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1.
Semin Cancer Biol ; 86(Pt 2): 499-510, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35346801

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) consists of multiple cell types interspersed by dense fibrous stroma. These cells communicate through low molecular weight signaling molecules called cytokines. The cytokines, through their receptors, facilitate PDAC initiation, progression, metastasis, and distant colonization of malignant cells. These signaling mediators secreted from tumor-associated macrophages, and cancer-associated fibroblasts in conjunction with oncogenic Kras mutation initiate acinar to ductal metaplasia (ADM), resulting in the appearance of early preneoplastic lesions. Further, M1- and M2-polarized macrophages provide proinflammatory conditions and promote deposition of extracellular matrix, whereas myofibroblasts and T-lymphocytes, such as Th17 and T-regulatory cells, create a fibroinflammatory and immunosuppressive environment with a significantly reduced cytotoxic T-cell population. During PDAC progression, cytokines regulate the expression of various oncogenic regulators such as NFκB, c-myc, growth factor receptors, and mucins resulting in the formation of high-grade PanIN lesions, epithelial to mesenchymal transition, invasion, and extravasation of malignant cells, and metastasis. During metastasis, PDAC cells colonize at the premetastatic niche created in the liver, and lung, an organotropic function primarily executed by cytokines in circulation or loaded in the exosomes from the primary tumor cells. The indispensable contribution of these cytokines at every stage of PDAC tumorigenesis makes them exciting candidates in combination with immune-, chemo- and targeted radiation therapy.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Microambiente Tumoral , Citocinas , Transição Epitelial-Mesenquimal/genética , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Carcinogênese/genética , Neoplasias Pancreáticas
2.
Gastroenterology ; 162(1): 253-268.e13, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34534538

RESUMO

BACKGROUND & AIMS: A major clinical challenge for patients with pancreatic cancer (PC) is metabolic adaptation. Neoplastic cells harboring molecular perturbations suffice for their increased anabolic demand and nucleotide biosynthesis to acquire chemoresistance. The mucin 5AC expressed de novo in malignant pancreas promotes cancer cell stemness and is significantly associated with poor patient survival. Identification of MUC5AC-associated drivers of chemoresistance through metabolic alterations may facilitate the sculpting of a new combinatorial regimen. METHODS: The contributions of MUC5AC to glutaminolysis and gemcitabine resistance were examined by The Cancer Genome Atlas data analysis, RNA sequencing, and immunohistochemistry analysis on pancreatic tissues of KrasG12D;Pdx1-Cre (KC) and KrasG12D;Pdx1-Cre;Muc5ac-/- mice. These were followed by metabolite flux assays as well as biochemical and xenograft studies on MUC5AC-depleted human and murine PC cells. Murine and human pancreatic 3-dimensional tumoroids were used to evaluate the efficacy of gemcitabine in combination with ß-catenin and glutaminolysis inhibitors. RESULTS: Transcriptional analysis showed that high MUC5AC-expressing human and autochthonous murine PC tumors exhibit higher resistance to gemcitabine because of enhanced glutamine use and nucleotide biosynthesis. Gemcitabine treatment led to MUC5AC overexpression, resulting in disruption of E-cadherin/ß-catenin junctions and the nuclear translocation of ß-catenin, which increased c-Myc expression, with a concomitant rise in glutamine uptake and glutamate release. MUC5AC depletion and glutamine deprivation sensitized human PC cells to gemcitabine, which was obviated by glutamine replenishment in MUC5AC-expressing cells. Coadministration of ß-catenin and glutaminolysis inhibitors with gemcitabine abrogated the MUC5AC-mediated resistance in murine and human tumoroids. CONCLUSIONS: The MUC5AC/ß-catenin/c-Myc axis increases the uptake and use of glutamine in PC cells, and cotargeting this axis along with gemcitabine may improve therapeutic efficacy in PC.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético/efeitos dos fármacos , Glutamina/metabolismo , Mucina-5AC/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/metabolismo , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Bases de Dados Genéticas , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores Enzimáticos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Glutaminase/antagonistas & inibidores , Glutaminase/metabolismo , Humanos , Masculino , Camundongos Knockout , Camundongos Nus , Mucina-5AC/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/antagonistas & inibidores , beta Catenina/genética , Gencitabina
3.
Front Cardiovasc Med ; 8: 732282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34708087

RESUMO

Evidence suggests the existence of an intracardiac dopaminergic system that plays a pivotal role in regulating cardiac function and fibrosis through G-protein coupled receptors, particularly mediated by dopamine receptor 3 (D3R). However, the expression of dopamine receptors in cardiac tissue and their role in cardiac fibroblast function is unclear. In this brief report, first we determined expression of D1R and D3R both in left ventricle (LV) tissue and fibroblasts. Then, we explored the role of D3R in the proliferation and migration of fibroblast cell cultures using both genetic and pharmaceutical approaches; specifically, we compared cardiac fibroblasts isolated from LV of wild type (WT) and D3R knockout (D3KO) mice in response to D3R-specific pharmacological agents. Finally, we determined if loss of D3R function could significantly alter LV fibroblast expression of collagen types I (Col1a1) and III (Col3a1). Cardiac fibroblast proliferation was attenuated in D3KO cells, mimicking the behavior of WT cardiac fibroblasts treated with D3R antagonist. In response to scratch injury, WT cardiac fibroblasts treated with the D3R agonist, pramipexole, displayed enhanced migration compared to control WT and D3KO cells. Loss of function in D3R resulted in attenuation of both proliferation and migration in response to scratch injury, and significantly increased the expression of Col3a1 in LV fibroblasts. These findings suggest that D3R may mediate cardiac fibroblast function during the wound healing response. To our knowledge this is the first report of D3R's expression and functional significance directly in mouse cardiac fibroblasts.

4.
Biochem Biophys Res Commun ; 515(4): 693-698, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31186140

RESUMO

Previous studies have extensively demonstrated the effect of endothelin-1 (ET-1), angiotensin II (Ang II), and TGF-ß1 on the stimulation of collagen type I expression in cardiac myofibroblasts. However, the role of pro-remodeling peptides in the transcriptional regulation of the collagen promoter remains unclear. Thus, the purpose of this study was to investigate the net regulatory effects of pro-remodeling peptides on collagen type I promoter activity. Constructs of various lengths (300 bp, 1.1 kbp, 1.7 kbp, 2.3 kbp and 3.5 kbp) of the rat collagen α1(I) promoter were transfected into cardiac myofibroblasts in vitro and promoter activity was measured using chloramphenicol acetyl transferase (CAT) assays. Reduced promoter activity occurred across all treatments in myofibroblasts transfected with the 1.7 kbp construct. ET-1 was unable to increase promoter activity with constructs 300, 1.1, and 1.7 kbp, but induced promoter activity in cells with the 2.3 kbp construct. Additionally, while a combination of pro-remodeling peptides induced promoter activity across constructs, the resultant increase in the 2.3 and 3.5 kbp constructs were comparable to that observed from ET-1 treatment alone. Lastly, cells transfected with the entire promoter sequence had the lowest promoter activity. This data suggests that the collagen promoter is tightly regulated and that pro-remodeling factors produce an overall net effect on collagen expression, rather than additive.


Assuntos
Colágeno Tipo I/genética , Endotelina-1/metabolismo , Miocárdio/metabolismo , Miofibroblastos/metabolismo , Regiões Promotoras Genéticas , Animais , Cloranfenicol O-Acetiltransferase/análise , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Regulação da Expressão Gênica , Masculino , Peptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo
5.
Life Sci ; 228: 30-34, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31004660

RESUMO

Collagen is the most abundant protein in mammalian systems; it can be found in organs such as bones, the liver, kidney, heart, teeth, and skin. Collagen provides the necessary structural framework for tissues in which it is found. However, if there are any alterations in the delicate balance of collagen types in the extracellular matrix (ECM), then problems arise. For example, increasing collagen I:III ratio would provide additional rigidity to tissue structure, whereas decreasing this ratio would provide elasticity and flexibility to the tissue. The proper function of tissues is reliant on this scale not tipping too far in either direction. Major players in the process of ECM remodeling, both normal and adverse, are the fibroblast cells via the secretion of collagen precursors and matrix metalloproteinases, with the latter responsible for ECM degradation. The collagen peptides created by the proteolytic cleavage of these collagen fibrils, while once thought to have an absence of function, have been shown over recent years to potentiate and regulate a variety of cellular processes acting through integrin receptors. Many collagen peptides have been identified from many different collagen types and have been shown to regulate processes such as cell proliferation, migration, apoptosis, and reduce angiogenesis. The collagen peptides of interest are those generated from the primary collagen type of tissue interstitial matrix, collagen type I, and the basement membrane, collagen type IV. Thus, this review looks to highlight some examples of unorthodox functional roles of collagen and its peptides in regulating physiological health and disease.


Assuntos
Colágeno Tipo IV/metabolismo , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Animais , Apoptose , Movimento Celular , Proliferação de Células , Colágeno Tipo I/análise , Colágeno Tipo IV/análise , Matriz Extracelular/química , Humanos , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/metabolismo , Proteólise
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