a Câncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Animais , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Fibroblastos Associados a Câncer/metabolismo , Antígenos CD/metabolismo , Progressão da Doença , Linhagem Celular Tumoral , Quimiocina CXCL9/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Knockout , Microambiente Tumoral , Fator de Transcrição STAT1/metabolismo , Quimiocina CXCL10/metabolismo , Masculino , Antígenos de Neoplasias , Proteínas de Neoplasias
16.
Cancer Immunol Immunother ; 73(11): 229, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39249543

RESUMO

Immune checkpoint inhibitors are approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) but the response rate is only 13-18%. For an effective antitumor immune response, trafficking of immune cells to the tumor microenvironment (TME) is essential. We aimed to better understand immune cell migration as well as the involved chemokines in HNSCC. A transwell assay was used to study immune cell migration toward TME-conditioned medium. While T cell migration was not observed, conventional dendritic cell (cDC) migration was induced by TME-conditioned media. cDC migration correlated with various proteins in the TME secretome. CCL8, CXCL5, CCL13 and CCL7 were tested in validation experiments and addition of these chemokines induced cDC migration. Using single cell RNA-sequencing, we observed expression of CCL8, CXCL5, CCL13 and CCL7 in cancer-associated fibroblasts (CAFs). Depleting fibroblasts led to reduced cDC migration. Thus CAFs, while often seen as suppressors of antitumor immunity, play a role in attracting cDCs toward the head and neck cancer TME, which might be crucial for effective antitumor immunity and response to therapies. Indeed, we found RNA expression signatures of the indicated chemokines, cDC and CAF subpopulations, to be significantly higher in baseline tumor specimen of patients with a major pathological response to pre-surgical anti-PD-1 treatment compared to non-responding patients.


Assuntos
Movimento Celular , Células Dendríticas , Neoplasias de Cabeça e Pescoço , Microambiente Tumoral , Humanos , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Microambiente Tumoral/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Secretoma/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/imunologia , Quimiocinas/metabolismo
17.
BMC Cancer ; 24(1): 1117, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39251966

RESUMO

BACKGROUND/AIMS: Gastric cancer (GC) ranks among the prevalent types of cancer, and its progression is influenced by the tumor microenvironment (TME). A comprehensive comprehension of the TME associated with GC has the potential to unveil therapeutic targets of significance. METHODS: The complexity and heterogeneity of TME interactions were revealed through our investigation using an integrated analysis of single-cell and bulk-tissue sequencing data. RESULTS: We constructed a single-cell transcriptomic atlas of 150,913 cells isolated from GC patients. Our analysis revealed the intricate nature and heterogeneity of the GC TME and the metabolic properties of major cell types. Furthermore, two cell subtypes, LOX+ Fibroblasts and M2 Macrophages, were enriched in tumor tissue and related to the outcome of GC patients. In addition, LOX+ Fibroblasts were significantly associated with M2 macrophages. immunofluorescence double labeling indicated LOX+ Fibroblasts and M2 Macrophages were tightly localized in GC tissue. The two cell subpopulations strongly interacted in a hypoxic microenvironment, yielding an immunosuppressive phenotype. Our findings further suggest that LOX+ Fibroblasts may act as a trigger for inducing the differentiation of monocytes into M2 Macrophages via the IL6-IL6R signaling pathway. CONCLUSIONS: Our study revealed the intricate and interdependent communication network between the fibroblast and macrophage subpopulations, which could offer valuable insights for targeted manipulation of the tumor microenvironment.


Assuntos
Fibroblastos , Macrófagos , Análise de Célula Única , Neoplasias Gástricas , Microambiente Tumoral , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Humanos , Microambiente Tumoral/imunologia , Análise de Célula Única/métodos , Macrófagos/metabolismo , Macrófagos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Receptores Depuradores Classe E/metabolismo , Receptores Depuradores Classe E/genética , Comunicação Celular/imunologia , Proteína-Lisina 6-Oxidase/metabolismo , Proteína-Lisina 6-Oxidase/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Transcriptoma , Transdução de Sinais
18.
Cancer Cell ; 42(9): 1480-1485, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39255773

RESUMO

Cancer-associated fibroblasts (CAFs) are heterogeneous and ubiquitous stromal cells within the tumor microenvironment (TME). Numerous CAF types have been described, typically using single-cell technologies such as single-cell RNA sequencing. There is no general classification system for CAFs, hampering their study and therapeutic targeting. We propose a simple CAF classification system based on single-cell phenotypes and spatial locations of CAFs in multiple cancer types, assess how our scheme fits within current knowledge, and invite the CAF research community to further refine it.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias , Análise de Célula Única , Microambiente Tumoral , Fibroblastos Associados a Câncer/patologia , Fibroblastos Associados a Câncer/metabolismo , Humanos , Neoplasias/classificação , Neoplasias/patologia , Neoplasias/genética , Análise de Célula Única/métodos , Fenótipo , Animais
19.
Cells ; 13(17)2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39273037

RESUMO

The microenvironment of a cancer stem cell (CSC) niche is often found in coexistence with cancer-associated fibroblasts (CAFs). Here, we show the first in-depth analysis of the interaction between primary triple-negative breast cancer stem cells (BCSCs) with fibroblasts. Using 2D co-culture models with specific seeding ratios, we identified stromal fibroblast aggregation at the BCSC cluster periphery, and, on closer observation, the aggregated fibroblasts was found to encircle BCSC clusters in nematic organization. In addition, collagen type I and fibronectin accumulation were also found at the BCSC-stromal periphery. MACE-Seq analysis of BCSC-encapsulating fibroblasts displayed the transformation of stromal fibroblasts to CAFs and the upregulation of fibrosis regulating genes of which the Interferon Regulatory Factor 6 (IRF6) gene was identified. Loss of function experiments with the IRF6 gene decreased fibroblast encapsulation around BCSC clusters in 2D co-cultures. In BCSC xenografts, fibroblast IRF6 expression led to an increase in the stromal area and fibroblast density in tumors, in addition to a reduction in necrotic growth. Based on our findings, we propose that fibroblast IRF6 function is an important factor in the development of the stromal microenvironment and in sustaining the BCSC tumor niche.


Assuntos
Técnicas de Cocultura , Fibroblastos , Fatores Reguladores de Interferon , Células-Tronco Neoplásicas , Células Estromais , Microambiente Tumoral , Regulação para Cima , Humanos , Feminino , Fatores Reguladores de Interferon/metabolismo , Fatores Reguladores de Interferon/genética , Células Estromais/metabolismo , Células Estromais/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Animais , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação para Cima/genética , Camundongos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral
20.
Int J Oncol ; 65(4)2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39219285

RESUMO

While preclinical studies consistently implicate FGFR­signalling in breast cancer (BC) progression, clinical evidence fails to support these findings. It may be that the clinical significance of FGFR ought to be analysed in the context of the stroma, activating or repressing its function. The present review aimed to provide such a context by summarizing the existing data on the prognostic and/or predictive value of selected cancer­associated fibroblasts (CAFs)­related factors, that either directly or indirectly may affect FGFR­signalling. PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Medline (https://www.nlm.nih.gov/medline/medline_home.html) databases were searched for the relevant literature related to the prognostic and/or predictive significance of: CAFs phenotypic markers (αSMA, S100A4/FSP­1, PDGFR, PDPN and FAP), CAFs­derived cognate FGFR ligands (FGF2, FGF5 and FGF17) or inducers of CAFs' paracrine activity (TGF­ß1, HDGF, PDGF, CXCL8, CCL5, CCL2, IL­6, HH and EGF) both expressed in the tumour and circulating in the blood. A total of 68 articles were selected and thoroughly analysed. The findings consistently identified upregulation of αSMA, S100A4/FSP­1, PDGFR, PDPN, HDGF, PDGF, CXCL8, CCL5, CCL2, IL­6, HH and EGF as poor prognostic markers in BC, while evaluation of the prognostic value of the remaining markers varied between the studies. The data confirm an association of CAFs­specific features with BC prognosis, suggesting that both quantitative and qualitative profiling of the stroma might be required for an assessment of the true FGFR's clinical value.


Assuntos
Neoplasias da Mama , Fibroblastos Associados a Câncer , Receptores de Fatores de Crescimento de Fibroblastos , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , Prognóstico , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Biomarcadores Tumorais/metabolismo , Transdução de Sinais , Fenótipo , Regulação Neoplásica da Expressão Gênica
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