Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance

Clinical Cancer Research, Journal Year: 2021, Volume and Issue: 27(9), P. 2636 - 2647

Published: Feb. 23, 2021

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment, but a systematic investigation their molecular characteristics and clinical relevance lacking. Here, we sought to compare CAFs across multiple cancer types identify critical pathways activated in CAF subtypes, which may contribute outcome, disease progression, immunotherapy resistance.We performed integrated analysis from melanoma, head neck squamous cell carcinoma, lung cancer, identified that distinctly active each subtype. Gene signatures for individual subtypes were used study association subtype abundance with outcome six (pan-CAF) shared uncovered genetic distinguishing them. Interestingly, these express distinct immunosuppressive factors, such as CXCL12 CXLC14, stem cell-promoting factor IL6. In addition, novel transcriptional drivers (MEF2C, TWIST1, NR1H3, RELB, FOXM1) key heterogeneity. Furthermore, showed associated different outcomes could activate or suppress progression involved resistance anti-PD1 anti-PD-L1 immunotherapy.Our identifies several types, implicates benefit targeted therapies, specific resistance.

Language: Английский

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Epigenetic heterogeneity in cancer

Biomarker Research, Journal Year: 2019, Volume and Issue: 7(1)

Published: Oct. 31, 2019

Phenotypic and functional heterogeneity is one of the hallmarks human cancers. Tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, variability multiple same type arising in patient referred to intra-patient heterogeneity. Subpopulations cancer cells with distinct phenotypic molecular features a tumor called intratumor (ITH). Since Nowell proposed clonal evolution cell populations 1976, especially ITH, was actively studied. Research has focused on genetic basis cancer, particularly mutational activation oncogenes or inactivation tumor-suppressor genes (TSGs). The phenomenon ITH commonly explained by Darwinian-like single tumor. Despite monoclonal origin most cancers, new clones arise during progression due continuous acquisition mutations. It clear that disruption "epigenetic machinery" plays an important role development. Aberrant epigenetic changes occur more frequently than gene mutations epigenome at intersection environment genome. Epigenetic dysregulation occurs earliest stage cancer. current trend therapy use drugs reverse and/or delay future resistance therapies. A majority therapies fail achieve durable responses, which often attributed ITH. may drug heterogeneous Complete understanding assist designing combinations targeted based information extracted from individual tumors.

Language: Английский

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Cancer-associated fibroblasts: overview, progress, challenges, and directions

Cancer Gene Therapy, Journal Year: 2021, Volume and Issue: 28(9), P. 984 - 999

Published: March 12, 2021

Language: Английский

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Biomarkers for cancer-associated fibroblasts

Biomarker Research, Journal Year: 2020, Volume and Issue: 8(1)

Published: Nov. 11, 2020

Cancer-associated fibroblasts (CAFs) are the key component of tumor stromal. High heterogeneity CAFs reflects in their origin, phenotype and function. Biological function which can be suggested by biomarkers distinct CAF subgroups may different, even opposite, just like water fire. Identifying subpopulations expressing different reconciling relationship "water fire" among subsets a breakthrough therapy. Herein, we briefly summarize commonly used or newly identified for terms features potential clinical benefits.

Language: Английский

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Single-Cell Transcriptomic Analysis of Tumor-Derived Fibroblasts and Normal Tissue-Resident Fibroblasts Reveals Fibroblast Heterogeneity in Breast Cancer

Cancers, Journal Year: 2020, Volume and Issue: 12(5), P. 1307 - 1307

Published: May 21, 2020

Cancer-associated fibroblasts (CAFs) are a prominent stromal cell type in solid tumors and molecules secreted by CAFs play an important role tumor progression metastasis. coexist as heterogeneous populations with potentially different biological functions. Although major component of the breast cancer stroma, molecular phenotypic heterogeneity is poorly understood. In this study, we investigated CAF triple-negative (TNBC) using syngeneic mouse model, BALB/c-derived 4T1 mammary tumors. Using single-cell RNA sequencing (scRNA-seq), identified six subpopulations including: 1) myofibroblastic CAFs, enriched for α-smooth muscle actin several other contractile proteins; 2) 'inflammatory' elevated expression inflammatory cytokines; 3) subpopulation expressing histocompatibility complex (MHC) class II proteins that generally expressed antigen-presenting cells. Comparison 4T1-derived to from pancreatic revealed these three exist both types. Interestingly, cells MHC II-expressing profiles were also detected normal breast/pancreas tissue, suggesting phenotypes not microenvironment-induced. This work enhances our understanding heterogeneity, specifically targeting could be effective therapeutic approach treating highly aggressive TNBCs.

Language: Английский

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Tumor microenvironment: barrier or opportunity towards effective cancer therapy

Journal of Biomedical Science, Journal Year: 2022, Volume and Issue: 29(1)

Published: Oct. 17, 2022

Abstract Tumor microenvironment (TME) is a specialized ecosystem of host components, designed by tumor cells for successful development and metastasis tumor. With the advent 3D culture advanced bioinformatic methodologies, it now possible to study TME’s individual components their interplay at higher resolution. Deeper understanding immune cell’s diversity, stromal constituents, repertoire profiling, neoantigen prediction TMEs has provided opportunity explore spatial temporal regulation therapeutic interventions. The variation TME composition among patients plays an important role in determining responders non-responders towards cancer immunotherapy. Therefore, there could be possibility reprogramming overcome widely prevailing issue immunotherapeutic resistance. focus present review understand complexity comprehending future perspective its as potential targets. later part describes sophisticated models emerging valuable means extensive account tools profile predict neoantigens. Overall, this provides comprehensive current knowledge available target TME.

Language: Английский

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Fibroblast heterogeneity in tumor micro-environment: Role in immunosuppression and new therapies

Seminars in Immunology, Journal Year: 2020, Volume and Issue: 48, P. 101417 - 101417

Published: April 1, 2020

In tumors, Cancer-Associated Fibroblasts (CAFs) constitute the most prominent component of tumor microenvironment (TME). CAFs are heterogeneous and composed different CAF subsets exerting distinct functions in tumors. Specific subpopulations actively influence various aspects growth, including cancer cell survival proliferation, angiogenesis, extracellular matrix (ECM) remodeling, metastatic spread chemoresistance. During past decade, some have also been shown to modulate anti-tumor immune response. Indeed, they can increase content regulatory T lymphocytes inhibit activity effector cytotoxic cells. These mainly controlled by their constitutive secretion cytokines, chemokines, growth factors ECM proteins, either directly surrounding space or through micro-vesicles. Some express key regulators checkpoints. The roles played CAFs, both as immunosuppressor physical support for progression, set them promising targets therapies. this review, we describe main current knowledge on heterogeneity immunosuppressive microenvironment, well potential therapeutic implications.

Language: Английский

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Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Sept. 11, 2020

Abstract Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging overall survival (OS) advanced stage patients. Over recent years IO been broadly integrated into first-line setting non-oncogene driven NSCLC, either in combination with chemotherapy, or selected patients PD-L1 high expression as monotherapy. Still, a significant proportion suffer from disease progression. A better understanding resistance mechanisms depicts central goal to avoid overcome and improve patient outcome. We here review major cellular molecular pathways within tumor microenvironment (TME) that may impact evolution resistance. summarize upcoming treatment options after including novel targets (e.g. RIG-I, STING) well interesting combinational approaches such combined anti-angiogenic agents metabolic IDO-1, adenosine signaling, arginase). By discussing fundamental mode action TME, we aim understand manage seed new ideas for effective therapeutic concepts.

Language: Английский

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TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: April 21, 2020

Endothelial to mesenchymal transition (EndMT) is a complex biological process that gives rise cells with multipotent potential. EndMT essential for the formation of cardiovascular system during embryonic development. Emerging results link postnatal onset and progression fibrotic diseases cancer. Moreover, recent reports have emphasized potential in tissue engineering regenerative applications by regulating differentiation status cells. Transforming growth factor β (TGF-β) engages many important physiological processes potent inducer EndMT. In this review, we first summarize mechanisms TGF-β signaling pathway as it relates Thereafter, discuss pivotal role TGF-β-induced development diseases, fibrosis cancer, well application engineering.

Language: Английский

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Gene Therapy in Cancer Treatment: Why Go Nano?

Pharmaceutics, Journal Year: 2020, Volume and Issue: 12(3), P. 233 - 233

Published: March 5, 2020

The proposal of gene therapy to tackle cancer development has been instrumental for the novel approaches and strategies fight this disease, but efficacy proposed still fallen short delivering full potential in clinic. Despite plethora modulation approaches, e.g., silencing, antisense therapy, RNA interference, genome editing, finding a way efficiently deliver these effectors desired cell tissue challenge. Nanomedicine put forward several innovative platforms overcome obstacle. Most rely on application nanoscale structures, with particular focus nanoparticles. Herein, we review current trends use nanoparticles designed including inorganic, organic, or biological (e.g., exosomes) variants, clinical their progress towards applications.

Language: Английский

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