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1.
Anticancer Res ; 39(10): 5565-5572, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570451

RESUMO

BACKGROUND/AIM: The aim of the study was to evaluate the status of extravasated platelet activation (EPA) surrounding podoplanin (PDPN)-positive cancer-associated fibroblasts (CAFs) in pancreatic cancer stroma by neoadjuvant chemotherapy. PATIENTS AND METHODS: A total of 74 patients were enrolled in this study. We investigated CD42b and PDPN expression in the groups of untreated, gemcitabine (GEM) alone, GEM plus S-1 (GS) and GEM plus nab-paclitaxel (GnP). RESULTS: CD42b expression in surrounding CAFs was observed in 58% patients. CD42b expression was significantly correlated with PDPN expression. CD42b-positive cases were significantly lower in the group treated with GnP than in the untreated group and groups treated with GEM alone or GS. PDPN expression was reduced in the GnP group, as revealed by markedly disorganized collagen and a low density of PDPN-positive fibroblasts. There was a significantly lower CD42b expression and fewer PDPN-positive fibroblasts in the GnP group than in untreated, GEM alone, and GS groups, but there was no significant difference between the latter three groups. CONCLUSION: There is a significant association between EPA and PDPN-positive CAFs in pancreatic cancer stroma. Our data suggest that the GnP regimen decreases EPA through PDPN-positive CAF depletion.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fibroblastos Associados a Câncer/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/uso terapêutico , Fibroblastos Associados a Câncer/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Ácido Oxônico/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Tegafur/uso terapêutico
2.
Oncol Rep ; 42(4): 1319-1328, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364748

RESUMO

Oral squamous cell carcinoma (OSCC), with high potential for metastasis, is the most common malignant tumor of the head and neck. Cancer­associated fibroblasts (CAFs) are the main stromal cells in the microenvironment and aggravate tumor progression. However, whether CAFs are associated with the progression of OSCC remains unknown and the underlying mechanism remains unclear. In the present study, the role of CAFs in mediating OSCC cell migration and invasion was investigated, and the participation of exosomal miR­382­5p in this process was elucidated. In this study, according to the α­SMA staining with immunohistochemistry, 47 OSCC patients were divided into CAFs­rich and CAFs poor groups, and association of CAF density and clinicopathologic features of the OSCC patients were analyzed with Pearson χ2 test. Transwell assay was used for evaluating cell migration and invasion ability of OSCC cells after being co­cultured with NFs or CAFs, or after added exosomes. qPCR was used to detect the expression of miR­382­5p. Western blot analysis was used to measure the expression of migration and invasion­associated proteins. In the present study, the CAF density in tumor tissues was found to be relevant to OSCC lymph node metastasis and TNM stage. Furthermore, we revealed that miR­382­5p was overexpressed in CAFs compared with that in fibroblasts of adjacent normal tissue and miR­382­5p overexpression was responsible for OSCC cell migration and invasion. Finally, we demonstrated that CAF­derived exosomes transported miR­382­5p to OSCC cells. The present study confirmed a new mechanism of CAF­facilitated OSCC progression and may be beneficial for identifying new cancer therapeutic targets.


Assuntos
Fibroblastos Associados a Câncer/patologia , Exossomos/genética , MicroRNAs/biossíntese , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Actinas/biossíntese , Adulto , Idoso , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Exossomos/metabolismo , Exossomos/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Metástase Neoplásica , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo
3.
Cancer Sci ; 110(9): 2783-2793, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325403

RESUMO

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1ß (IL-1ß) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1ß, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1ß-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Quimiocina CCL22/metabolismo , Interleucina-1beta/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Quimiocina CCL22/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1beta/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Mucosa Bucal/cirurgia , Neoplasias Bucais/imunologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/cirurgia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Prognóstico , RNA Interferente Pequeno/metabolismo , Receptores CCR4/metabolismo , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Biochim Biophys Acta Rev Cancer ; 1872(1): 111-121, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31265878

RESUMO

The functional importance of the tumor stroma for cancer growth and progression is increasingly recognized, but has not resulted in notable therapeutic developments yet. Within the mesenchymal tumor microenvironment, cancer-associated fibroblasts take the center stage and fuel tumor progression in various ways including malignant cell potentiation, immune regulation and fibrosis. However, recent studies have demonstrated pronounced heterogeneity of the fibroblastic tumor stroma, which comprises a plethora of individual cell subsets with varying phenotypes and functions, some of which suppress malignant growth through immune engagement or crosstalk with the tumor vasculature. This article summarizes the various levels at which the fibroblastic tumor stroma may impact cancer progression and highlights potential target structures for future therapeutic intervention(s).


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral/genética , Fibroblastos Associados a Câncer/patologia , Progressão da Doença , Humanos , Neoplasias/patologia , Neoplasias/terapia , Transdução de Sinais/genética , Células Estromais/metabolismo , Células Estromais/patologia
5.
Virchows Arch ; 475(3): 341-348, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31076902

RESUMO

Desmoplastic reaction (DR) involves the growth of fibrous or connective tissues around a tumor and has recently attracted attention as an indicator of malignant potential. Previous studies have confirmed that histological categorization of DR in the primary tumor is an independent prognostic factor in patients with colorectal liver metastases (CRLM). However, it remains unclear whether the DR status of the metastatic liver lesion (DRliver) is a useful prognostic factor. This pathological review evaluated records from 204 patients who underwent hepatectomy for CRLM at the National Defense Medical College Hospital in Japan. Each case's DRliver was classified as mature, intermediate, or immature based on the presence of keloid-like collagen and myxoid stroma in the metastatic liver lesion. This resulted in 12 cases of mature DRliver, 101 cases of intermediate DRliver, and 91 cases of immature DRliver. There was a significant correlation between the DR statuses of the primary tumor and the metastatic liver lesion (Spearman's rho = 0.3, P = 0.0001). The 5-year relapse-free survival rates after hepatectomy were 33.8% for mature/intermediate DRliver and 16.7% for immature DRliver (P = 0.0021). The 5-year overall survival rate after hepatectomy was higher in the mature/intermediate DRliver group (64.8%) than in the immature DRliver group (35.0%; P = 0.0012). The multivariate analysis confirmed that DRliver categorization could independently predict relapse-free survival and overall survival. In conclusion, DRliver categorization may be valuable for predicting prognosis after hepatectomy among patients with CRLM.


Assuntos
Fibroblastos Associados a Câncer/patologia , Neoplasias Colorretais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibroblastos Associados a Câncer/metabolismo , Neoplasias Colorretais/classificação , Intervalo Livre de Doença , Feminino , Fibroblastos/patologia , Fibrose , Hepatectomia , Humanos , Estimativa de Kaplan-Meier , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Células Estromais/patologia , Taxa de Sobrevida
6.
Medicine (Baltimore) ; 98(18): e15164, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045759

RESUMO

The aim of this study was to evaluate the cytomorphologic maturity and molecular activation of cancer-associated fibroblasts (CAFs) in the intratumoral stroma and invasive front in colorectal cancer and understand how they affect cancer invasion and long-term oncological outcomes.The cytomorphologic maturity of and α-smooth muscle actin (α-SMA), fibroblast activation protein α (FAPα), and fibroblast-specific protein 1 (FSP-1) expression in CAFs in the intratumoral stroma (CAF) and the invasive front (CAF) of colorectal cancer tissues were compared (n = 147). The correlations between CAF maturation, molecular activity markers, and cancer invasion were evaluated by network analysis. Overall survival and systemic recurrence were analyzed to assess the oncological effects of CAF properties.The cytomorphologic maturation rate was comparable between CAF and CAF. The presence of mature CAFs was related to epidermal growth factor receptor overexpression in cancer cells. Expression rates of α-SMA (96.6%-98.0%) and FAPα (18.6%-22.9%) were similar between CAF and CAF. FSP-1 expression was more frequent in CAF than in CAF (66.4% vs 58.2%, P = .038). There was a significant decrease in FSP-1 expression in CAF and CAF in higher stages. The infiltrating growth pattern of the tumor was more frequent in the immature CAF. In colorectal cancer with perineural invasion and lymph node metastasis, FSP-1 expression in CAF was significantly lower. On multivariate analysis using the Cox proportional hazards model, immature CAF was found to be an independent prognostic factor of overall survival. In non-metastatic (stage I-III) colorectal cancer patients, CAF maturity was not a prognostic factor for systemic recurrence.Cytomorphologic maturity and molecular activation markers were similar between CAFs in the intratumoral stroma and invasive front of colorectal cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/patologia , Neoplasias Colorretais/patologia , Tumores do Estroma Gastrointestinal/patologia , Invasividade Neoplásica/patologia , Actinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Fibroblastos Associados a Câncer/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Receptores ErbB/metabolismo , Feminino , Tumores do Estroma Gastrointestinal/metabolismo , Gelatinases/metabolismo , Humanos , Metástase Linfática/patologia , Masculino , Proteínas de Membrana/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Serina Endopeptidases/metabolismo , Análise de Sobrevida
7.
Biomed Res Int ; 2019: 2585743, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119158

RESUMO

Purpose: Leptin is a nutritional cytokine encoded by the obesity gene whose concentration in the tumor microenvironment is closely related to the occurrence and progression of cancer. However, previous evidence has suggested that there is no clear relationship between serum leptin concentrations and lung cancer progression. Cancer-associated fibroblasts (CAFs), the most abundant component of the tumor microenvironment in a variety of solid tumors, were recently reported to produce leptin. Therefore, it was inferred that leptin is most likely to affect non-small-cell lung cancer (NSCLC) through an autocrine and paracrine mechanism. In the current study, we investigated the paracrine effect and mechanism of leptin produced by CAFs on NSCLC by establishing a novel in vitro cell coculture system. Methods: A noncontact coculture device was designed and made by 3D printing. CAFs and paired normal lung fibroblasts (NLFs) from 5 patients were successfully isolated and cocultured with two NSCLC cell lines in a coculture system. The background expression of leptin was detected by western blot. The in situ expression of leptin and its receptor (Ob-R) in NSCLC tissues and paired normal lung tissues was analyzed by immunohistochemistry. Furthermore, we downregulated the expression of leptin in CAFs and assessed changes in its promotion on NSCLC cells in the coculture system. Finally, changes in the phosphorylation of ERK1/2 and AKT were examined to investigate the molecular mechanisms responsible for the paracrine promotion of NSCLC cells by leptin. Results: Leptin was overexpressed in nearly all five primary CAF lines compared with its expression in paired NLFs. IHC staining showed that the expression of leptin was high in NSCLC cells, slightly lower in CAF, and negative in normal lung tissue. Ob-R was strongly expressed in NSCLC cells. The ability of A549 and H1299 cells to proliferate and migrate was enhanced by high leptin levels in both the cocultured fibroblasts and the culture medium. Furthermore, western blot assays suggested that the MAPK/ERK1/2 and PI3K/AKT signaling pathways were activated by leptin produced by CAFs, which demonstrated that the functions of paracrine leptin in NSCLC are as those of the serum leptin to other cancers. Conclusion: Leptin produced by CAF promotes proliferation and migration of NSCLC cells probably via PI3K/AKT and MAPK/ERK1/2 signaling pathways in a paracrine manner.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/dietoterapia , Proliferação de Células/efeitos dos fármacos , Leptina/farmacologia , Comunicação Parácrina/efeitos dos fármacos , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Técnicas de Cocultura , Humanos , Leptina/genética , Leptina/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Comunicação Parácrina/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Microambiente Tumoral/efeitos dos fármacos
8.
Mol Cancer ; 18(1): 70, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30927908

RESUMO

In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epithelial-to-mesenchymal transition (EMT), activation of survival pathways or stemness-related programs and metabolic reprogramming in tumor cells. Importantly, the recently unveiled heterogeneity in CAFs claims tailored therapeutic efforts aimed at eradicating the specific subset facilitating tumor progression, therapy resistance and relapse. However, despite the large amount of pre-clinical data, much effort is still needed to translate CAF-directed anti-cancer strategies from the bench to the clinic.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias/metabolismo , Antineoplásicos/farmacologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/tratamento farmacológico , Comunicação Parácrina , Transdução de Sinais , Microambiente Tumoral
9.
Mol Cancer ; 18(1): 68, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30927911

RESUMO

BACKGROUND: Although the tumor stroma in solid tumors like gastric cancer (GC) plays a crucial role in chemo-resistance, specific targets to inhibit the interaction between the stromal and cancer cells have not yet been utilized in clinical practice. The present study aims to determine whether cancer-associated fibroblasts (CAFs), a major component of the tumor stroma, confer chemotherapeutic resistance to GC cells, and to discover potential targets to improve chemo-response in GC. METHODS: To identify CAF-specific proteins and signal transduction pathways affecting chemo-resistance in GC cells, secretome and transcriptome analyses were performed. We evaluated the inhibiting effect of CAF-specific protein in in vivo and in vitro models and investigated the expression of CAF-specific protein in human GC tissues. RESULTS: Secretome and transcriptome data revealed that interleukin-6 (IL-6) is a CAF-specific secretory protein that protects GC cells via paracrine signaling. Furthermore, CAF-induced activation of the Janus kinase 1-signal transducer and activator of transcription 3 signal transduction pathway confers chemo-resistance in GC cells. CAF-mediated inhibition of chemotherapy-induced apoptosis was abrogated by the anti-IL-6 receptor monoclonal antibody tocilizumab in various experimental models. Clinical data revealed that IL-6 was prominently expressed in the stromal portion of GC tissues, and IL-6 upregulation in GC tissues was correlated with poor responsiveness to chemotherapy. CONCLUSIONS: Our data provide plausible evidence for crosstalk between GC cells and CAFs, wherein IL-6 is a key contributor to chemoresistance. These findings suggest the potential therapeutic application of IL-6 inhibitors to enhance the responsiveness to chemotherapy in GC.


Assuntos
Fibroblastos Associados a Câncer/citologia , Fluoruracila/administração & dosagem , Interleucina-6/genética , RNA Interferente Pequeno/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Camundongos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Mol Cancer ; 18(1): 67, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30927930

RESUMO

Although solid tumors comprise malignant cells, they also contain many different non-malignant cell types in their micro-environment. The cellular components of the tumor stroma consist of immune and endothelial cells combined with a heterogeneous population of stromal cells which include cancer-associated fibroblasts. The bi-directional interactions between tumor and stromal cells therefore substantially affect tumor cell biology.Herein, we discuss current available information on these interactions in breast cancer chemo-resistance. It is acknowledged that stromal cells extrinsically alter tumor cell drug responses with profound consequences for therapy efficiency, and it is therefore essential to understand the molecular mechanisms which contribute to these substantial alterations because they provide potential targets for improved cancer therapy. Although breast cancer patient survival has improved over the last decades, chemo-resistance still remains a significant obstacle to successful treatment.Appreciating the important experimental evidence of mesenchymal stromal cells and cancer-associated fibroblast involvement in breast cancer clinical practice can therefore have important therapeutic implications.


Assuntos
Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Células Estromais/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Feminino , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Células Estromais/patologia , Microambiente Tumoral
11.
Mol Cancer ; 18(1): 77, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943988

RESUMO

Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Recently, intensive evidences reveal that inhibition of neddylation pathway, in addition to acting on tumor cells, also influences the functions of multiple important components of the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs) and some factors, all of which are crucial for tumorigenesis. Here, we briefly summarize the latest progresses in this field to clarify the roles of neddylation in the TME, thus highlighting the overall anticancer efficacy of neddylaton inhibition.


Assuntos
Ciclopentanos/uso terapêutico , Proteína NEDD8/metabolismo , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular , Ensaios Clínicos como Assunto , Ciclopentanos/farmacologia , Humanos , Proteína NEDD8/antagonistas & inibidores , Neoplasias/metabolismo , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
12.
J Exp Clin Cancer Res ; 38(1): 151, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961650

RESUMO

BACKGROUND: Head and neck cancer (HNC) is one of the most common deadly diseases worldwide. An increasing number of studies have recently focused on the malignant functions of cancer-associated fibroblasts (CAFs) in numerous cancers. However, the underlying mechanisms by which CAF-derived exosomes promote tumor progression need to be further elucidated. This study aims to determine whether the loss of specific miRNAs in CAF-derived exosomes may be involved in the malignant transformation of HNC. METHODS: MiRNA array and real-time PCR assays were used to analyze the differential expression of miRNAs in exosomes from normal fibroblasts (NFs) and CAFs. Cell proliferation, EdU incorporation, colony formation, apoptosis, cell cycle distribution and xenograft assays were performed to examine the effects of miR-3188 on HNC in vitro and in vivo. Real-time PCR, western blotting and luciferase reporter assays were used to identify the target genes of miR-3188. Furthermore, tumor-bearing mouse models were used to prove the potential therapeutic value of miR-3188-loaded exosomes in HNC. RESULTS: Our results showed that miR-3188 expression is reduced in exosomes and their parental CAFs from HNC tissues. In addition, miR-3188 can be transferred from fibroblasts to HNC cells by exosomes. Further exploration demonstrated that exosomal miR-3188 can influence the proliferation and apoptosis of HNC cells by directly targeting B-cell lymphoma 2 (BCL2) in vitro and in vivo. More importantly, we also found that miR-3188-loaded exosomes significantly inhibited tumor growth in vivo. CONCLUSIONS: Our findings revealed that CAF-derived exosomes contain lower miR-3188 levels than NFs, and the loss of miR-3188 in exosomes contributes to the malignant phenotypes of HNC cells through the derepression of BCL2. Furthermore, these data suggest the potential therapeutic value of exosomal miR-3188 for inhibiting HNC growth.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Exossomos/metabolismo , Neoplasias de Cabeça e Pescoço/genética , MicroRNAs/genética , Linhagem Celular Tumoral , Progressão da Doença , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Transdução de Sinais , Transfecção
13.
Int J Mol Sci ; 20(8)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010006

RESUMO

Vincristine is used in the clinical treatment of colon cancer, especially in patients diagnosed in the advanced phase of cancer development. Unfortunately, similar to other agents used during antitumor therapy, vincristine might induce chemoresistance. Studies of this process focus mainly on the analysis of the molecular mechanisms within cancer, usually ignoring the role of stromal cells. Our present findings confirm that vincristine stimulates the secretion of tumor growth factors class beta and interleukin-6 from cancer-associated fibroblasts as a result of paracrine stimulation by cancer cells. Based on alterations in morphology, modulation of capillary formation, and changes in endothelial and mesenchymal marker profile, our findings demonstrate that higher levels of tumor growth factor-ßs and interleukin-6 enhance cancer-associated fibroblast-like cell formation through endothelial-mesenchymal transition and that nonsteroidal anti-inflammatory drug treatment (aspirin and ibuprofen) is able to inhibit this phenomenon. The process appears to be regulated by the rate of microtubule polymerization, depending on ß-tubulin composition. While higher levels of tubulin-ß2 and tubulin-ß4 caused slowed polymerization and reduced the level of factors secreted to the extracellular matrix, tubulin-ß3 induced the opposite effect. We conclude that nonsteroidal anti-inflammatory drugs should be considered for use during vincristine monotherapy in the treatment of patients diagnosed with colorectal cancer.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Fibroblastos Associados a Câncer/patologia , Vincristina/farmacologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Comunicação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Transdiferenciação Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio/efeitos dos fármacos , Endotélio/patologia , Humanos , Mesoderma/efeitos dos fármacos , Mesoderma/patologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Polimerização , Tubulina (Proteína)/metabolismo
14.
J Exp Clin Cancer Res ; 38(1): 170, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999932

RESUMO

BACKGROUND: Cancer stem cells (CSCs) require stromal signals for maintaining pluripotency and self-renewal capacities to confer tumor metastasis. Resolvin D1 (RvD1), an endogenous anti-inflammatory lipid mediator, has recently been identified to display anti-cancer effects by acting on stroma cells. Our previous study reveals that hepatic stellate cells (HSCs)-derived cartilage oligomeric matrix protein (COMP) contributes to hepatocellular carcinoma (HCC) progression. However, whether RvD1 inhibits paracrine of cancer-associated fibroblasts (CAFs)-derived COMP to prevent epithelial-mesenchymal transition (EMT) and cancer stemness in HCC remains to be elucidated. METHODS: CAFs were isolated from HCC tissues. Direct and indirect co-culture models were established to analyze the interactions between HCC cells and CAFs in the presence of RvD1 in vitro. The transwell and tumor sphere formation assays were used to determine invasion and stemness of HCC cells. The subcutaneous tumor formation and orthotopic liver tumor models were established by co-implantation of CAFs and HCC cells to evaluate the role of RvD1 in vivo. To characterize the mechanism of RvD1 inhibited paracrine of COMP in CAFs, various signaling molecules were analyzed by ELISA, western blotting, reactive oxygen species (ROS) detection, immunofluorescence staining, dual luciferase reporter assay and chromatin immunoprecipitation assay. RESULTS: Our data revealed that RvD1 treatment can impede the CAFs-induced cancer stem-like properties and the EMT of HCC cells under co-culture conditions. In vivo studies indicated that RvD1 intervention repressed the promoting effects of CAFs on tumor growth and metastasis of HCC. Furthermore, RvD1 inhibited CAF-induced EMT and stemness features of HCC cells by suppressing the secretion of COMP. Mechanistically, formyl peptide receptor 2 (FPR2) receptor mediated the suppressive effects of RvD1 on COMP and forkhead box M1 (FOXM1) expression in CAFs. Notably, RvD1 impaired CAF-derived COMP in a paracrine manner by targeting FPR2/ROS/FOXM1 signaling to ultimately abrogate FOXM1 recruitment to the COMP promoter. CONCLUSION: Our results indicated that RvD1 impaired paracrine of CAFs-derived COMP by targeting FPR2/ROS/FOXM1 signaling to repress EMT and cancer stemness in HCC. Thus, RvD1 may be a potential agent to promote treatment outcomes in HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Proteína de Matriz Oligomérica de Cartilagem/genética , Proteína Forkhead Box M1/genética , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Formil Peptídeo/genética , Receptores de Lipoxinas/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Comunicação Parácrina/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
J Exp Clin Cancer Res ; 38(1): 171, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014370

RESUMO

Cancer-associated fibroblasts (CAFs) plays an essential role in cancer cell growth, metabolism and immunoreaction. Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis. Targeting autophagy has gained interest with multiple preclinical and clinical trials, such as the pharmacological inhibitor chloroquine or the inducer rapamycin, especially in exploiting its ability to modulate the secretory capability of CAFs to enhance drug delivery or inhibit it to prevent its influence on cancer cell chemoresistance. In this review, we summarize the reports on autophagy in cancer-associated fibroblasts by detailing the mechanism and role of autophagy in CAFs, including the hypoxic-autophagy positive feedback cycle, the metabolic cross-talk between CAFs and tumors induced by autophagy, CAFs secreted cytokines promote cancer survival by secretory autophagy, CAFs autophagy-induced EMT, stemness, senescence and treatment sensitivity, as well as the research of antitumor chemicals, miRNAs and lncRNAs. Additionally, we discuss the evidence of molecules in CAFs that are relevant to autophagy and the contribution to sensitive treatments as a potential target for cancer treatment.


Assuntos
Autofagia/genética , Transformação Celular Neoplásica/genética , Neoplasias/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , MicroRNAs/genética , Neoplasias/patologia , RNA Longo não Codificante/genética
16.
Int J Mol Sci ; 20(8)2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-31013896

RESUMO

The formation and maintenance of renal cell carcinomas (RCC) involve many cell types, such as cancer stem and differentiated cells, endothelial cells, fibroblasts and immune cells. These all contribute to the creation of a favorable tumor microenvironment to promote tumor growth and metastasis. Extracellular vesicles (EVs) are considered to be efficient messengers that facilitate the exchange of information within the different tumor cell types. Indeed, tumor EVs display features of their originating cells and force recipient cells towards a pro-tumorigenic phenotype. This review summarizes the recent knowledge related to the biological role of EVs, shed by renal tumor cells and renal cancer stem cells in different aspects of RCC progression, such as angiogenesis, immune escape and tumor growth. Moreover, a specific role for renal cancer stem cell derived EVs is described in the formation of the pre-metastatic niche. We also highlight the tumor EV cargo, especially the oncogenic miRNAs, which are involved in these processes. Finally, the circulating miRNAs appear to be a promising source of biomarkers in RCC.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , MicroRNA Circulante , Vesículas Extracelulares/metabolismo , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , MicroRNAs/genética , Biomarcadores , Fibroblastos Associados a Câncer/metabolismo , Carcinoma de Células Renais/patologia , Progressão da Doença , Humanos , Neoplasias Renais/patologia , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Células Estromais/metabolismo , Microambiente Tumoral/genética
17.
J Exp Clin Cancer Res ; 38(1): 162, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987642

RESUMO

BACKGROUND: Pancreatic cancer is one of the most lethal type of cancers, with an overall five-year survival rate of less than 5%. It is usually diagnosed at an advanced stage with limited therapeutic options. To date, no effective treatment options have demonstrated long-term benefits in advanced pancreatic cancer patients. Compared with other cancers, pancreatic cancer exhibits remarkable resistance to conventional therapy and possesses a highly immunosuppressive tumor microenvironment (TME). MAIN BODY: In this review, we summarized the evidence and unique properties of TME in pancreatic cancer that may contribute to its resistance towards immunotherapies as well as strategies to overcome those barriers. We reviewed the current strategies and future perspectives of combination therapies that (1) promote T cell priming through tumor associated antigen presentation; (2) inhibit tumor immunosuppressive environment; and (3) break-down the desmoplastic barrier which improves tumor infiltrating lymphocytes entry into the TME. CONCLUSIONS: It is imperative for clinicians and scientists to understand tumor immunology, identify novel biomarkers, and optimize the position of immunotherapy in therapeutic sequence, in order to improve pancreatic cancer clinical trial outcomes. Our collaborative efforts in targeting pancreatic TME will be the mainstay of achieving better clinical prognosis among pancreatic cancer patients. Ultimately, pancreatic cancer will be a treatable medical condition instead of a death sentence for a patient.


Assuntos
Hospedeiro Imunocomprometido , Imunomodulação/efeitos dos fármacos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/metabolismo , Estudos Clínicos como Assunto , Terapia Combinada , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Terapia de Alvo Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
18.
Cancer Invest ; 37(3): 134-143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30961403

RESUMO

Cancer-associated fibroblasts (CAFs) play an important role in the development and progression of cancer by inducing epithelial-mesenchymal transition (EMT). In this study, we investigated the role of CAFs in endometrial cancer (EC) cells. We found that the pituitary tumor transforming gene (PTTG) expression was significantly increased in EC cell lines compared to normal human endometrial epithelial cells. Furthermore, CAFs could induce PTTG over-expression and increase EC cell invasion and migration in vitro. In addition, CAFs also induced EMT in EC cells. This study demonstrated that CAFs induced EMT in endometrial cancer cells by regulating PTTG.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Neoplasias do Endométrio/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Securina/genética , Fibroblastos Associados a Câncer/citologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Técnicas de Cocultura , Neoplasias do Endométrio/patologia , Endométrio/metabolismo , Endométrio/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Invasividade Neoplásica
19.
J Exp Clin Cancer Res ; 38(1): 115, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30841909

RESUMO

The extracellular matrix (ECM) plays an important role in cancer progression. It can be divided into the basement membrane (BM) that supports epithelial/endothelial cell behavior and the interstitial matrix (IM) that supports the underlying stromal compartment. The major components of the ECM are the collagens. While breaching of the BM and turnover of e.g. type IV collagen, is a well described part of tumorigenesis, less is known regarding the impact on tumorigenesis from the collagens residing in the stroma. Here we give an introduction and overview to the link between tumorigenesis and stromal collagens, with focus on the fibrillar collagens type I, II, III, V, XI, XXIV and XXVII as well as type VI collagen. Moreover, we discuss the impact of the cells responsible for this altered stromal collagen remodeling, the cancer associated fibroblasts (CAFs), and how these cells are key players in orchestrating the tumor microenvironment composition and tissue microarchitecture, hence also driving tumorigenesis and affecting response to treatment. Lastly, we discuss how specific collagen-derived biomarkers reflecting the turnover of stromal collagens and CAF activity may be used as tools to non-invasively interrogate stromal reactivity in the tumor microenvironment and predict response to treatment.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Carcinogênese/genética , Colágeno Tipo I/genética , Neoplasias/genética , Fibroblastos Associados a Câncer/patologia , Colágeno Tipo I/metabolismo , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente Tumoral/genética
20.
Kaohsiung J Med Sci ; 35(4): 214-221, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30896889

RESUMO

The present study aimed to investigate the effects of c-Ski on cell proliferation, invasion and migration of gastric cancer associated fibroblasts (CAFs). Expression of c-Ski in gastric cancer (GC) tissues was determined using immunohistochemistry. Both CAFs and non-cancerous gastric fibroblasts (NGFs) were isolated and cultured. c-Ski and Smad3 were over-expressed or knocked down using pcDNA3.0-c-Ski/Smad3 or siRNA, respectively. Cell viability, invasion and migration were measured and expression of c-Ski, α-SMA, and Smad3 in cells was determined using real time quantitative PCR (RT-qPCR) and Western blotting. Expression of c-Ski was significantly higher in both in GC tissues and cell lines, and was the highest in tissues of diffuse type. Both c-Ski and α-SMA were significantly over-expressed in CAFs compared with that in the NGFs. When c-Ski was over-expressed in NGFs, cell viability, cell invasion and migration were all enhanced and expression of Smad3 was downregulated. When c-Ski was inhibited, cell viability, cell invasion, and migration were all suppressed and expression of Smad3 was upregulated. Meanwhile, overexpression of Smad3 significantly reversed the effects of over-expressed c-Ski in NGFs, and knockdown of Smad3 dramatically reversed the effects of si-c-Ski in CAFs. Over-expressed c-Ski could enhance cell viability, promote cell invasion, and migration of GC CAFs, and the effects might be through regulation of Smad3 signaling. This study may give deeper insights for relationship between c-Ski and CAFs, as well as role of c-Ski in cancer development, and also provide some novel research targets for treatment of GC.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Movimento Celular/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais , Proteína Smad3/metabolismo , Regulação para Cima/genética
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