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1.
J Exp Clin Cancer Res ; 41(1): 276, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114508

RESUMO

The extracellular matrix (ECM) is an important component of the tumor microenvironment (TME), having several important roles related to the hallmarks of cancer. In cancer, multiple components of the ECM have been shown to be altered. Although most of these alterations are represented by the increased or decreased quantity of the ECM components, changes regarding the functional alteration of a particular ECM component or of the ECM as a whole have been described. These alterations can be induced by the cancer cells directly or by the TME cells, with cancer-associated fibroblasts being of particular interest in this regard. Because the ECM has this wide array of functions in the tumor, preclinical and clinical studies have assessed the possibility of targeting the ECM, with some of them showing encouraging results. In the present review, we will highlight the most relevant ECM components presenting a comprehensive description of their physical, cellular and molecular properties which can alter the therapy response of the tumor cells. Lastly, some evidences regarding important biological processes were discussed, offering a more detailed understanding of how to modulate altered signalling pathways and to counteract drug resistance mechanisms in tumor cells.


Assuntos
Resistência a Medicamentos , Matriz Extracelular , Neoplasias , Matriz Extracelular/patologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Microambiente Tumoral
2.
BMC Musculoskelet Disord ; 23(1): 872, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127685

RESUMO

BACKGROUND: Our previous study identified miR-99a as a negative regulator of early chondrogenic differentiation. However, the functional role of miR-99a in the pathogenesis of osteoarthritis (OA) remains unclear. METHODS: We examined the levels of miR-99a and Frizzled 8 (FZD8) expression in tissue specimens. Human SW1353 chondrosarcoma cells were stimulated with IL-6 and TNF-α to construct an in vitro OA environment. A luciferase reporter assay was performed to analyze the relationship between miR-99a and FZD8. CCK-8 assays, flow cytometry, and ELISA assays were used to assess cell viability, apoptosis, and inflammatory molecule expression, respectively. Percutaneous intra-spinal injections of papain mixed solution were performed to create an OA Sprague-Dawley rat model. Alcian Blue staining, Safranin O Fast Green staining, and Toluidine Blue O staining were performed to detect the degrees of cartilage injury. RESULTS: MiR-99a expression was downregulated in the severe spine OA patients when compared with the mild spine OA patients, and was also decreased in the experimentally induced in vitro OA environment when compared with the control environment. Functionally, overexpression of miR-99a significantly suppressed cell apoptosis and extracellular matrix degradation stimulated by IL-6 and TNF-α. FZD8 was identified as a target gene of miR-99a. Furthermore, the suppressive effects of miR-99a on cell injury induced by IL-6 and TNF-α were reversed by FZD8 overexpression. Moreover, the levels of miR-99a expression were also reduced in the induced OA model rats, and miR-99a agomir injection relieved the cartilage damage. At the molecular level, miR-99a overexpression downregulated the levels of MMP13, ß-catenin, Bax, and caspase-3 protein expression and upregulated the levels of COL2A1 and Bcl-2 protein expression in the in vitro OA-like chondrocyte model and also in the experimental OA model rats. CONCLUSIONS: Our data showed that miR-99a alleviated apoptosis and extracellular matrix degradation by targeting FZD8, and thereby suppressed the development and progression of experimentally induced spine osteoarthritis.


Assuntos
MicroRNAs , Osteoartrite da Coluna Vertebral , Osteoartrite , Azul Alciano/metabolismo , Azul Alciano/farmacologia , Animais , Apoptose/genética , Caspase 3/metabolismo , Matriz Extracelular/patologia , Humanos , Interleucina-6/metabolismo , Luciferases/metabolismo , Luciferases/farmacologia , Metaloproteinase 13 da Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite/patologia , Osteoartrite da Coluna Vertebral/metabolismo , Papaína/metabolismo , Papaína/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular , Sincalida/metabolismo , Sincalida/farmacologia , Cloreto de Tolônio/metabolismo , Cloreto de Tolônio/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , beta Catenina/metabolismo , beta Catenina/farmacologia
3.
J Biomech ; 141: 111229, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35933917

RESUMO

Spheroids are multicellular systems with an interesting rheology giving rise to elasto-visco-plastic properties. They are good tumor models, but the role of the extracellular matrix (ECM) is not fully understood. ECM is an important link between cells and may have a significant impact on tissue organization. Here we determine viscoelastic properties of spheroids including different collagen I amounts using AFM and predict new frequency-dependent properties leading to soft glassy rheology behavior. A unified model - similar to single cell behavior - is proposed and discussed, while complementary confocal experiments reveal the microstructure of spheroids, with collagen I fibers serving as a skeleton for cells, thus reinforcing the spheroid viscoelastic behavior.


Assuntos
Neoplasias , Esferoides Celulares , Colágeno/análise , Colágeno Tipo I , Matriz Extracelular/patologia , Neoplasias/patologia , Reologia , Esferoides Celulares/patologia
4.
Nat Commun ; 13(1): 4587, 2022 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-35933466

RESUMO

The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse.


Assuntos
Neoplasias da Mama , Colágeno Tipo XII/metabolismo , Metástase Neoplásica , Microambiente Tumoral , Neoplasias da Mama/patologia , Colágeno , Colágeno Tipo I , Matriz Extracelular/patologia , Feminino , Humanos , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Proteômica
5.
Acta Biomater ; 150: 34-47, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35948177

RESUMO

The tumor microenvironment (TME) is a complex macromolecular network filled with a series of stromal cells. It plays an important role in tumorigenesis, development, immune escape, drug resistance, and other processes and has received increasing attention in recent years. Currently, tumor cell-centered treatments are insufficient to eradicate malignancies, and researchers are constantly searching for better treatments. Over the past decade, the TME has been recognized as a rich resource for anti-cancer drug development. As a significant mechanical feature in the microenvironment of solid tumors, matrix stiffness is increased owing to stromal deposition and remodeling. The effect of matrix stiffness on cancer cells has been described in many studies, whereas its effect on cancer stromal cell fate has rarely been summarized. Therefore, this review discusses the relevant content and drug treatment studies targeting matrix stiffness. STATEMENT OF SIGNIFICANCE: Biochemical and biophysical interactions between tumor cells, stromal cells, and the extracellular matrix (ECM) co-create a distinct tumor microenvironment (TME), which impacts disease outcome. In recent years, there has been a greater emphasis on the physical properties of the ECM, with matrix stiffness being one of the most thoroughly investigated. The matrix stiffness of solid tumors is now commonly acknowledged to be greater than that of normal tissues. Cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and endothelial cells (ECs) can all respond to matrix stiffness. At the same time, our current understanding of the TME is insufficient, and an in-depth examination of interactions between ECM and cells could lead to the development of more efficient and specialized treatments.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias , Células Endoteliais/patologia , Matriz Extracelular/patologia , Humanos , Neoplasias/patologia , Neoplasias/terapia , Células Estromais/patologia , Microambiente Tumoral
6.
Cells ; 11(15)2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35954246

RESUMO

Hepatic fibrosis is a common type of liver disease that is attracting increasing attention of basic scientists and clinicians worldwide [...].


Assuntos
Células Estreladas do Fígado , Hepatopatias , Matriz Extracelular/patologia , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/patologia , Hepatopatias/patologia
7.
Cell Stem Cell ; 29(8): 1161-1180, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35931028

RESUMO

Fibroblasts are highly dynamic cells that play a central role in tissue repair and fibrosis. However, the mechanisms by which they contribute to both physiologic and pathologic states of extracellular matrix deposition and remodeling are just starting to be understood. In this review article, we discuss the current state of knowledge in fibroblast biology and heterogeneity, with a primary focus on the role of fibroblasts in skin wound repair. We also consider emerging techniques in the field, which enable an increasingly nuanced and contextualized understanding of these complex systems, and evaluate limitations of existing methodologies and knowledge. Collectively, this review spotlights a diverse body of research examining an often-overlooked cell type-the fibroblast-and its critical functions in wound repair and beyond.


Assuntos
Fibroblastos , Cicatrização , Matriz Extracelular/patologia , Fibroblastos/patologia , Fibrose , Humanos , Pele/patologia , Cicatrização/fisiologia
8.
Am J Physiol Cell Physiol ; 323(3): C678-C693, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35876288

RESUMO

Cancer immunoediting progresses through elimination, equilibrium, and escape. Each of these phases is characterized by breaching, remodeling, and rebuilding tissue planes and structural barriers that engage extracellular matrix (ECM) components, in particular matrix proteoglycans. Some of the signals emanating from matrix proteoglycan remodeling are readily co-opted by the growing tumor to sustain an environment of tumor-promoting and immune-suppressive inflammation. Yet other matrix-derived cues can be viewed as part of a homeostatic response by the host, aiming to eliminate the tumor and restore tissue integrity. These latter signals may be harnessed for therapeutic purposes to tip the polarity of the tumor immune milieu toward anticancer immunity. In this review, we attempt to showcase the importance and complexity of matrix proteoglycan signaling in both cancer-restraining and cancer-promoting inflammation. We propose that the era of matrix diagnostics and therapeutics for cancer is fast approaching the clinic.


Assuntos
Neoplasias , Proteoglicanas , Matriz Extracelular/patologia , Humanos , Inflamação , Neoplasias/patologia , Transdução de Sinais
9.
Clin Transl Med ; 12(8): e997, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35908277

RESUMO

BACKGROUND: The biological function of mesenchymal stem-like cells (MSLCs), a type of stromal cells, in the regulation of the tumour microenvironment is unclear. Here, we investigated the molecular mechanisms underlying extracellular matrix (ECM) remodelling and crosstalk between MSLCs and glioblastomas (GBMs) in tumour progression. METHODS: In vitro and in vivo co-culture systems were used to analyze ECM remodelling and GBM infiltration. In addition, clinical databases, samples from patients with GBM and a xenografted mouse model of GBM were used. RESULTS: Previous studies have shown that the survival of patients with GBM from whom MSLCs could be isolated is substantially shorter than that of patients from whom MSLCs could not be isolated. Therefore, we determined the correlation between changes in ECM-related gene expression in MSLC-isolatable patients with that in MSLC non-isolatable patients using gene set enrichment analysis (GSEA). We found that lysyl oxidase (LOX) and COL1A1 expressions increased in MSLCs via GBM-derived clusters of differentiation 40 ligand (CD40L). Mechanistically, MSLCs are reprogrammed by the CD40L/CD40/NFκB2 signalling axis to build a tumour infiltrative microenvironment involving collagen crosslinking. Importantly, blocking of CD40L by a neutralizing antibody-suppressed LOX expression and ECM remodelling, decreasing GBM infiltration in mouse xenograft models. Clinically, high expression of CD40L, clusters of differentiation 40 (CD40) and LOX correlated with poor survival in patients with glioma. This indicated that GBM-educated MSLCs promote GBM infiltration via ECM remodelling in the tumour microenvironment. CONCLUSION: Our findings provide mechanistic insights into the pro-infiltrative tumour microenvironment produced by GBM-educated MSLCs and highlight a potential therapeutic target that can be used for suppressing GBM infiltration.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Ligante de CD40/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Microambiente Tumoral
10.
Adv Biol (Weinh) ; 6(9): e2200039, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35798312

RESUMO

Perineural invasion (PNI) refers to the cancerous invasion of nerves. It provides an alternative route for metastatic invasion and can exist independently in the absence of lymphatic or vascular invasion. It is a prominent characteristic of specific aggressive malignancies where it correlates with poor prognosis. The clinical significance of PNI is widely recognized despite a lack of understanding of the molecular mechanisms underlying its pathogenesis. The interaction between the nerve and the cancer cells is the most pivotal PNI step which is mediated by the activation or inhibition of multiple signaling pathways that include chemokines, interleukins, nerve growth factors, and matrix metalloproteinases, to name a few. The nerve-cancer cell interaction brings about specific changes in the perineural niche, which not only affects the regular nerve functions, but also enhances the migratory, invasive, and adherent properties of the tumor cells. This review aims to elucidate the vital role of adhesion molecules, extracellular matrix, and epithelial-mesenchymal proteins that promote PNI, which may serve as therapeutic targets in the future.


Assuntos
Matriz Extracelular , Transdução de Sinais , Comunicação Celular , Matriz Extracelular/patologia , Humanos , Invasividade Neoplásica/patologia
11.
Photodiagnosis Photodyn Ther ; 39: 103008, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35817370

RESUMO

Glioma is the most common tumor in the central nervous system, which is often accompanied by poor prognosis. Brain extracellular matrix (ECM) plays an important role in regulating the growth and migration of glioma. Photodynamic therapy (PDT) has been an effective method for the treatment of solid tumors by oxidative modifications in recent years, and ECM may have an impact on the cytotoxicity of photodynamic therapy. In this work, we prepared decellularized brain ECM by chemical method to investigate the influence of the photodynamic effect of glioma C6 cells. Compared with decellularized liver ECM, brain ECM reduces PDT cytotoxicity. By observing the content of reactive oxygen species produced by near-infrared light active indocyanine green in cells, it was found that ECM did not affect the production of reactive oxygen species. Therefore, it is speculated that brain ECM may enhance the oxidative stress adaptability of glioma cells through potential signal regulation, or protect photodynamic targeting biomolecules (such as proteins and other cellular components) from oxidation in PDT mediated by indocyanine green and 808 nm laser in glioma cells.


Assuntos
Neoplasias Encefálicas , Glioma , Fotoquimioterapia , Encéfalo/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Verde de Indocianina/uso terapêutico , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio
12.
Fluids Barriers CNS ; 19(1): 58, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35821139

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most aggressive and common type of primary brain tumor in adults. Tumor location plays a role in patient prognosis, with tumors proximal to the lateral ventricles (LVs) presenting with worse overall survival, increased expression of stem cell genes, and increased incidence of distal tumor recurrence. This may be due in part to interaction of GBM with factors of the subventricular zone (SVZ), including those contained within the cerebrospinal fluid (CSF). However, direct interaction of GBM tumors with CSF has not been proved and would be hindered in the presence of an intact ependymal cell layer. METHODS: Here, we investigate the ependymal cell barrier and its derived extracellular matrix (ECM) fractones in the vicinity of a GBM tumor. Patient-derived GBM cells were orthotopically implanted into immunosuppressed athymic mice in locations distal and proximal to the LV. A PBS vehicle injection in the proximal location was included as a control. At four weeks post-xenograft, brain tissue was examined for alterations in ependymal cell health via immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. RESULTS: We identified local invading GBM cells within the LV wall and increased influx of CSF into the LV-proximal GBM tumor bulk compared to controls. In addition to the physical disruption of the ependymal cell barrier, we also identified increased signs of compromised ependymal cell health in LV-proximal tumor-bearing mice. These signs include increased accumulation of lipid droplets, decreased cilia length and number, and decreased expression of cell channel proteins. We additionally identified elevated numbers of small fractones in the SVZ within this group, suggesting increased indirect CSF-contained molecule signaling to tumor cells. CONCLUSIONS: Our data is the first to show that LV-proximal GBMs physically disrupt the ependymal cell barrier in animal models, resulting in disruptions in ependymal cell biology and increased CSF interaction with the tumor bulk. These findings point to ependymal cell health and CSF-contained molecules as potential axes for therapeutic targeting in the treatment of GBM.


Assuntos
Glioblastoma , Animais , Cílios , Epêndima/metabolismo , Matriz Extracelular/patologia , Glioblastoma/metabolismo , Humanos , Ventrículos Laterais/patologia , Camundongos
13.
JCI Insight ; 7(16)2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-35852874

RESUMO

Usual interstitial pneumonia (UIP) is a histological pattern characteristic of idiopathic pulmonary fibrosis (IPF). The UIP pattern is patchy with histologically normal lung adjacent to dense fibrotic tissue. At this interface, fibroblastic foci (FF) are present and are sites where myofibroblasts and extracellular matrix (ECM) accumulate. Utilizing laser capture microdissection-coupled mass spectrometry, we interrogated the FF, adjacent mature scar, and adjacent alveoli in 6 fibrotic (UIP/IPF) specimens plus 6 nonfibrotic alveolar specimens as controls. The data were subjected to qualitative and quantitative analysis and histologically validated. We found that the fibrotic alveoli protein signature is defined by immune deregulation as the strongest category. The fibrotic mature scar classified as end-stage fibrosis whereas the FF contained an overabundance of a distinctive ECM compared with the nonfibrotic control. Furthermore, FF were positive for both TGFB1 and TGFB3, whereas the aberrant basaloid cell lining of FF was predominantly positive for TGFB2. In conclusion, spatial proteomics demonstrated distinct protein compositions in the histologically defined regions of UIP/IPF tissue. These data revealed that FF are the main site of collagen biosynthesis and that the adjacent alveoli are abnormal. This essential information will inform future mechanistic studies on fibrosis progression.


Assuntos
Fibrose Pulmonar Idiopática , Cicatriz/patologia , Colágeno , Matriz Extracelular/patologia , Fibrose , Humanos , Fibrose Pulmonar Idiopática/patologia
14.
Int J Mol Sci ; 23(13)2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35805895

RESUMO

Pulmonary fibrosis (PF) is characterized by aberrant extracellular matrix (ECM) deposition, activation of fibroblasts to myofibroblasts and parenchymal disorganization, which have an impact on the biomechanical traits of the lung. In this context, the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) is lost. Interestingly, several MMPs are overexpressed during PF and exhibit a clear profibrotic role (MMP-2, -3, -8, -11, -12 and -28), but a few are antifibrotic (MMP-19), have both profibrotic and antifibrotic capacity (MMP7), or execute an unclear (MMP-1, -9, -10, -13, -14) or unknown function. TIMPs are also overexpressed in PF; hence, the modulation and function of MMPs and TIMP are more complex than expected. EMMPRIN/CD147 (also known as basigin) is a transmembrane glycoprotein from the immunoglobulin superfamily (IgSF) that was first described to induce MMP activity in fibroblasts. It also interacts with other molecules to execute non-related MMP aactions well-described in cancer progression, migration, and invasion. Emerging evidence strongly suggests that CD147 plays a key role in PF not only by MMP induction but also by stimulating fibroblast myofibroblast transition. In this review, we study the structure and function of MMPs, TIMPs and CD147 in PF and their complex crosstalk between them.


Assuntos
Basigina , Fibrose Pulmonar , Matriz Extracelular/patologia , Humanos , Metaloproteinases da Matriz , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Inibidores Teciduais de Metaloproteinases
15.
Int J Mol Sci ; 23(14)2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35886995

RESUMO

Collagen VI-related disorders (COL6-RD) represent a severe form of congenital disease for which there is no treatment. Dominant-negative pathogenic variants in the genes encoding α chains of collagen VI are the main cause of COL6-RD. Here we report that patient-derived fibroblasts carrying a common single nucleotide variant mutation are unable to build the extracellular collagen VI network. This correlates with the intracellular accumulation of endosomes and lysosomes triggered by the increased phosphorylation of the collagen VI receptor CMG2. Notably, using a CRISPR-Cas9 gene-editing tool to silence the dominant-negative mutation in patients' cells, we rescued the normal extracellular collagen VI network, CMG2 phosphorylation levels, and the accumulation of endosomes and lysosomes. Our findings reveal an unanticipated role of CMG2 in regulating endosomal and lysosomal homeostasis and suggest that mutated collagen VI dysregulates the intracellular environment in fibroblasts in collagen VI-related muscular dystrophy.


Assuntos
Colágeno Tipo VI , Distrofias Musculares , Colágeno Tipo VI/genética , Matriz Extracelular/patologia , Humanos , Morfogênese , Distrofias Musculares/terapia , Mutação
16.
Sci Rep ; 12(1): 10290, 2022 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-35717344

RESUMO

The extracellular matrix (ECM) collagen undergoes major remodeling during tumorigenesis. However, alterations to the ECM are not widely considered in cancer diagnostics, due to mostly uniform appearance of collagen fibers in white light images of hematoxylin and eosin-stained (H&E) tissue sections. Polarimetric second-harmonic generation (P-SHG) microscopy enables label-free visualization and ultrastructural investigation of non-centrosymmetric molecules, which, when combined with texture analysis, provides multiparameter characterization of tissue collagen. This paper demonstrates whole slide imaging of breast tissue microarrays using high-throughput widefield P-SHG microscopy. The resulting P-SHG parameters are used in classification to differentiate tumor from normal tissue, resulting in 94.2% for both accuracy and F1-score, and 6.3% false discovery rate. Subsequently, the trained classifier is employed to predict tumor tissue with 91.3% accuracy, 90.7% F1-score, and 13.8% false omission rate. As such, we show that widefield P-SHG microscopy reveals collagen ultrastructure over large tissue regions and can be utilized as a sensitive biomarker for cancer diagnostics and prognostics studies.


Assuntos
Neoplasias , Microscopia de Geração do Segundo Harmônico , Colágeno/química , Matriz Extracelular/patologia , Aprendizado de Máquina , Neoplasias/diagnóstico , Neoplasias/patologia , Prognóstico , Microscopia de Geração do Segundo Harmônico/métodos
17.
Am J Physiol Cell Physiol ; 323(2): C486-C493, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35759433

RESUMO

One in three persons will develop cancer in their lifetime (Siegel RL, Miller KD, Fuchs HE, Jemal A. CA Cancer J Clin 71: 7-33, 2021) and the majority of these patients will die from the spread of cancer throughout their body-a process known as metastasis. Metastasis is strongly regulated by the tumor microenvironment (TME) comprising cellular and noncellular components. In this review, we will focus on the role of neutrophils regulating the extracellular matrix (ECM), enabling ECM remodeling and cancer progression. In particular, we highlight the role of neutrophil-secreted proteases (NSP) and how these promote metastasis.


Assuntos
Neoplasias , Neutrófilos , Matriz Extracelular/patologia , Granulócitos/patologia , Humanos , Neoplasias/patologia , Neutrófilos/patologia , Microambiente Tumoral/fisiologia
18.
Nanoscale Horiz ; 7(7): 779-789, 2022 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-35703339

RESUMO

Nano-tumor interactions are fundamental for cancer nanotherapy, and the cross-talk of nanomedicines with the extracellular matrix (ECM) is increasingly considered essential. Here, we specifically investigate the nano-ECM interactivity using drug-free nanoparticulates (NPs) and highly metastatic cancer cells as models. We discover with surprise that NPs closely bind to specific types of ECM components, namely, retraction fibers (RFs) and migrasomes, which are located at the rear of tumor cells during their migration. This interaction is observed to alter cell morphology, limit cell motion range and change cell adhesion. Importantly, NPs are demonstrated to inhibit tumor cell removal in vitro, and their anti-metastasis potential is preliminarily confirmed in vivo. Mechanically, the NPs are found to coat and form a rigid shell on the surface of migrasomes and retraction fibers via interaction with lipid raft/caveolae substructures. In this way, NPs block the recognition, endocytosis and elimination of migrasomes by their surrounding tumor cells. Thereby, NPs interfere with the cell-ECM interaction and reduce the promotion effect of migrasomes on cell movement. Additionally, NPs trigger alteration of the expression of proteins related to cell-cell adhesion and cytoskeleton organization, which also restricts cell migration. In summary, all the findings here provide a potential target for anti-tumor metastasis nanomedicines.


Assuntos
Matriz Extracelular , Neoplasias , Cavéolas/patologia , Adesão Celular , Movimento Celular , Endocitose , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos
19.
Circ Cardiovasc Imaging ; 15(6): e013379, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35678191

RESUMO

BACKGROUND: Rapid screening and accurate diagnosis of acute myocardial infarction are critical to reduce the progression of myocardial necrosis, in which proteolytic degradation of myocardial extracellular matrix plays a major role. In previous studies, we found that targeting the extracellular matrix metalloprotease inducer (EMMPRIN) by injecting nanoparticles conjugated with the specific EMMPRIN-binding peptide AP9 significantly improved cardiac function in mice subjected to ischemia/reperfusion. METHODS: In a porcine model of coronary ischemia/reperfusion, we tested the theragnostic effects of administering 0.1 mg/kg gadolinium-containing nanoparticles conjugated with AP9 (NAP9), a synthetic peptide that targets EMMPRIN or a control nanoparticle (NAPSC). Cardiac magnetic resonance assessment of the infarct progression, ventricular function, and nanoparticle distribution was performed the next 7 days. We also measured the infarcted area of the heart and cardiac remodeling at 7 or 21 days after ischemia/reperfusion. RESULTS: After 21 days of ischemia/reperfusion, NAP9 reduced the extension of cardiac necrosis (14.1±9.7 versus 35.5±1.8) and the levels of collagenolytic activity of MMPs (matrix metalloproteases), along with a significant reduction in collagen deposition (7.5±4.5 versus 41.3±20); including the ratio of type I versus III collagen fibers in the necrotic myocardium. In terms of cardiac function, the response to NAP9 administration resulted in a significant improvement of cardiac performance overtime, as evidenced by the left ventricle ejection fraction (64.0±7.8), when compared with those present in the NAPSC group (47.3±4.7). As shown by magnetic resonance imaging, noninvasive molecular imaging of NAP9 enabled us to find a significant reduction in cardiac necrosis, myocardial edema, hemorrhage, and microvascular obstruction, suggesting that NAP9 may reduce myocardial injury and preserve left ventricular function, at least, by preventing the effect of EMMPRIN on extracellular matrix degradation. CONCLUSIONS: Our data point towards NAP9 as a promising theragnostic tool in managing acute myocardial infarction, by inhibiting EMMPRIN-induced extracellular matrix degradation and allowing noninvasive visualization of cardiac necrosis progression over time.


Assuntos
Doença da Artéria Coronariana , Infarto do Miocárdio , Nanopartículas , Animais , Basigina/metabolismo , Colágeno , Doença da Artéria Coronariana/patologia , Matriz Extracelular/patologia , Humanos , Metaloproteinases da Matriz/metabolismo , Camundongos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Nanopartículas/química , Medicina de Precisão , Reperfusão , Suínos
20.
Pharmacol Rev ; 74(3): 712-768, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35738680

RESUMO

The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.


Assuntos
Inibidores de Metaloproteinases de Matriz , Neoplasias , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Inibidores de Metaloproteinases de Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Metaloproteinases da Matriz/metabolismo , Metaloproteinases da Matriz/uso terapêutico , Neoplasias/metabolismo , Proteólise
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