Cancer microenvironment
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Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.
- MeSH
- cílená molekulární terapie MeSH
- karcinogeneze účinky léků genetika MeSH
- lidé MeSH
- nádorové mikroprostředí účinky léků genetika MeSH
- nádory farmakoterapie genetika prevence a kontrola MeSH
- patologická angiogeneze farmakoterapie genetika prevence a kontrola MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky terapeutické užití MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
Cancer-associated fibroblasts (CAFs) are involved in critical aspects of head and neck squamous cell carcinoma (HNSCC) pathogenesis, such as the formation of a tumor-permissive extracellular matrix structure, angiogenesis, or immune and metabolic reprogramming of the tumor microenvironment (TME), with implications for metastasis and resistance to radiotherapy and chemotherapy. The pleiotropic effect of CAFs in TME is likely to reflect the heterogeneity and plasticity of their population, with context-dependent effects on carcinogenesis. The specific properties of CAFs provide many targetable molecules that could play an important role in the future therapy of HNSCC. In this review article, we will focus on the role of CAFs in the TME of HNSCC tumors. We will also discuss clinically relevant agents targeting CAFs, their signals, and signaling pathways, which are activated by CAFs in cancer cells, with the potential for repurposing for HNSCC therapy.
- MeSH
- dlaždicobuněčné karcinomy hlavy a krku metabolismus MeSH
- fibroblasty asociované s nádorem * metabolismus MeSH
- lidé MeSH
- nádorové mikroprostředí MeSH
- nádory hlavy a krku * metabolismus MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Karcinomy hlavy a krku tvoří prognosticky nepříznivou skupinu onemocnění zatíženou jak vysokou mortalitou, tak i morbiditou způsobenou klasickými léčebnými postupy, jako je chirurgie, radioterapie a chemoterapie. Tyto nádory však patří mezi onemocnění s početným zastoupením imunitních buněk, které je ještě umocněno u tumorů indukovaných HPV, a jsou tak velmi perspektivním cílem imunoterapeutických postupů. Imunoterapie za využití blokátorů kontrolních bodů imunitního systému se v posledních letech stala jedním z pilířů onkologické terapie, kterou lze aplikovat již v 1. linii léčby u rekurentního a metastatického karcinomu hlavy a krku. Na tuto léčbu ale překvapivě reaguje pouze malá část pacientů. Podrobná analýza imunitního infiltrátu v nádorovém mikroprostředí je pak jedním z klíčů ke zlepšení léčebných výsledků a k efektivnější stratifikaci pacientů, kteří mohou z aplikace imunoterapie a zmírnění klasické terapie profitovat.
Head and neck cancer is prognostically unfavourable group of diseases burdened by high mortality and morbidity following classic treatment regimens, such as surgery, radiotherapy and chemotherapy. Nevertheless, these tumors are highly infiltrated by immune cells, especially in case of HPV induced tumors, and constitute a perspective target for immune-based treatment. Immunotherapy with checkpoint inhibitors has become one of the basic pillars of cancer therapy, that is applicable as a first line treatment in recurrent and metastatic head and neck cancer. However, only a small fraction of patients is responsive to the therapy. In-depth analysis of immune cells in the tumor microenvironment could be the key element for improvement of current treatment regimens and effective stratification of patients that could benefit from immunotherapy and de-intensification of classic therapeutic protocols.
- Klíčová slova
- tumor-infiltrující leukocyty,
- MeSH
- imunoterapie MeSH
- infekce papilomavirem MeSH
- lidé MeSH
- nádorové mikroprostředí MeSH
- nádory hlavy a krku * imunologie terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: Galectin-7 (Gal-7) is negatively regulated in cervical cancer, and appears to be a link between the apoptotic response triggered by cancer and the anti-tumoral activity of the immune system. Our understanding of how cervical cancer cells and their molecular networks adapt in response to the expression of Gal-7 remains limited. METHODS: Meta-analysis of Gal-7 expression was conducted in three cervical cancer cohort studies and TCGA. In silico prediction and bisulfite sequencing were performed to inquire epigenetic alterations. To study the effect of Gal-7 on cervical cancer, we ectopically re-expressed it in the HeLa and SiHa cervical cancer cell lines, and analyzed their transcriptome and SILAC-based proteome. We also examined the tumor and microenvironment host cell transcriptomes after xenotransplantation into immunocompromised mice. Differences between samples were assessed with the Kruskall-Wallis, Dunn's Multiple Comparison and T tests. Kaplan-Meier and log-rank tests were used to determine overall survival. RESULTS: Gal-7 was constantly downregulated in our meta-analysis (p < 0.0001). Tumors with combined high Gal-7 and low galectin-1 expression (p = 0.0001) presented significantly better prognoses (p = 0.005). In silico and bisulfite sequencing assays showed de novo methylation in the Gal-7 promoter and first intron. Cells re-expressing Gal-7 showed a high apoptosis ratio (p < 0.05) and their xenografts displayed strong growth retardation (p < 0.001). Multiple gene modules and transcriptional regulators were modulated in response to Gal-7 reconstitution, both in cervical cancer cells and their microenvironments (FDR < 0.05 %). Most of these genes and modules were associated with tissue morphogenesis, metabolism, transport, chemokine activity, and immune response. These functional modules could exert the same effects in vitro and in vivo, even despite different compositions between HeLa and SiHa samples. CONCLUSIONS: Gal-7 re-expression affects the regulation of molecular networks in cervical cancer that are involved in diverse cancer hallmarks, such as metabolism, growth control, invasion and evasion of apoptosis. The effect of Gal-7 extends to the microenvironment, where networks involved in its configuration and in immune surveillance are particularly affected.
Colorectal cancer (CRC) is one of the most common cancers worldwide. Despite the improvement of treatment options that bettered advanced-stage patient's overall survival, the clinical outcome is still poor. The tumor microenvironment is thought to be an essential participant in the metastasis process. Liver metastases are the most frequent metastases that occur in CRC patients. It is believed that colorectal cancer has the liver as a preferential site for metastasis, and this is possible due to the multiple interactions that happen in the tumor microenvironment and due to the tumor stem cells input. As a means to investigate this biological process, microRNAs (miRNAs) have established a name for themselves as putative biomarkers in cancer and especially colorectal cancer. In this pilot study, we explored miRNAs expression that by influencing the tumor stem cells can help prevail liver metastasis in advanced-stage CRC patients.
- MeSH
- dospělí MeSH
- exprese genu fyziologie MeSH
- klinická studie jako téma MeSH
- kolorektální nádory * patofyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů terapie MeSH
- mikro RNA fyziologie terapeutické užití MeSH
- nádorové biomarkery MeSH
- nádorové kmenové buňky fyziologie MeSH
- nádorové mikroprostředí * MeSH
- nádory jater sekundární terapie MeSH
- pilotní projekty MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
Cancer represents an extremely complicated ecosystem where cancer cells communicate with non-cancer cells present in the tumour niche through intercellular contacts, paracrine production of bioactive factors and extracellular vesicles, such as exosomes [...].
- MeSH
- ekosystém MeSH
- exozómy * metabolismus MeSH
- extracelulární vezikuly * metabolismus MeSH
- lidé MeSH
- mezibuněčná komunikace MeSH
- nádorové mikroprostředí MeSH
- nádory * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- úvodníky MeSH
The immune microenvironment in inflammatory breast cancer (IBC) is poorly characterised, and molecular and cellular pathways that control accumulation of various immune cells in IBC tissues remain largely unknown. Here, we discovered a novel pathway linking the expression of the tetraspanin protein CD151 in tumour cells with increased accumulation of macrophages in cancerous tissues. It is notable that elevated expression of CD151 and a higher number of tumour-infiltrating macrophages correlated with better patient responses to chemotherapy. Accordingly, CD151-expressing IBC xenografts were characterised by the increased infiltration of macrophages. In vitro migration experiments demonstrated that CD151 stimulates the chemoattractive potential of IBC cells for monocytes via mechanisms involving midkine (a heparin-binding growth factor), integrin α6β1, and production of extracellular vesicles (EVs). Profiling of chemokines secreted by IBC cells demonstrated that CD151 increases production of midkine. Purified midkine specifically stimulated migration of monocytes, but not other immune cells. Further experiments demonstrated that the chemoattractive potential of IBC-derived EVs is blocked by anti-midkine antibodies. These results demonstrate for the first time that changes in the expression of a tetraspanin protein by tumour cells can affect the formation of the immune microenvironment by modulating recruitment of effector cells to cancerous tissues. Therefore, a CD151-midkine pathway can be considered as a novel target for controlled changes of the immune landscape in IBC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- MeSH
- antigeny CD151 imunologie metabolismus MeSH
- chemokiny metabolismus MeSH
- lidé MeSH
- makrofágy metabolismus patologie MeSH
- midkin metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí fyziologie MeSH
- zánětlivé nádory prsu metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Small leucine rich proteoglycans (SLRPs), major non-collagen components of the extracellular matrix (ECM), have multiple biological roles with diverse effects. Asporin, a member of the SLRPs class I, competes with other molecules in binding to collagen and affects its mineralization. Its role in cancer is only now being elucidated. METHODS: The PubMed online database was used to search relevant reviews and original articles. Furthermore, altered asporin expression was analysed in publicly available genome-wide expression data at the Gene Expression Omnibus database. RESULTS: Polymorphisms in the N-terminal polyaspartate domain, which binds calcium, are associated with osteoarthritis and prostate cancer. Asporin also promotes the progression of scirrhous gastric cancer where it is required for coordinated invasion by cancer associated fibroblasts and cancer cells. Besides the enhanced expression of asporin observed in multiple cancer types, such as breast, prostate, gastric, pancreas and colon cancer, tumour suppressive effects of asporin were described in triple-negative breast cancer. We also discuss a number of factors modulating asporin expression in different cell types relevant for alterations toing the tumour microenvironment. CONCLUSION: The apparent contradicting tumour promoting and suppressive effects of asporin require further investigation. Deciphering the role of asporin and other SLRPs in tumour-stroma interactions is needed for a better understanding of cancer progression and potentially also for novel tumour microenvironment based therapies.
- MeSH
- extracelulární matrix - proteiny genetika metabolismus fyziologie MeSH
- lidé MeSH
- mikro RNA fyziologie MeSH
- nádorové mikroprostředí genetika fyziologie MeSH
- nádory etiologie genetika MeSH
- polymorfismus genetický genetika MeSH
- progrese nemoci MeSH
- tuková tkáň fyziologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules, such as PD-1/PD-L1 and T cell immunoglobulin-3 (TIM-3) are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the "cold" tumor microenvironment (TME) to a "hot" one by depleting immunosuppressive cells and enhancing tumor immunogenicity. SUMMARY: This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa's low immunogenicity complicates immunotherapy. KEY MESSAGES: The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated T regs and TAMs promote tumor growth, metastasis, and resistance. TANs and natural killer (NK) cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting T regs and myeloid-derived suppressor cells, offering therapeutic promise.
- MeSH
- imunoterapie metody MeSH
- lidé MeSH
- makrofágy spojené s nádory imunologie MeSH
- nádorové mikroprostředí * imunologie MeSH
- nádory prostaty * imunologie patologie terapie MeSH
- regulační T-lymfocyty imunologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
