Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Oct. 2, 2023

Abstract Despite centuries since the discovery and study of cancer, cancer is still a lethal intractable health issue worldwide. Cancer-associated fibroblasts (CAFs) have gained much attention as pivotal component tumor microenvironment. The versatility sophisticated mechanisms CAFs in facilitating progression been elucidated extensively, including promoting angiogenesis metastasis, inducing drug resistance, reshaping extracellular matrix, developing an immunosuppressive Owing to their robust tumor-promoting function, are considered promising target for oncotherapy. However, highly heterogeneous group cells. Some subpopulations exert inhibitory role growth, which implies that CAF-targeting approaches must be more precise individualized. This review comprehensively summarize origin, phenotypical, functional heterogeneity CAFs. More importantly, we underscore advances strategies clinical trials CAF various cancers, also progressions immunotherapy.

Language: Английский

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Phenotype Switching and the Melanoma Microenvironment; Impact on Immunotherapy and Drug Resistance

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1601 - 1601

Published: Jan. 13, 2023

Melanoma, a highly heterogeneous tumor, is comprised of functionally diverse spectrum cell phenotypes and subpopulations, including stromal cells in the tumor microenvironment (TME). Melanoma has been shown to dynamically shift between different transcriptional states or phenotypes. This referred as phenotype switching melanoma, it involves quiescent proliferative cycle states, dramatic shifts invasiveness, well changes signaling pathways melanoma cells, immune composition TME. plasticity associated with altered gene expression cancer-associated fibroblasts, extracellular matrix, which drive metastatic cascade therapeutic resistance. Therefore, resistance therapy not only dependent on genetic evolution, but also suggested be driven by adaptive phenotypic plasticity. review discusses recent findings switching, immunotherapy resistance, balancing homeostatic TME subpopulations. We discuss future perspectives biology neural crest-like state(s) melanoma.

Language: Английский

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Melanoma cells with diverse invasive potential differentially induce the activation of normal human fibroblasts

Cell Communication and Signaling, Journal Year: 2022, Volume and Issue: 20(1)

Published: May 10, 2022

Abstract Background The tumor microenvironment consists of stromal cells, extracellular matrix, and physicochemical properties (e.g., oxygenation, acidification). An important element the niche are cancer-associated fibroblasts (CAFs). They may constitute up to 80% mass share some features with myofibroblasts involved in process wound healing. CAFs can facilitate cancer progression. However, their interaction melanoma cells is still poorly understood. Methods We obtained using conditioned media derived from primary metastatic via co-culture on Transwell inserts. Using 2D 3D healing assays invasion method we evaluated CAFs’ motile activities, while coverslips FITC-labeled gelatin, gelatin zymography, fluorescence-based activity assay were employed determine proteolytic examined cells. Western Blotting was used for identification markers as well estimation mediators MMPs’ (matrix metalloproteinases) expression levels. Lastly, secretome cytokine angiogenesis proteomic arrays, lactate chemiluminescence-based assay. Results Acquired FAP-α/IL6-positive exhibited elevated motility expressed increased migration ratio, higher (area digestion, MMP2, MMP14). Furthermore, activated by showed upregulation mediators’ levels (pERK, p-p38, CD44, RUNX), enhanced secretion lactate, several cytokines (IL8, IL6, CXCL1, CCL2, ICAM1), proteins related (GM-CSF, DPPIV, VEGFA, PIGF). Conclusions Observed changes biology mainly driven highly aggressive (A375, WM9, Hs294T) compared less WM1341D could promote invasion, impact inflammation, angiogenesis, acidification niche. Interestingly, different approaches acquisition seem complement each other showing interactions between studied

Language: Английский

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Tumor-associated fibrosis impairs the response to immunotherapy

Matrix Biology, Journal Year: 2023, Volume and Issue: 119, P. 125 - 140

Published: April 18, 2023

Language: Английский

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Understanding the Tumor Microenvironment in Melanoma Patients with In-Transit Metastases and Its Impacts on Immune Checkpoint Immunotherapy Responses

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4243 - 4243

Published: April 11, 2024

Melanoma is the leading cause of global skin cancer-related death and currently ranks as third most commonly diagnosed cancer in Australia. patients with in-transit metastases (ITM), a type locoregional metastasis located close to primary tumor site, exhibit high likelihood further disease progression poor survival outcomes. Immunotherapies, particularly immune checkpoint inhibitors (ICI), have demonstrated remarkable efficacy ITM reduced occurrence prolonged survival. The major challenge immunotherapeutic lies limited understanding melanoma biology, hindering our ability identify who likely respond ICIs effectively. In this review, we provided an overview disease. We outlined key ICI therapies critical features associated therapy response or resistance. Lastly, dissected underlying biological components, including cellular compositions their communication networks within compartment, enhance interactions between immunotherapy melanoma, providing insights for future investigation development drug targets predictive biomarkers.

Language: Английский

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Angiogenesis Still Plays a Crucial Role in Human Melanoma Progression

Cancers, Journal Year: 2024, Volume and Issue: 16(10), P. 1794 - 1794

Published: May 8, 2024

Angiogenesis plays a pivotal role in tumor progression, particularly melanoma, the deadliest form of skin cancer. This review synthesizes current knowledge on intricate interplay between angiogenesis and microenvironment (TME) melanoma progression. Pro-angiogenic factors, including VEGF, PlGF, FGF-2, IL-8, Ang, TGF-β, PDGF, integrins, MMPs, PAF, modulate contribute to metastasis. Additionally, cells within TME, such as cancer-associated fibroblasts, mast cells, melanoma-associated macrophages, influence Anti-angiogenic therapies, while showing promise, face challenges drug resistance tumor-induced activation alternative angiogenic pathways. Rational combinations anti-angiogenic agents immunotherapies are being explored overcome resistance. Biomarker identification for treatment response remains crucial personalized therapies. highlights complexity underscores need innovative therapeutic approaches tailored dynamic TME.

Language: Английский

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Advances in Melanoma: From Genetic Insights to Therapeutic Innovations

Biomedicines, Journal Year: 2024, Volume and Issue: 12(8), P. 1851 - 1851

Published: Aug. 14, 2024

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between alterations, such as mutations BRAF, NRAS, KIT, pathogenesis. The MAPK PI3K/Akt/mTOR signaling pathways are highlighted for their roles tumor growth resistance mechanisms. Additionally, this delves impact of epigenetic modifications, including DNA methylation histone changes, on progression. microenvironment, characterized by immune cells, stromal soluble factors, plays a pivotal role modulating behavior treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, AI-driven diagnostics transforming research, offering precise personalized approaches treatment. Immunotherapy, particularly checkpoint inhibitors mRNA vaccines, has revolutionized therapy enhancing body’s response. Despite these advances, mechanisms remain challenge, underscoring need combined therapies ongoing achieve durable comprehensive overview aims highlight current state transformative impacts advancements clinical practice.

Language: Английский

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Cancer-associated fibroblast subtypes modulate the tumor-immune microenvironment and are associated with skin cancer malignancy

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 8, 2024

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the intra-tumoral diversity of CAFs basal cell carcinoma, squamous melanoma using molecular spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix (mCAFs), immunomodulatory (iCAFs). Large-cohort tissue analysis reveals significant shifts subtype patterns with increasing malignancy. Two subtypes exhibit properties via different mechanisms. mCAFs sythesize extracellular may restrict T invasion low-grade tumors ensheathing tumor nests, while iCAFs are enriched late-stage tumors, express high levels cytokines chemokines to aid immune recruitment activation. is supported by induction an iCAF-like phenotype functions primary healthy exposed skin secretomes. Thus, targeting variants holds promise enhance immunotherapy efficacy cancers.

Language: Английский

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The Keratinocyte in the Picture Cutaneous Melanoma Microenvironment

Cancers, Journal Year: 2024, Volume and Issue: 16(5), P. 913 - 913

Published: Feb. 23, 2024

Melanoma progression is a multistep evolution from common melanocytic nevus through radial superficial growth phase, the invasive vertical phase finally leading to metastatic dissemination into distant organs. aggressiveness largely depends on propensity metastasize, which means capacity escape physiological microenvironment since tissue damage due primary melanoma lesions generally modest. Physiologically, epidermal melanocytes are attached basement membrane, and their adhesion/migration under control of surrounding keratinocytes. Thus, compartment represents first responsible for spread. This complex process involves cell-cell contact broad range secreted bioactive molecules. Invasion, or at beginning microinvasion, implies breakdown dermo-epidermal membrane followed by migration neoplastic cells in papillary dermis. Correspondingly, several experimental evidences documented structural functional rearrangement entire neoplasm that some way reflects atypia tumor cells. Lastly, must support proliferation survival outside normal epidermal-melanin units. task presumably mostly delegated fibroblasts ultimately self-autonomous review will discuss remodeling occurs epidermis during formation as well skin changes occur independently hyperproliferation having possible pro-tumoral features.

Language: Английский

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Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 28, 2022

Melanoma is a highly aggressive skin cancer, which, although immunogenic, frequently escapes the body's immune defences. Immune checkpoint inhibitors (ICI), such as anti-PD1, anti-PDL1, and anti-CTLA4 antibodies lead to reactivation of pathways, promoting rejection melanoma. However, benefits ICI therapy remain limited relatively small proportion patients who do not exhibit resistance. Moreover, precise mechanisms underlying innate acquired resistance unclear. Here, we have investigated differences in melanoma tissues responder non-responder anti-PD1 terms tumour cell gene-associated signatures. We performed multi-omics investigations on tissues, which were collected from before starting treatment with inhibitors. Patients subsequently categorized into responders non-responders based RECIST criteria. Multi-omics analyses included RNA-Seq NanoString analysis. From data carried out HLA phenotyping well gene enrichment analysis, pathway analysis deconvolution studies. Consistent previous studies, our showed that had higher scores (median score for = 0.1335, median 0.05426, p-value 0.01, Mann-Whitney U two-tailed exact test) compared non-responders. Responder melanomas more enriched combination CD8+ T cells, dendritic cells (p-value 0.03) an M1 subtype macrophages 0.001). In addition, exhibited differentiated expression pattern, high proliferative- low invasive-associated signatures, whereas tumours invasive- neural crest-like type Our findings suggest de-differentiated signature, associated poorer infiltration, establishes pattern characteristic therapy. Improved understanding tumour-intrinsic patterns response will help identify predictive biomarkers may new targets anticancer treatment, especially capacity function adjuvants improve outcomes.

Language: Английский

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