Metabolic changes driven by the hostile tumor microenvironment surrounding cancer cells and the effect of these changes on tumorigenesis and metastatic potential have been known for a long time. The usual point of interest is glucose and changes in its utilization by cancer cells, mainly in the form of the Warburg effect. However, amino acids, both intra- and extracellular, also represent an important aspect of tumour microenvironment, which can have a significant effect on cancer cell metabolism and overall development of the tumor. Namely, alterations in the metabolism of amino acids glutamine, sarcosine, aspartate, methionine and cysteine have been previously connected to the tumor progression and aggressivity of cancer. The aim of this review is to pinpoint current gaps in our knowledge of the role of amino acids as a part of the tumor microenvironment and to show the effect of various amino acids on cancer cell metabolism and metastatic potential. This review shows limitations and exceptions from the traditionally accepted model of Warburg effect in some cancer tissues, with the emphasis on prostate cancer, because the traditional definition of Warburg effect as a metabolic switch to aerobic glycolysis does not always apply. Prostatic tissue both in a healthy and transformed state significantly differs in many metabolic aspects, including the metabolisms of glucose and amino acids, from the metabolism of other tissues. Findings from different tissues are, therefore, not always interchangeable and have to be taken into account during experimentation modifying the environment of tumor tissue by amino acid supplementation or depletion, which could potentially serve as a new therapeutic approach.

• Klíčová slova
• Cancer metabolism, Warburg effect, amino acids, cancer-associated fibroblasts, lactate, tumor microenvironment,
• MeSH
• aminokyseliny MeSH
• glykolýza MeSH
• lidé MeSH
• nádorová transformace buněk MeSH
• nádorové mikroprostředí * MeSH
• nádory * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• aminokyseliny MeSH

Similarly to other types of malignant tumours, the incidence of head and neck cancer is increasing globally. It is frequently associated with smoking and alcohol abuse, and in a broader sense also with prolonged exposure to these factors during ageing. A higher incidence of tumours observed in younger populations without a history of alcohol and tobacco abuse may be due to HPV infection. Malignant tumours form an intricate ecosystem of cancer cells, fibroblasts, blood/lymphatic capillaries and infiltrating immune cells. This dynamic system, the tumour microenvironment, has a significant impact on the biological properties of cancer cells. The microenvironment participates in the control of local aggressiveness of cancer cells, their growth, and their consequent migration to lymph nodes and distant organs during metastatic spread. In cancers originating from squamous epithelium, a similarity was demonstrated between the cancer microenvironment and healing wounds. In this review, we focus on the specificity of the microenvironment of head and neck cancer with emphasis on the mechanism of intercellular crosstalk manipulation for potential therapeutic application.

• Klíčová slova
• IL-6, cancer, cancer ecosystem, cancer microenvironment, cancer therapy, cancer-associated fibroblast, cytokine, extracellular matrix, tumour-associated macrophages,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Colorectal cancer (CRC) is one of the most common cancers worldwide. The patient's prognosis largely depends on the tumor stage at diagnosis. The pathological TNM Classification of Malignant Tumors (pTNM) staging of surgically resected cancers represents the main prognostic factor and guidance for decision-making in CRC patients. However, this approach alone is insufficient as a prognostic predictor because clinical outcomes in patients at the same histological tumor stage can still differ. Recently, significant progress in the treatment of CRC has been made due to improvements in both chemotherapy and surgical management. Immunotherapy-based approaches are one of the most rapidly developing areas of tumor therapy. This review summarizes the current knowledge about the tumor microenvironment (TME), immune response and its interactions with CRC development, immunotherapy and prognosis.

• Klíčová slova
• colorectal cancer, consensus molecular subtypes, immune cells, immunoscore, tumor microenvironment, tumorigenesis,
• MeSH
• imunita MeSH
• imunoterapie MeSH
• kolorektální nádory * patologie   MeSH
• lidé MeSH
• nádorové mikroprostředí * MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy 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.

• Klíčová slova
• IBC, macrophages, midkine, tetraspanins, tumour microenvironment,
• 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
• Názvy látek
• antigeny CD151 MeSH
• CD151 protein, human MeSH Prohlížeč
• chemokiny MeSH
• MDK protein, human MeSH Prohlížeč
• midkin MeSH

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.

• MeSH
• karcinogeneze chemicky indukované   MeSH
• lidé MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory chemicky indukované   MeSH
• nebezpečné látky škodlivé účinky   MeSH
• vystavení vlivu životního prostředí škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• nebezpečné látky MeSH

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.

• Klíčová slova
• Cancer biology, Cancer prevention, Cancer therapy, Tumor microenvironment,
• 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
• Názvy látek
• protinádorové látky MeSH

Aspartate is a proteinogenic non-essential amino acid with several essential functions in proliferating cells. It is mostly produced in a cell autonomous manner from oxalacetate via glutamate oxalacetate transaminases 1 or 2 (GOT1 or GOT2), but in some cases it can also be salvaged from the microenvironment via transporters such as SLC1A3 or by macropinocytosis. In this review we provide an overview of biosynthetic pathways that produce aspartate endogenously during proliferation. We discuss conditions that favor aspartate uptake as well as possible sources of exogenous aspartate in the microenvironment of tumors and bone marrow, where most available data have been generated. We highlight metabolic fates of aspartate, its various functions, and possible approaches to target aspartate metabolism for cancer therapy.

• Klíčová slova
• Amino acid, Biosynthesis, Cancer, Leukemia, Malate-aspartate shuttle, Respiratory chain, Tumor microenvironment,
• MeSH
• kyselina asparagová * metabolismus   MeSH
• lidé MeSH
• nádorové mikroprostředí * MeSH
• nádory * metabolismus   patologie   MeSH
• proliferace buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• kyselina asparagová * MeSH

The stroma is a considerable part of the tumor microenvironment. Because of its complexity, it can influence both cancer and immune cells in their behavior and cross-talk. Aside from soluble products released by non-cancer and cancer cells, extracellular matrix components have been increasingly recognized as more than just minor players in the constitution, development and regulation of the tumor microenvironment. The variations in the connective scaffold architecture, induced by transforming growth factor beta, lysyl oxidase and metalloproteinase activity, create different conditions of ECM density and stiffness. They exert broad effects on immune cells (e.g. physical barriers, modulation by release of stored TGF-β1), mesenchymal cells (transition to myofibroblasts), epithelial cells (epithelial-to-mesenchymal transition), cancer cells (progression to metastatic phenotype) and stem cells (activation of differentiation addressed by the microenvironment characteristics). Physiological mechanisms of the wound healing process, as well as mechanisms of fibrosis in some chronic pathologies, closely recall aspects of cancer deregulated biology. Their elucidation can provide a better understanding of tumor microenvironment immunobiology. In the following short review, we will focus on some aspects of the fibrous stroma to highlight its active participation in the tumor microenvironment constitution, tumor progression and the local immunological network.

• Klíčová slova
• Fibrosis, LOX, Stiffness, TGF-β, Tumor microenvironment, Tumor stroma,
• Publikační typ
• časopisecké články 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.

• Klíčová slova
• Cervical cancer, Differential network analysis, Galectin-7, Microenvironment crosstalk,
• MeSH
• galektiny metabolismus   MeSH
• lidé MeSH
• nádorové mikroprostředí fyziologie   MeSH
• nádory děložního čípku metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Názvy látek
• galektiny MeSH
• LGALS7 protein, human MeSH Prohlížeč

The physiological functions of transforming growth factor (TGF)-β in cell signaling include regulation of developmental processes and cell growth. Tumor cells very often display altered regulation of the TGFβ signaling pathway, either by defects in TGFβ itself or in downstream components of the pathway. TGFβ can play a dual role in tumorigenesis, i.e. it can be either tumor-suppressive or tumor-promoting. TGFβ suppresses the growth of tumor cells; however, in advanced tumors, it is associated with induction of progression, resulting in poor prognosis for patients. The TGFβ negative regulation of cytotoxic cell function, together with the promotion of T-regulatory cell maturation, impairs anti-tumor responses. Recent studies have elucidated new roles for TGFβ signaling in the tumor microenvironment. Abrogation of proper signaling induces epithelial-to-mesenchymal transition with pro-metastatic functions, resulting in cancer progression. Thus, TGFβ signaling in the tumor microenvironment plays an important role in tumor initiation, progression, and metastasis by its capacity to regulate cross-talk between tumor cells and other components of the local environment.

• Klíčová slova
• Epithelial-to-mesenchymal transition, TGFβ, immune regulation, inflammation, tumor microenvironment, tumor stroma,
• MeSH
• buněčná diferenciace MeSH
• cytotoxické T-lymfocyty imunologie   MeSH
• epitelo-mezenchymální tranzice MeSH
• imunosupresivní léčba MeSH
• karcinogeneze MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádorové mikroprostředí MeSH
• regulační T-lymfocyty imunologie   MeSH
• signální transdukce MeSH
• transformující růstový faktor beta imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• transformující růstový faktor beta MeSH