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PubMed1994

Phospholipid metabolite expression by head and neck squamous cell carcinoma.

OBJECTIVE: To characterize the presence and production of various phospholipid metabolites by head and neck squamous cell carcinoma (HNSCC) and squamous cell carcinoma cell lines in vitro and in vivo. DESIGN: The HNSCC tumor homogenates and supernatants of HNSCC tumor cultures and established squamous cell carcinoma cell lines were assayed for prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and platelet activating factor (PAF). In vitro experiments were carried out under baseline conditions or with exposure to several known immunomodulators (epidermal growth factor, bacterial lipopolysaccharide, and interleukin 1). PATIENTS: The HNSCC tumor tissue was obtained from primary tumor or cervical lymph node metastasis of surgical resections. MAIN OUTCOME MEASURES: Prostaglandin E2, LTB4, and PAF were measured in tumor homogenates and cell culture supernatants using standardized radioimmunoassay kits. RESULTS: All tumor homogenates (eight of eight) contained detectable levels of PGE2 (range, 324 to 2258 pg/g of tumor tissue) and LTB4 (range, 790 to 41,900 pg/g of tumor tissue); PAF was detected in six of eight homogenates (range, 7362 to 40,788 pg/g of tumor tissue). All of the short-term primary HNSCC tumor cultures and squamous carcinoma lines produced PGE2 (range, 90 to 1160 pg/10(6) cells), and half of the cultures produced LTB4 (range, 100 to 1700 pg/10(6) cells); none of the cultures or cell lines produced detectable levels of PAF. Interleukin 1 significantly enhanced production of PGE2 by tumor cultures (P < .02). Characterization of tumor cultures with a fibroblast antibody marker, BR2, revealed that 26% to 64% of tumor culture cells were fibroblasts. CONCLUSIONS: Prostaglandin E2, LTB4, and PAF are present in the tumor microenvironment, where they may be involved in the local immunosuppression phenomenon seen in HNSCC. Both PGE2 and LTB4 were produced in vitro by tumor cultures and squamous cell carcinoma cell lines; PAF was not produced by tumor cultures in vitro and therefore may be a product of local immune cells in HNSCC in vivo. Interleukin 1 and PGE2 may interact in immunoregulation in the HNSCC tumor microenvironment.

Aged↗

PubMed2003

Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers.

BACKGROUND AND PURPOSE: Tumor oxygenation is recognized as an important determinant of the outcome of radiotherapy and possibly also of other treatment modalities in a number of tumor types and in particular in squamous cell carcinomas. The hypoxic status of various solid tumors has been related to a poor prognosis due to tumor progression towards a more malignant phenotype, with increased metastatic potential, and an increased resistance to treatment. It has been demonstrated in head and neck cancer that hypoxic radioresistance can be successfully counteracted by hypoxia modifying approaches. The microregional distribution and the level of tumor hypoxia depend on oxygen consumption and temporal and spatial variations in blood supply. It is unclear if severely hypoxic cells can resume clonogenicity when O(2) and nutrients become available again as a result of (treatment related) changes in the tumor microenvironment. Non-terminally differentiated hypoxic cells that are capable of proliferation are important for outcome because of their resistance to radiotherapy and possibly other cytotoxic treatments. Various exogenous and endogenous markers for hypoxia are currently available and can be studied in relation to each other, the tumor architecture and the tumor microenvironment. Use of nitroimidazole markers with immunohistochemical detection allows studying tumor cell hypoxia at the microscopic level. Co-registration with other microenvironmental parameters, such as vascular architecture (vascular density), blood perfusion, tumor cell proliferation and apoptosis, offers the possibility to obtain a comprehensive functional image of tumor patho-physiology and to study the effects of different modalities of cancer treatment. CONCLUSION: A number of functional microregional parameters have emerged that are good candidates for future use as indicators of tumor aggressiveness and treatment response. The key question is whether these parameters can be used as tools for selection of treatment strategies for individual patients. This requires testing of these markers in prospective randomized clinical trials comparing standard treatment against experimental treatments targeting the relevant microregional constituent.

Antigens, Neoplasm↗

PubMed2007

Conventional and proteomic technologies for the detection of early stage malignancies: markers for ovarian cancer.

Our understanding of the tumor microenvironment continues to evolve and allows for the identification of biomarkers that should detect the presence of early stage malignancies. Recent advances in computational analysis and biomedical technologies have come together to elucidate signatures associated with cancer and that are capable of identifying unique tumor-specific proteins. Within the tumor microenvironment, we continue to characterize the proteophysiology of the different steps associated with tumor progression. The urgent need for biomarkers accurately detecting early-stage epithelial ovarian cancer has prompted us, and others, to engage in a search for specific peptide signatures that may discriminate transformed cells from those of the normal ovarian microenvironment. This endeavor also provides new insights into the biology of the disease, which may not only be applicable to detection but may also help to initiate new therapies and optimize patient care.

Biomarkers, Tumor↗

PubMed2026

Predictive biomarkers in cancer immunotherapy for genitourinary malignancies.

Immunotherapy has transformed the management of genitourinary cancers, offering durable responses in selected patient groups. However, the clinical benefit of immune checkpoint inhibitors varies significantly across renal cell carcinoma, urothelial carcinoma, and prostate cancer, underscoring the need for reliable predictive biomarkers. This review summarizes current knowledge on established and emerging biomarkers, including PD L1 expression, tumor mutational burden, molecular subtypes, genomic alterations, tumor microenvironment characteristics, circulating biomarkers, microbiome influences, and multi omic integrative approaches. We discuss their potential clinical relevance, limitations, and applicability across different tumor types. Future directions emphasize the development of composite biomarkers, standardization of testing platforms, real time monitoring strategies, and the integration of advanced technologies such as artificial intelligence and spatial profiling. Understanding and validating these biomarkers will be essential for optimizing personalized immunotherapy in genitourinary cancers.

Circulating tumor DNA↗

PubMed2005

Metabolic mechanisms of tumor resistance to T cell effector function.

Established tumors develop ways to elude destruction by the host immune system. Recent work has revealed that tumors can take advantage of the generation of metabolic dysregulation to inhibit immune responses. Effector T-cell functions are particularly sensitive to nutrient availability in the tumor microenvironment. In this review, we highlight experimental data supporting the importance of glucose, oxygen, tryptophan, and arginine for optimal T-cell function, and the mechanisms by which these nutrients may become depleted in the tumor microenvironment. These observations provide a conceptual framework for modulating metabolic features of the T cell-tumor interaction, toward the end of promoting more effective immune-mediated tumor destruction in vivo.

Amino Acids↗

PubMed2026

Mast Cells Selectively Deliver Extracellular Vesicle-Encapsulated mRNA to Colorectal Cancer Cells.

Mast cells (MCs), a type of granulocytic immune cell, exert contrasting effects on tumorigenesis. The anti- or pro-tumorigenic activity of MCs depends on the cancer type, tumor microenvironment, and MC localization within the tumor. Consequently, their role remains controversial and poorly understood across multiple cancer types, including colorectal cancer (CRC). Most proposed mechanisms underlying MC activity in CRC have focused on MC secretion of biological factors. In this study, we demonstrated that MCs transfer extracellular vesicles containing mRNAs and proteins to CRC cells. This process occurs through a tightly regulated mechanism that requires direct cell-cell contact, calcium signaling, and integrin-mediated interactions. Such requirements resemble aspects of immunological synapses observed between lymphocytes and cancer cells. The novel mode of intercellular communication between MCs and cancer cells described here may help refine our understanding of MC functions in cancer biology.

Mast Cells↗

PubMed2026

Stage-Independent Real-Time Subtype Classification and Comprehensive Biopsy Profiling of Urothelial Carcinomas by the Lund Taxonomy System.

Bladder cancer is a heterogeneous malignancy with diverse clinical outcomes, and conventional pathological assessment alone is insufficient to capture its underlying biology. Gene expression profiling can stratify tumors into molecular subtypes with prognostic and predictive potential, but the reliability of transcriptomic classification and its clinical utility remains to be established. The translational/observational UROSCANSEQ study (ISRCTN15459149) prospectively evaluates RNA-based Lund Taxonomy (LundTax) molecular subtype classification in a clinical setting. Among 784 consecutive biopsies collected between 2018 and 2022, RNA sequencing was successful for 90% of all biopsies, encompassing 662 bladder cancer patients with a stage distribution of 48% Ta, 27% T1, 24% ≥T2, and 1% CIS. We demonstrate that the LundTax subtype classification algorithm, applied to individual samples, accurately identifies cancer cell phenotypes with characteristic gene and protein expression patterns in a manner robust to RNA quality, data preprocessing strategies, and batch effects, supporting its clinical feasibility across both non-muscle-invasive and muscle-invasive disease. We further extend the LundTax framework by incorporating single-sample molecular risk scores reflecting tumor grade, proliferation, and progression risk, as well as tumor microenvironment signatures. Both risk scores and overall immune and stromal content in biopsies were significantly associated with an increased risk of clinical progression in noninvasive disease. In a separate analysis of the relative cellular composition of the tumor microenvironment, however, only the fraction of natural killer cells remained significant. Together, the expanded LundTax system provides a comprehensive molecular portrait of individual tumor biopsies. By explicitly separating cancer cell-intrinsic phenotypes, prognostic indexes, and microenvironmental signals, the framework minimizes biological confounding and establishes a strong foundation for future studies evaluating clinical outcomes and treatment responses.

Humans↗

PubMed2025

Histology-Based Virtual RNA Inference Identifies Pathways Associated With Metastasis Risk in Colorectal Cancer.

Colorectal cancer (CRC) remains a major health concern, with >150,000 new diagnoses and >50,000 deaths annually in the United States, underscoring an urgent need for improved screening, prognostication, disease management, and therapeutic approaches. The tumor microenvironment (TME)-comprising cancerous and immune cells interacting within the tumor's spatial architecture-plays a critical role in disease progression and treatment outcomes, reinforcing its importance as a prognostic marker for metastasis and recurrence risk. However, traditional methods for TME characterization, such as bulk transcriptomics and multiplex protein assays, lack sufficient spatial resolution. Although spatial transcriptomics (ST) allows for the high-resolution mapping of whole transcriptomes at near-cellular resolution, current ST technologies (eg, Visium and Xenium) are limited by high costs, low throughput, and issues with reproducibility, preventing their widespread application in large-scale molecular epidemiology studies. In this study, we refined and implemented virtual RNA inference (VRI) to derive ST-level molecular information directly from hematoxylin and eosin (H&E)-stained tissue images. Our VRI models were trained on the largest matched CRC ST data set to date, comprising 45 patients and >300,000 Visium spots from primary tumors. Using state-of-the-art deep learning models (UNI, ResNet-50, Vision Transformer, and Vision Mamba), we achieved a median Spearman's correlation coefficient of 0.546 between predicted and measured spot-level expression. As validation, VRI-derived gene signatures linked to specific tissue regions (tumor, interface, submucosa, stroma, serosa, muscularis, and inflammation) showed strong concordance with signatures generated via direct ST, and VRI performed accurately in estimating cell-type proportions spatially from H&E slides. In an expanded CRC cohort controlling for tumor invasiveness and clinical factors, we further identified VRI-derived gene signatures significantly associated with key prognostic outcomes, including metastasis status. Although certain tumor-related pathways are not fully captured by histology alone, our findings highlight the ability of VRI to infer a wide range of "histology-associated" biological pathways at near-cellular resolution without requiring ST profiling. Future efforts will extend this framework to expand TME phenotyping from standard H&E tissue images, with the potential to accelerate translational CRC research at scale.

Humans↗

PubMed2000

Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages.

IL-12 is a central cytokine in the activation of inflammation and immunity and in the generation of Th1-type responses. Tumor-associated macrophages (TAM) from mouse and human tumors showed defective production of IL-12. Defective IL-12 production was associated with lack of p50/p65 NF-kappa B activation. TAM produced increased amounts of the immunosuppressive cytokine IL-10. Abs against IL-10 restored the defective capacity of TAM to produce IL-12. Our data suggest that during tumor growth an IL-10-dependent pathway of diversion of macrophage function can be activated into the tumor microenvironment and results in the promotion of the IL-10+ IL-12- phenotype of TAM. Blocking IL-10, as well as other immunosuppressive cytokines present in the tumor microenvironment, such as TGF-beta, may complement therapeutic strategies aimed at activating type I antitumor immune responses.

Animals↗

PubMed2026

IDH3-dependent mitochondrial function in stromal fibroblasts suppresses malignant tumor growth.

Malignant solid tumors comprise not only cancer cells but also diverse non-cancerous stromal cells that shape the tumor microenvironment. The tricarboxylic acid (TCA) cycle has an overarching presence in providing substrates needed to drive the electron transport chain and, ultimately, ATP synthesis. However, it remains unclear which stromal cell lineages influence tumor growth through TCA-dependent mitochondrial function, and whether such activities act in a tumor-promoting or tumor-suppressive manner. Isocitrate dehydrogenase 3 (IDH3), a rate-limiting TCA cycle enzyme that generates NADH to support mitochondrial respiration, provides a genetic entry point to interrogate mitochondrial TCA-dependent function in stromal cells. In this study, we established a mouse model in which tamoxifen administration induces CreERT2-dependent knockout of the α subunit of IDH3 (IDH3α) in all somatic cells. Using this model with transplantation of Idh3a-intact murine cancer cells, we found that host Idh3a deficiency accelerated growth of murine MC38 tumors in a cancer cell line-dependent manner. Bone marrow chimera experiments indicated that hematopoietic lineages were not responsible for this phenotype, suggesting a contribution from tissue-resident non-hematopoietic stromal cells that are not replaced by bone marrow transplantation. Single-cell RNA sequencing of human tumor specimens revealed broad IDH3A expression across multiple tumor microenvironment compartments, including fibroblasts. Consistently, in vitro co-culture assays demonstrated that Idh3a-intact, but not Idh3a-KO, fibroblasts suppressed cancer cell proliferation in a contact-dependent manner. Together, these findings identify IDH3α-dependent mitochondrial function in fibroblasts as a critical determinant of tumor progression and suggest that stromal mitochondrial metabolism represents an important axis for modulating tumor behavior.

Cancer↗

PubMed2006

Oestrogen receptor-beta expression in melanocytic lesions.

Melanomas rarely occur before puberty, have a higher death rate for males, and tend to be more invasive during pregnancy. Prior to the discovery of a second oestrogen receptor (ERbeta), studies with the initial oestrogen receptor, ERalpha, showed no obvious role for oestrogen in the pathophysiology of benign or malignant melanocytic lesions. To investigate the specific immunostaining patterns of ERalpha and ERbeta, benign nevocytic nevi, dysplastic nevi with mild, moderate and severe cytological atypia, lentigo malignas and melanomas of varying depth (Clark) and thickness (Breslow) were studied. ERbeta but not ERalpha was the predominant oestrogen receptor we found in all types of benign and malignant melanocytic lesions. The most intense ERbeta immunostaining was seen in melanocytes in dysplastic nevi with severe cytological atypia and in lentigo malignas. ERbeta expression levels also correlated with the malignant tumor microenvironment; i.e., melanocytes in proximity with keratinocytes>deeper dermal melanocytes in contact with stroma>minimally invasive melanomas>Clark Level III/IV or thick melanomas (Breslow). Discovery that ERbeta expression varies in relation to the tumor microenvironment and increasing depth of invasion suggests its possible usefulness as a surrogate marker for neoplasia and prognosis in malignant melanoma.

Biomarkers, Tumor↗

PubMedDate not supplied

Mechanisms of lymphocyte traffic in neoplasia.

The composition of tumor infiltrating lymphocyte populations is often reported to be different from that of the lymphocyte pool of peripheral blood. This suggests that infiltration-regulating mechanisms reside in or near the tumor microenvironment. Available evidence indicates that these mechanisms exert their effects on lymphocyte traffic. Two models of regulation are proposed. In the selective immigration model, different lymphocyte types display different tendencies to extravasate into the tumor. Selective immigration could reflect heterogeneity of such lymphocyte properties as binding to vascular endothelium, response to chemotactic factors, or spontaneous locomotion. In the other model, selective entrapment, different types of lymphocytes exit from the tumor microenvironment at different rates. Entrapment could be regulated by selectively acting adhesive, locomotion-inhibiting, or negatively chemotactic factors. Available information supporting each model is presented. The composition of infiltrate may also be influenced by the composition of the circulating lymphocyte pool. Evidence is presented that this pool in turn may be influenced by tumor-induced systemic changes in lymphocyte traffic. Deliberate manipulation of lymphocyte traffic should improve the effectiveness of immunotherapeutic regimes. One promising method of traffic manipulation is the modulation of spontaneous motility. A collagen gel assay for spontaneous lymphocyte motility is described.

Animals↗

PubMed2006

Design of hypoxia-targeting drugs as new cancer chemotherapeutics.

The tumor microenvironment is now recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also helps define the potential for malignant progression and metastasis. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment. Furthermore, discovery of the hypoxia inducible factor 1alpha (HIF-1alpha) has led to a rapidly increasing understanding of the molecular mechanisms involved in tumor hypoxia. This in turn has led to the current extensive interest in the signal molecules related to tumor hypoxia as potential molecular targets for cancer therapeutics. In this paper we give an overview of recent advances in hypoxia research, including cancer treatments that target tumor hypoxia. Progress in the development of hypoxia-targeting drugs will be discussed, including antiangiogenic hypoxic cell radiosensitizers and hypoxic cytotoxins, hypoxia targeting boron carriers and p53-inhibiting bifunctional radiosensitizers. We will also review our own recent research results in these areas. For example, we have found that certain of the 2-nitroimidazole radiosensitizers and heterocycle-N-oxide hypoxic cytotoxins we developed have antiangiogenic activity and antimetastatic activity. We propose that these activities are based on the inhibition of signal transduction mediated by HIF-1alpha. The anti-tumor activities of hypoxia response are considered to be cytostatic (tumor dormancy-inducing) effects in contrast to cytotoxic DNA damaging effects. The combination of these cytostatic effects that are related to radiosensitization with the cytotoxic effects of radiation should improve the prognosis and QOL of patients receiving radiation and lead to an overall response to treatment. Based on these considerations, we developed the antiangiogenic hypoxic cell radiosensitizers, TX-1877, TX-1898 and the hypoxic cytotoxin TX-402 that inhibits the HIF-1alpha pathway We will also discuss our research involved with the development of other drugs to exploit tumor hypoxia, including a hypoxia-targeting boron carrier for boron neutron capture therapy (BNCT) and a p53 inhibiting radiosensitizer.

Angiogenesis Inhibitors↗

PubMed2024

Uncovering essential anesthetics-induced exosomal miRNAs related to hepatocellular carcinoma progression: a bioinformatic investigation.

BACKGROUND: Anesthetic drugs may alter exosomal microRNA (miRNA) contents and mediate cancer progression and tumor microenvironment remodeling. Our study aims to explore how the anesthetics (sevoflurane and propofol) impact the miRNA makeup within exosomes in hepatocellular carcinoma (HCC), alongside the interconnected signaling pathways linked to the tumor immune microenvironment. METHODS: In this prospective study, we collected plasma exosomes from two groups of HCC patients (n = 5 each) treated with either propofol or sevoflurane, both before anesthesia and after hepatectomy. Exosomal miRNA profiles were assessed using next-generation sequencing (NGS). Furthermore, the expression data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) was used to pinpoint the differentially expressed exosomal miRNAs (DEmiRNAs) attributed to the influence of propofol or sevoflurane in the context of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to dissect the signaling pathways and biological activities associated with the identified DEmiRNAs and their corresponding target genes. RESULTS: A total of 35 distinct DEmiRNAs were exclusively regulated by either propofol (n = 9) or sevoflurane (n = 26). Through TCGA-LIHC database analysis, 8 DEmiRNAs were associated with HCC. These included propofol-triggered miR-452-5p and let-7c-5p, as well as sevoflurane-induced miR-24-1-5p, miR-122-5p, miR-200a-3p, miR-4686, miR-214-3p, and miR-511-5p. Analyses revealed that among these 8 DEmiRNAs, the upregulation of miR-24-1-5p consistently demonstrated a significant association with lower histological grades (p < 0.0001), early-stage tumors (p < 0.05) and higher survival (p = 0.029). Further analyses using GSEA and GSVA indicated that miR-24-1-5p, along with its target genes, were involved in governing the tumor immune microenvironment and potentially inhibiting tumor progression in HCC. CONCLUSIONS: This study provided bioinformatics evidence suggesting that sevoflurane-induced plasma exosomal miRNAs may have a potential impact on the immune microenvironment of HCC. These findings established a foundation for future research into mechanistic outcomes in cancer patients.

Carcinoma, Hepatocellular↗

PubMed2005

Social support, psychological distress, and natural killer cell activity in ovarian cancer.

PURPOSE: Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL). PATIENTS AND METHODS: Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses. RESULTS: Peripheral NK cell activity was significantly lower among ovarian cancer patients than in patients with benign masses. Among ovarian cancer patients, NK cytotoxicity in TIL was significantly lower than in PBMC or ascitic fluid. Social support was related to higher NK cytotoxicity in PBMC and TIL, adjusting for stage. Distress was related to lower NK cytotoxicity in TIL. A multivariate model indicated independent associations of both distress and social support with NK cell activity in TIL. CONCLUSION: Psychosocial factors, such as social support and distress, are associated with changes in the cellular immune response, not only in peripheral blood, but also at the tumor level. These relationships were more robust in TIL. These findings support the presence of stress influences in the tumor microenvironment.

Adult↗

PubMed2006

Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis.

The chemokine stroma-derived factor (SDF-1/CXCL12) plays multiple roles in tumor pathogenesis. It has been demonstrated that CXCL12 promotes tumor growth and malignancy, enhances tumor angiogenesis, participates in tumor metastasis, and contributes to immunosuppressive networks within the tumor microenvironment. Therefore, it stands to reason that the CXCL12/CXCR4 pathway is an important target for the development of novel anti-cancer therapies. In this review, we consider the pathological nature and characteristics of the CXCL12/CXCR4 pathway in the tumor microenvironment. Strategies for therapeutically targeting the CXCL12/CXCR4 axis also are discussed.

Cell Transformation, Neoplastic↗

PubMed2002

A role for hypoxia and hypoxia-inducible transcription factors in tumor physiology.

Cumulative acquisition of genetic alterations affecting oncogenes or tumor suppressor genes may select for tumor cell clones with enhanced proliferation and survival potential. As a result oxygen and nutrient consumption increases, leading to a tumor microenvironment characterized by low oxygen tension, low glucose levels, and an acidic pH. Hypoxia-inducible transcription factors (HIF) are activated in response to hypoxia, apparently via reduced activity of the recently identified class of 2-oxoglutarate dependent oxygenases, as well as various tumor specific genetic alterations. A widespread HIF activation can be observed in a variety of malignant tumors. The HIF system induces adaptive responses including angiogenesis, glycolysis, and pH regulation which confer increased resistance towards the hostile tumor microenvironment. Apart from protumorigenic the wide-ranging HIF pathway may also have antitumorigenic components, which might, however, be counteracted by specific genetic mechanisms. Thus mounting evidence suggests that the HIF system plays a decisive role in tumor physiology and progression. Moreover, recent insight into this pathway has opened novel and potentially selective therapeutic approaches.

Animals↗

PubMed2005

Stromagenesis: the changing face of fibroblastic microenvironments during tumor progression.

During tumorigenesis, reciprocal changes in stromal fibroblasts and tumor cells induce changes to the neoplastic microenvironmental landscape. In stromagenesis, both the complex network of bi-directional stromal fibroblastic signaling pathways and the stromal extracellular matrix are modified. The presence of a 'primed' stroma during the early, reversible stage of tumorigenesis is optimal for stromal-directed therapeutic intervention. Three-dimensional (3D) cell culture systems have been developed that mimic the in vivo microenvironment. These systems provide unique experimental tools to identify early alterations in stromagenesis that are supportive of tumor progression with the ultimate goal of blocking neoplastic permissiveness and restoring normal phenotypes.

Cell Adhesion↗