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Results for “Tumor microenvironment”

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PubMed2004

Cathepsin B and tumor proteolysis: contribution of the tumor microenvironment.

Tumor-stromal interactions induce expression of matrix metalloproteinases and serine proteases and, as shown recently, the cysteine protease cathepsin B. We speculate that such interactions upregulate the transcription factor Ets1, resulting in increased cathepsin B expression. This would be consistent with the observed concomitant upregulation of matrix metalloproteinases and serine proteases as well as with the ability of extracellular matrices and their binding partners to alter cathepsin B expression and secretion. Using a confocal assay to analyze the contribution of tumor-stromal interactions to proteolysis, we have been able to confirm enhanced degradation of extracellular matrices by all three classes of proteases.

Animals↗
PubMed2006

The tumor microenvironment in the post-PAGET era.

The research area of tumor microenvironment is considered, at present, to be an important factor in tumorigenesis and especially in tumor progression. The present mini review is focused on three principles characterizing the nature of the tumor microenvironment. We first discuss the regulatory functions of the tumor microenvironment and the complexity of the combinatorial signaling pathways operating in it. We then address the aspect that the tumor microenvironment incorporates both pro and anti malignancy factors and that a balance between these factors regulates tumor progression. Thirdly we provide evidence that the non-tumor cells in the tumor microenvironment and their products may be different from those of their counterparts residing in non-tumor microenvironments. The conclusion of this mini review is that the tumor microenvironment, by exerting regulatory functions and selective pressures drives cancer cells into one of several molecular evolution pathways thereby determining and shaping their malignancy phenotype.

Cell Transformation, Neoplastic↗
PubMed2002

The tumor microenvironment: a potential arbitrator of the tumor suppressive and promoting actions of TGFbeta.

Transforming growth factor beta (TGFbeta) members are secreted in biologically inactive complexes that must be activated in order to enable binding to their cell surface receptors. Interestingly, many of the proteins that can activate TGFbeta have been implicated in either suppressing or promoting tumorigenesis. Included among these are matrix proteins (thrombospondin-1), receptors (integrins alphanubeta6 and alphanubeta8) and proteases (matrix metalloproteases and plasmin). These proteins cannot only activate TGFbeta, but can also modulate cell responsiveness to TGFbeta. In this section, we review data highlighting the complexity and bidirectionality of TGFbeta matrix interactions within the tumor microenvironment, and propose that these dynamic interactions are a critical spatial and temporal determinant of the effects of TGFbeta on tumorigenesis.

Animals↗
PubMed1995

Modification of tumor microenvironment by cytokine gene transfer.

The tumor microenvironment is determined by the interactions between host and tumor cells, a process in which cytokines play a major role. We have used retroviral vectors to insert and express cytokine genes in tumor cells so as to induce predictable changes in the host cells that infiltrate tumors. This frequently caused changes in tumor cell phenotype through autocrine/intracrine pathways. We reasoned that cytokine-induced alterations in tumor cell phenotype and/or in infiltrating host cells might alter the in vitro and in vivo cellular response to irradiation. In the present paper we document some of the effects of expression of interleukin-6 (IL-6) and IL-7 genes in tumor cells in this regard. The studies support the hypothesis that cytokines may play a role in determining both intrinsic tumor radioresponsiveness and the tumor microenvironment and in these ways may influence in vivo tumor irradiation responses. Possible cytokine gene-mediated approaches to radiotherapy cancer are discussed.

Animals↗
PubMed2026

A pan-cancer single-cell atlas uncovers the role of sex hormones and chromosomes in sex-divergent reprogramming of the tumor microenvironment.

BACKGROUND: Sex bias is pervasive in tumors; however, how sex chromosomes and hormone-responsive signaling shape the tumor microenvironment (TME) remains insufficiently characterized. Considering the critical impact of the TME on tumor progression and response to immunotherapy, a pan-cancer investigation of sex-specific and cancer-context-dependent TME features is warranted. METHOD: Based on stringent inclusion criteria, we constructed a high-resolution pan-cancer single-cell sequencing atlas by integrating 31 publicly available single-cell RNA-seq datasets, comprising a total of 1,831,436 cells by integrating 468 samples from eight types of non-sex-specific solid tumors (282 males and 186 females). After correcting for batch effects, we identified major and minor cellular subsets. Multiple computational approaches were applied to investigate sex-associated differences in cellular composition, gene expression, pathway activity, malignant cell states and intercellular communication. RESULTS: We systematically compared sex-specific TME features across eight common solid malignancies. Male-biased CD8+ T cell exhaustion emerged as a recurrent but non-uniform feature, with its magnitude varying across cancer types and being modified by tissue-specific contexts. This pattern was associated with androgen-response signature scores and expression-based loss of the Y chromosome (LOY) scores. M2-like macrophage polarization showed a more cancer-type-dependent pattern; although female-biased enrichment was observed in selected malignancies, it did not represent a uniform pan-cancer feature. Expression-based X chromosome inactivation (XCI)/XCI escape-related programs, estrogen-response signature scores and stromal components, including fibroblasts and endothelial cells, were associated with macrophage and immune-regulatory states in specific tumor contexts. Tumor cells of male origin displayed higher genomic instability and more aggressive phenotypes, with androgen-response signatures and LOY contributing to the development of a male biased malignant state. Furthermore, expression-based LOY scores in malignant cells were associated with CD8+ T cell exhaustion based on transcriptomic proxies. CONCLUSION: Our study uncovers extensive but heterogeneous sex-specific differences in the TME across multiple cancer types. We propose a regulatory framework linking sex chromosomes, hormone-responsive signaling and TME interactions, which is consistent with recurrent male-biased CD8⁺ T cell exhaustion and context-dependent M2-like macrophage polarization. Importantly, the magnitude and, in some cancers, the direction of these sex-biased features are modified by tissue-specific contexts. These findings underscore the need to include sex chromosome and hormone status as essential biological variables in studies of the tumor microenvironment and the design of immunotherapies.

Tumor Microenvironment↗
PubMed2006

Meeting report: exploiting the tumor microenvironment for therapeutics.

Recent progress in understanding the role of the tumor microenvironment in cancer progression was the subject of the 2nd International Tumor Metabolism Summit entitled "Exploiting the Tumor Microenvironment for Therapeutics," a meeting held at Palazzo Ducale in Genoa, Italy, October 7 to 8, 2005. One of the major conceptual advances in oncology over the last decade has been the appreciation that all major aspects of cancer biology are influenced by the tumor microenvironment. Two important means by which cancer cells adapt to their microenvironment are by reprogramming cellular glucose/energy metabolism to use pathways that generate ATP in the absence of O(2) and by stimulating angiogenesis to increase O(2) delivery. These responses are principally mediated at the transcriptional level by hypoxia-inducible factor-1. This meeting emphasized the complexity of the tumor microenvironment and opportunities for therapeutic intervention by targeting transcriptional and metabolic pathways that are activated during cancer progression. A better understanding of the crosstalk between signaling pathways and metabolic alterations that contribute to the cancer phenotype may provide insights leading to the development of novel therapeutic strategies.

Animals↗
PubMed2003

Use of quantitative real-time PCR to determine immune cell density and cytokine gene profile in the tumor microenvironment.

BACKGROUND: The molecular mechanisms underlying tumor responsiveness to immunotherapeutic manipulations remain elusive. Investigators are therefore searching for new technologies to study immune-related events occurring in the tumor microenvironment. AIM: To validate the use of quantitative real-time PCR (qrt-PCR) for assessing immune cell density and cytokine (CK) gene profile in tumor biopsies obtained from patients treated with TNFalpha-based isolated limb perfusion. MATERIALS AND METHODS: We first assessed in vitro the ability of cell marker coding genes (CD4, CD8, CD14, CD56) to serve as housekeeping genes for helper and cytotoxic T-lymphocytes, macrophages and NK cells, respectively. Then, the correspondence between mRNA and protein levels of five CK (IL-2, IFNgamma, IL-4, IL-10 and TGFbeta1) expressed by stimulated PBMC was evaluated by means of qrt-PCR and ELISA, respectively. Finally, six patients affected with locally advanced soft tissue sarcomas underwent tumor biopsy before and after TNFalpha-based isolated limb perfusion. After RNA extraction and amplification, transcriptional levels of the above cell markers and CK were evaluated by qrt-PCR. RESULTS: In vitro, leukocyte cell subsets constantly expressed the corresponding marker gene both under resting conditions and after cell stimulation. Cytokine mRNA levels expressed by stimulated PBMC corresponded significantly to supernatant protein concentrations. Compared to the pre-treatment gene profile, post-treatment gene expression showed higher levels of CD4 and IFNgamma and a decreased abundance of the TGFbeta1 transcript. CONCLUSION: In vitro we found that qrt-PCR can determine accurately immune cell density and CK gene profiles in tumor biopsies. In vivo findings support the hypothesis that, after TNFalpha-based treatment, a Th1-type shift occurs in the tumor microenvironment.

Base Sequence↗
PubMed2005

Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis.

It has been well established that tumor progression is correlated with genetic instability. Growing evidence suggests that the tumor microenvironment itself constitutes a significant source of such genetic instability. The adverse conditions of this microenvironment are associated with the induction of mutagenesis and numerous types of DNA damage, including DNA strand breaks and oxidative base damage. While such DNA lesions pose a significant threat to genome integrity, recent studies now suggest that genetic instability in the tumor microenvironment also may arise from the dysregulation of DNA repair pathways. In this review, we will summarize the case for the tumor microenvironment as a key culprit in the induction of genetic instability and the potential mechanisms by which this phenomenon occurs.

Animals↗
PubMed2005

The role of the tumor microenvironment in hematological malignancies and implication for therapy.

The tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion, and metastasis by providing survival signals and a sanctuary site for tumor cells, by secretion of growth factors, pro-angiogenesis factors and direct adhesion molecule interactions. Our knowledge of microenvironment is only now beginning to unfold. In this review, the morphological and molecular characteristics of microenvironment in various hematological malignancies including acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, lymphoma, chronic lymphocytic leukemia, and multiple myeloma are summarized and the molecular mechanisms of microenvironment contributing to leukemogenesis are elucidated. We also aim to discuss the encouraging preclinical and clinical trials for treatment of hematological malignancies by targeting the tumor microenvironment. Further understanding of the signal transduction pathways between tumor cells and microenvironment will lead to the development of novel targeted therapeutic agents and more effective combination of current drugs for fighting hematological malignancies.

Angiogenesis Inhibitors↗
PubMed2006

Tumor microenvironment and drug resistance in hematologic malignancies.

Increasing evidence supports the role of the tumor microenvironment in conferring drug resistance as a major cause of relapse and incurability of cancers. The tumor microenvironment consists of normal stromal cells, extracellular matrix, and soluble factors such as cytokines and growth factors. Tumor-tumor cell interaction, tumor-stromal cell interaction, as well as tumor-ECM interaction, all contribute to direct cell contact mediated drug resistance. In addition, soluble factors produced in the tumor microenvironment provide further signals for tumor cell growth and survival. Environment mediated-drug resistance (EM-DR) could be considered as the totality of cell adhesion mediated drug resistance (CAM-DR) and soluble factor mediated drug resistance (SM-DR) produced by the tumor-host interaction. This review focuses on the EM-DR model system and signaling pathways involved in cell survival of hematological malignancies.

Cell Survival↗
PubMed2006

I2 imaging: cancer biology and the tumor microenvironment.

The use of imaging techniques to understand the role of the tumor microenvironment in cancer progression was the topic of a National Cancer Institute (NCI)-sponsored think tank entitled "I2 Imaging: Cancer Biology and the Tumor Microenvironment," held in Alexandria, Virginia on June 8 to 10, 2006. Participants discussed both recent progress in the use of imaging to dissect cellular and molecular interactions within the tumor microenvironment and the challenges that remain. Recommendations made to the NCI included (a) holding an annual meeting at which biologists, clinicians, and imaging scientists could exchange data, facilitating new collaborations within this multidisciplinary field; (b) funding both research and training specifically designed to foster a cross-disciplinary focus; (c) creating and making available a variety of resources to interested investigators, such as a repository of stromal cells and extracellular matrix molecules; and (d) taking steps to encourage translation of the basic research findings into the clinic.

Biomedical Research↗
PubMed2006

Use of immuno-LCM to identify the in situ expression profile of cellular constituents of the tumor microenvironment.

Expression profiling using microarrays has become an essential tool for interrogating tumor biology. However, profiling of whole tumor RNA reflects both tumor and host cells, making it difficult to dissect molecular events within specific cellular compartments in the tumor microenvironment. We developed and optimized a simple, rapid technique combining immunohistochemistry and laser-capture microdissection (immuno-LCM) to purify specific cell populations from the tumor microenvironment followed by RNA isolation and amplification for microarray analysis. Using this methodology, we were able to elucidate the in situ expression profile of pure tumor cells and tumor endothelial cells from ovarian tumors with brisk immune infiltrates. This technique not only increased the specificity of profiling isolated cell populations, eliminating genes expressed by surrounding cells, but also increased the sensitivity of analysis, allowing for the detection of low expression genes that were not detected in whole tumor arrays. Pathway analysis of tumor cells in situ identified distinct activation of signaling pathways converging on NF-kappaB, as compared to pathways identified in cultured tumor cell lines, which were primarily metabolic. Profiling of tumor vascular cells revealed most known panendothelial and tumor endothelial-specific markers, and unveiled genes specific to the myeloid-monocytic lineage. We propose that immuno-LCM coupled with transcriptional profiling is a convenient tool for dissecting molecular and cellular events in complex biological systems such as the tumor microenvironment.

Computational Biology↗
PubMed2026

Oncogenic Mutations and Tumor Microenvironment Alterations in Diffuse Large B-Cell Lymphoma With Bulky Disease.

BACKGROUND: Bulky disease represents a clinically aggressive subset of diffuse large B-cell lymphoma (DLBCL) associated with adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on bulky disease in DLBCL. METHODS: We analyzed a cohort of 939 patients with newly diagnosed DLBCL. Using DNA (n = 934) and RNA (n = 524) sequencing, we compared oncogenic mutations and tumor microenvironment (TME) alterations based on tumor diameter, with cutoff values at 5.0 cm and 10.0 cm. Further stratification by mutations in key genes (CD58, STAT6, EBF1) correlated with tumor diameter revealed distinct transcriptomic and immunologic profiles. Subsequent single-cell RNA sequencing, guided by these mutational signatures, resolved the cellular heterogeneity within the TME. RESULTS: Integrative analysis revealed that tumor diameter correlated with increased incidence of mutations in CD58, STAT6, and EBF1; adverse genetic subtypes such as EZB-like MYC+ and TP53Mut; activation of oncogenic pathways (JAK/STAT, BCR, PI3K, and MYC); and an immunosuppressive tumor microenvironment. Notably, immune checkpoint molecules varied across the bulky stages, with CTLA-4, TIGIT, ICOS, and CD28 expression inversely correlated with tumor diameter, while CD70 and 4-1BBL expression positively correlated. Single-cell RNA sequencing further revealed mutation-specific tumor microenvironment insights. CD58-mutated tumor exhibited a profoundly immune-deserted microenvironment dominated by malignant B cells with minimal immune infiltration, whereas STAT6-mutated tumor was associated with increased fibroblasts and CD4 + T cells, particularly regulatory T cells (Treg) and Th1-like cells; EBF1-mutated tumor was characterized by increased proportions of malignant B cells. CONCLUSIONS: Collectively, our findings highlight the biological complexity of bulky disease, identifying candidate molecular targets and providing a biological framework for future therapeutic hypothesis generation in this clinically aggressive subset of DLBCL.

Humans↗
PubMed2004

The hypoxic tumor microenvironment and gene expression.

Solid tumors are not static entities but are constantly responding to environmental signals as they grow and develop. One mechanism by which they respond to the adverse conditions of the tumor microenvironment is through coordinated changes in gene expression. The synchronized turning of genes on and off leads to biologic adaption to the adverse oxygen-poor environment. Because tumor hypoxia can be found in almost every solid tumor, it represents one of the most pervasive microenvironmental stresses that can impact malignant progression and therapeutic response. Interestingly, tumors that exhibit robust induction of hypoxia-responsive gene expression networks show a clinically more aggressive natural history. The contribution of hypoxia-responsive gene networks to malignant response is currently under investigation. An understanding of the coordinated functions of hypoxia induced and repressed genes can lead to a better understanding of the clinical significance of the hypoxic tumor phenotype.

Apoptosis↗
PubMed2026

Unraveling lung cancer complexity: Spatial omics in tumor microenvironment characterization and precision medicine.

Heterogeneous tumor microenvironment (TME) in lung cancer plays a crucial role in disease progression and resistance to therapy. Despite advances in single-cell and bulk omics profiling, these methods often overlook spatial context, which is vital for understanding cell-cell interactions and regional heterogeneity. In recent years, spatial omics technologies-including spatial genomics, transcriptomics, proteomics, and metabolomics-have revolutionized the ability to map molecular landscapes while maintaining tissue architecture. These advancements have become essential components of next-generation lung cancer management. By providing unprecedented resolution in characterizing the lung cancer TME, spatial omics could reveal prognostic and predictive biomarkers and identify new therapeutic vulnerabilities. This review will provide the first critical evaluation of spatial multi-omics approaches for lung cancer prognosis. It will also assess various integration strategies for multi-omics data to explore the clinical translational potential of these tools for therapy selection and patient stratification. Therefore, a deeper understanding of spatial omics technologies and their application in lung cancer can significantly improve precision diagnostics and therapeutic decision-making.

Lung cancer↗
PubMed1998

Mutagenesis induced by the tumor microenvironment.

Genomic instability is a commonly observed feature of tumors. Most investigations addressing the mechanism of tumor progression have focused on the genetic factors that may play a role. Growing evidence now suggests that, in addition to these endogenous factors, the exogenous environment within solid tumors may by itself be mutagenic and constitute a significant source of genetic instability. The tumor microenvironment is characterized by regions of fluctuating hypoxia, low pH, and nutrient deprivation. Each of these microenvironmental factors has been shown to cause severe disturbance in cell metabolism and physiology. Both in vivo and in vitro data demonstrate that exposure of tumor cells to adverse conditions can directly cause mutations, contributing to genetic instability. In this review, we will reexamine the current body of evidence on the role of the tumor microenvironment in inducing mutagenesis and consequent tumor progression.

Animals↗
PubMed2003

Use of laser scanning cytometry to study tumor microenvironment.

The study of phenomena occurring in the tumor microenvironment is a challenging task because of technical difficulties, particularly when dealing with hypocellular specimens. Laser scanning cytometry (LSC) is a new laboratory technology that has been recently introduced to overcome the limitations of other traditional technologies. By combining the properties and the advantages of flow cytometry (FC) and immunohistochemistry (IHC), LSC allows the investigator to obtain objective information on DNA content, protein expression and cellular localization is combination with morphological features. It has been already shown that LSC results are reliable compared to more traditional technologies, and its implementation in the clinical routine is under way. Its use in oncology, which is rapidly expanding, spans from apoptosis analysis to DNA content quantitation and tumor cell phenotyping. Here we describe the technology underlying this novel fluorescence-based device, review its use in oncology by dissecting the phenomena occurring in the tumor microenvironment and propose its application for the immunological follow-up of malignant lesions undergoing immunotherapeutic manipulation.

Animals↗