Biological and Therapeutic Implications of the Tumor Microenvironment in Pituitary Adenomas

Endocrine Reviews, Год журнала: 2022, Номер 44(2), С. 297 - 311

Опубликована: Окт. 21, 2022

Pituitary adenomas (PAs) are neoplasms derived from the endocrine cells of anterior pituitary gland. Most frequently, they benign tumors, but may sometimes display an aggressive course, and in some cases metastasize. Their biology, including their wide range behavior, is only partly understood. In terms therapeutic targeting, most PAs easily treated with available medical treatments, surgery, radiotherapy. Nevertheless, gonadotroph lack options, treatment carcinomas remains challenging. Here, we present overview implications tumor microenvironment PAs, reviewing its composition function, as well published that have been thus far using microenvironment-targeting therapies. Additionally, discuss emerging views, such concept nonangiogenic perspectives regarding treatments represent future potential options. Tumor-infiltrating lymphocytes, tumor-associated macrophages, folliculostellate cells, fibroblasts, angiogenesis, extracellular matrix remodeling, all complex roles biology PAs. They linked to hormone production/secretion, size, invasion, proliferation, progression/recurrence, response From a perspective, immune-checkpoint inhibitors bevacizumab already shown degree efficacy carcinomas, use numerous other therapies can be foreseen. conclusion, similar cancers, understanding improves our PA beyond genetics epigenetics, constitutes important tool for developing

Язык: Английский

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Prognostic Significance of Integrin Subunit Alpha 2 (ITGA2) and Role of Mechanical Cues in Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma (PDAC)

Cancers, Год журнала: 2023, Номер 15(3), С. 628 - 628

Опубликована: Янв. 19, 2023

PDAC is an extremely aggressive tumor with a poor prognosis and remarkable therapeutic resistance. The dense extracellular matrix (ECM) which characterizes progression considered fundamental determinant of chemoresistance, major contributions from mechanical factors. This study combined biomechanical pharmacological approaches to evaluate the role cell-adhesion molecule ITGA2, key regulator ECM, in resistance gemcitabine.The prognostic value ITGA2 was analysed publicly available databases tissue-microarrays two cohorts radically resected metastatic patients treated gemcitabine. PANC-1 its gemcitabine-resistant clone (PANC-1R) were by RNA-sequencing label-free proteomics. migration, proliferation, apoptosis investigated using hydrogel-coated wells, siRNA-mediated knockdown overexpression, while collagen-embedded spheroids assessed invasion ECM remodeling.High expression correlated shorter progression-free overall survival, supporting impact on lack efficacy gemcitabine treatment. These findings corroborated transcriptomic proteomic analyses showing that upregulated PANC-1R clone. behavior these cells significantly reduced silencing both vitro vivo, growing under conditions resembling stiffness acquired gemcitabine, associated increased expression. Collagen-embedded showed significant remodeling spreading potential via CXCR4 MMP2. Additionally, overexpression MiaPaCa-2 triggered upregulation phospho-AKT.ITGA2 emerged as new factor, highlighting relevance stroma properties targets counteract PDAC.

Язык: Английский

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Tumor-associated fibrosis impairs the response to immunotherapy

Matrix Biology, Год журнала: 2023, Номер 119, С. 125 - 140

Опубликована: Апрель 18, 2023

Язык: Английский

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1H-detected characterization of carbon–carbon networks in highly flexible protonated biomolecules using MAS NMR

Journal of Biomolecular NMR, Год журнала: 2023, Номер 77(3), С. 111 - 119

Опубликована: Июнь 1, 2023

Abstract In the last three decades, scope of solid-state NMR has expanded to exploring complex biomolecules, from large protein assemblies intact cells at atomic-level resolution. This diversity in macromolecules frequently features highly flexible components whose insoluble environment precludes use solution study their structure and interactions. While High-resolution Magic-Angle Spinning (HR-MAS) probes offer capacity for gradient-based 1 H-detected spectroscopy solids, such are not commonly used routine MAS experiments. As a result, most exploration regime entails either 13 C-detected experiments, partially perdeuterated systems, or ultra-fast MAS. Here we explore proton-detected pulse schemes probing through-bond C– C networks mobile sidechains as well polysaccharides broadband manner. We demonstrate mixture microtubule-associated (MAP) tau human microtubules (MTs), cell wall fungus Schizophyllum commune using 2D 3D spectroscopy, show its viability obtaining unambiguous correlations standard fast-spinning high ultra-high magnetic fields.

Язык: Английский

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Osteopontin is a therapeutic target that drives breast cancer recurrence

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 24, 2024

Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of recurrence. Osteopontin promotes cell proliferation, recruits macrophages, synergizes with IL-4 further polarize them into a pro-tumorigenic state. Macrophage depletion inhibition decrease recurrent growth. Furthermore, targeting primary tumor-bearing female mice prevents metastasis, permits T infiltration activation, improves anti-PD-1 immunotherapy response. Clinically, expression is higher metastatic tumors versus patient-matched tumors. positively correlates macrophage infiltration, increases grade, its elevated pathway activity associated poor prognosis Our findings suggest clinical implications alternative therapeutic strategy based on osteopontin's multiaxial role progression

Язык: Английский

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The mechanopathology of the tumor microenvironment: detection techniques, molecular mechanisms and therapeutic opportunities

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Март 18, 2025

The mechanical properties of the tumor microenvironment (TME) undergo significant changes during growth, primarily driven by alterations in extracellular (ECM) stiffness and viscoelasticity. These not only promote progression but also hinder therapeutic efficacy impairing drug delivery activating mechanotransduction pathways that regulate crucial cellular processes such as migration, proliferation, resistance to therapy. In this review, we examine mechanisms through which cells sense transmit signals maintain homeostasis biomechanically altered TME. We explore current computational modelling strategies for pathways, highlighting need developing models incorporate additional components mechanosignaling machinery. Furthermore, review available methods measuring tumors clinical settings aiming at restoring TME blocking deregulated pathways. Finally, propose proper characterization a deeper understanding landscape TME, both tissue levels, are essential account influence forces on treatment efficacy.

Язык: Английский

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Osteopontin in Cancer: Mechanisms and Therapeutic Targets

International Journal of Translational Medicine, Год журнала: 2022, Номер 2(3), С. 419 - 447

Опубликована: Авг. 19, 2022

Despite significant advances in the understanding of cancer biology, is still a leading cause death worldwide. Expression tumor microenvironment component, osteopontin, tissues, plasma, and serum, has been shown to be associated with poor prognosis survival rate various human cancers. Recent studies suggest that osteopontin drives development aggressiveness using strategies. In this review, we first provide an overview how promotes progression, such as growth, invasion, angiogenesis, immune modulation, well metastasis chemoresistance. Next, address functional activities are modulated by interaction integrins CD44 receptors, but also post-translational modification, proteolytic processing several proteases, phosphorylation, glycosylation. Then, review activates tumor-associated macrophages (TAMs) cancer-associated fibroblasts (CAFs), functions immunosuppressor regulating surveillance checkpoint microenvironment. Finally, discuss potential applications biomarker therapeutic target.

Язык: Английский

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Ablation of integrin-mediated cell–collagen communication alleviates fibrosis

Annals of the Rheumatic Diseases, Год журнала: 2023, Номер 82(11), С. 1474 - 1486

Опубликована: Июль 21, 2023

Activation of fibroblasts is a hallmark fibrotic processes. Besides cytokines and growth factors, are regulated by the extracellular matrix environment through receptors such as integrins, which transduce biochemical mechanical signals enabling cells to mount appropriate responses according biological demands. The aim this work was investigate in vivo role collagen-fibroblast interactions for regulating fibroblast functions fibrosis.Triple knockout (tKO) mice with combined ablation integrins α1β1, α2β1 α11β1 were created address significance integrin-mediated cell-collagen communication. Properties primary dermal lacking collagen-binding delineated vitro. Response tKO skin bleomycin induced challenge assessed.Triple integrin-deficient develop normally, transiently smaller reveal mild alterations mechanoresilience skin. Fibroblasts from these culture show defects cytoskeletal architecture, traction stress generation, production organisation. Ablation three leads increased levels discoidin domain receptor 2, an alternative recognising collagens However, overexpression fails compensate adhesion spreading on collagen substrates Mice severely attenuated response impaired mechanotransduction, reduced organisation.The data provide evidence crucial force generation differentiation vitro deposition tissue remodelling vivo. Targeting fibroblast-collagen might represent promising therapeutic approach regulate connective diseases.

Язык: Английский

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Therapeutic targeting of the pituitary tumor microenvironment

Pharmacology & Therapeutics, Год журнала: 2023, Номер 250, С. 108506 - 108506

Опубликована: Авг. 9, 2023

Язык: Английский

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Targeting integrin α5 in fibroblasts potentiates colorectal cancer response to PD-L1 blockade by affecting extracellular-matrix deposition

Journal for ImmunoTherapy of Cancer, Год журнала: 2023, Номер 11(12), С. e007447 - e007447

Опубликована: Дек. 1, 2023

Background One reason patients with cancer cannot benefit from immunotherapy is the lack of immune cell infiltration in tumor tissues. Cancer-associated fibroblasts (CAFs) are emerging as central players regulation that shapes microenvironment (TME). Earlier we reported integrin α5 was enriched CAFs colorectal (CRC), however, its role TME and remains unclear. Here, aimed to investigate for modulating antitumor immunity therapeutic efficacy combined checkpoint blockade CRC. Methods We analyzed CRC single-cell RNA sequencing (scRNA-seq) database define expression ITGA5 stroma. Experimentally, carried out vivo mouse xenograft models confirm targeting α5β1 inhibition anti-Programmed death ligand 1 (PD-L1) vitro cell-co-culture assay affecting T-cell activity. Clinically, association between infiltrating T cells evaluated their correlation patient survival prognosis Results revealed FAP -CAFs. Both knockout improved response anti-PD-L1 treatment subcutaneous models. Mechanistically, these treatments led increased tumor-infiltrating CD8 + cells. Furthermore, found correlated extracellular matrix (ECM)-related genes affected ECM deposition analysis culture killing experiment showed proteins influence confirmed high associated fewer CD3 cells, tissues low levels better a cohort 29 patients. Conclusions Our study identified by PD-L1

Язык: Английский

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