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PubMed1995

Altered HLA expression by metastatic cervical carcinoma cells as a factor in impaired immune surveillance.

The altered expression of histocompatibility leukocyte antigens (HLA) in the development to cervical carcinoma suggests that tumor progression may be related to impaired recognition by host immune defense mechanisms. To investigate whether this phenomenon plays a role in the process of metastasis of cervical cancer, we analyzed and compared the HLA expression with the number of infiltrating immune cells in primary cervical carcinoma and related autologous metastases (n = 30) by staining serial paraffin and corresponding frozen sections with a panel of monoclonal antibodies. In 60% of the cervical metastases, compared to 21% of the primary tumors, a downregulation of monomorphic HLA class I antigens was observed, with frequent allele-specific alterations. In 50% the HLA class II expression was slightly increased on the metastatic tumor cells in comparison to the primary tumor. In addition, variability of alterations in HLA expression was observed between different metastases in the same patient. A minor infiltration of immune cells was present in cervical metastases compared to the primary tumors, especially in the HLA class I-downregulated metastases. Furthermore, loss of HLA class I expression on the metastatic tumor cells resulted in a significant decrease of tumor-infiltrating CD8+ T lymphocytes. These findings suggest that in cervical carcinoma loss of HLA class I expression plays a decisive role in the escape from immune surveillance leading to a greater metastatic potential of tumor cells.

Adult↗
PubMed1992

Renal allograft rejection: induction and function of adhesion molecules on cultured epithelial cells.

The interaction of graft-infiltrating immune cells with donor parenchymal cells is an important early event in allograft rejection. This binding is stabilized by interaction of antigen-independent 'adhesion' molecules expressed on the two cell types. As the level of expression of these molecules can be altered during inflammation, a series of experiments was performed to examine the effects of the inflammatory cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) on adhesion molecules expressed by cultured human renal tubular epithelial cells. These cells constitutively expressed ICAM-1 and LFA-3. Incubation with IFN-gamma increased expression of ICAM-1 but had no significant effect on expression of LFA-3 (P greater than 0.05). Incubation with TNF-alpha increased expression of both ICAM-1 and LFA-3; IFN-gamma synergized with TNF-alpha to further augment expression of these molecules. Peripheral blood lymphocytes (PBL) showed an enhanced binding to allogeneic renal epithelial cell monolayers which had been pretreated with IFN-gamma or TNF-alpha. MoAbs specific for ICAM-1 or its ligand LFA-1 inhibited adhesion of PBL to either IFN-gamma- or TNF-alpha-pretreated renal cells. By contrast, antibodies specific for LFA-3 or its ligand CD2 only significantly blocked PBL adhesion to renal cells which had been pretreated with TNF-alpha. Combination of antibodies specific for multiple components of the adhesion systems produced greater inhibition of adhesion than was produced by any single MoAb. These results suggest that the inflammatory cytokines IFN-gamma and TNF-alpha up-regulate expression of functional ICAM-1 and LFA-3 molecules which can augment the binding of potentially graft-damaging lymphoid cells to renal tubular epithelial cells.

Antigens, CD↗
PubMed1992

M-CSF (monocyte colony stimulating factor) and M-CSF receptor expression by breast tumour cells: M-CSF mediated recruitment of tumour infiltrating monocytes?

Infiltrating immune cells in 30 primary human epithelial breast tumours were studied using specific anti-CD3 (T cells), anti-CD68 (macrophages), anti-CD57 (NK cells), and an anti-pan-B cell antibody (L26). The majority of tumour infiltrating inflammatory cells are T cells (40-50%) and monocytes/macrophages (15-35%). The macrophage specific chemo-attractant and growth factor CSF-1 is detected by immunohistochemical techniques (IHC) at the level of invasive breast cancer cells in 46/50 tumours but not at the level of in-situ (pre-invasive) cancer. A mosaic staining pattern was usually observed, with a very high expression in areas of obvious stromal invasion (90% cells positive) and absent or trace staining in intraductal carcinoma. Macrophages and plasma cells are equally intensely positive. In-situ hybridisation experiments confirm the production of CSF-1 (mRNA) by tumour cells and show the same pattern of expression. Expression of the CSF-1 receptor protein (fms) was also observed by IHC in 41/48 invasive tumours, albeit at weaker intensities than in tumour infiltrating monocytes/macrophages. A concomitant expression of both CSF-1 and fms in in-situ carcinoma was never seen (n = 14). It is therefore proposed that the associated expression of CSF-1 and its receptor may be linked to the invasive potential of breast cancer, the monocytic infiltrate being an indication of the quantitative importance of CSF-1 production by the tumour.

Antibodies, Monoclonal↗
PubMed2026

S100P as a Shared Biomarker in Inflammatory Bowel Disease, Colorectal Cancer, and Pancreatic Adenocarcinoma: An Integrated Transcriptomic Analysis.

Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC) and pancreatic adenocarcinoma (PAAD), yet the molecular features shared among these diseases remain incompletely understood. This study aimed to identify common genes and biological pathways associated with IBD, CRC, and PAAD through integrated transcriptomic analysis and experimental validation. Gene expression datasets for IBD, CRC, and PAAD were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Weighted gene co-expression network analysis and differential expression analysis were performed to identify disease-associated and shared genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (analyses were used to explore enriched biological functions and pathways. Immune cell infiltration was evaluated using Cell-type Identification by Estimating Relative Subsets of RNA Transcripts. Receiver operating characteristic analysis was performed to assess the diagnostic performance of common genes. Single-cell RNA sequencing analysis was conducted to examine the cellular distribution of S100P. In addition, the effects of S100P downregulation were evaluated in lipopolysaccharide (LPS)-stimulated colonic epithelial cells. A total of 162 disease-associated genes and four common genes were identified. Functional enrichment analyses indicated significant enrichment of immune- and inflammation-related pathways, including the interleukin-17 signaling pathway. Immune infiltration analysis revealed similar trends in several immune cell populations across IBD, CRC, and PAAD. Single-cell analysis showed elevated S100P expression in epithelial cells from all three diseases. Downregulation of S100P restored the proliferative capacity of LPS-stimulated colonic epithelial cells and reduced inflammatory cytokine expression. Integrated transcriptomic analysis identified S100P as a biomarker associated with IBD, CRC, and PAAD and highlighted shared immune-related features across these diseases.

Humans↗
PubMed2026

Identification of ultrasound-associated gene candidates in myeloid cells and construction of a prognostic risk model for acute myeloid leukemia.

BACKGROUND: Incorporating ultrasound (US) treatment sensitivity analysis may improve the treatment of acute myeloid leukemia (AML). METHODS: This study integrated single-cell and bulk datasets for analysis. Differential expression analysis between US-treated and control samples was performed using limma package. The AUCell package was used to calculate US-associated scores in the single-cell dataset. Differentially expressed genes (DEGs) between the specific groups were identified, followed by intersection analysis with previously identified DEGs. Univariate regression, Least Absolute Shrinkage and Selection Operator (LASSO) analysis (using the glmnet package), and stepwise multivariate regression (using the MASS package) were used to refine the candidate genes and to construct a risk model. The model genes were validated using in vitro experiments. Enrichment analysis was conducted using gene set enrichment analysis (GSEA), and immune infiltration was evaluate by single-sample GSEA (ssGSEA) and ESTIMATE algorithms. The correlations between RiskScores and drug sensitivity were analyzed by oncoPredict package. Finally, tumor mutational burden (TMB) and genomic mutations were compared between the risk groups. RESULTS: Nine prognostic signatures (SPINK2, HNRNPAB, SH3BGRL3, CLEC11A, ITGA4, RPL39L, MX1, HEXIM1, and MAP4K4) were identified. Particularly, low expression of SPINK2 attenuated the activity and invasion of AML cells. High-risk group had higher immune cell infiltration. Eight drugs were predicted to be correlated with the RiskScore model. DNMT3A and RUNX1 showed higher mutation frequencies in the high-risk group, whereas KIT and MUC16 showed higher mutation frequencies in the low-risk group. CONCLUSION: The RiskScore model established in this study provides a theoretical basis for clinically screening responsive populations and optimizing treatment strategies.

Humans↗
PubMed1995

Immunohistological findings in patients with superficial bladder carcinoma after intravesical instillation of keyhole limpet haemocyanin.

OBJECTIVE: To determine whether keyhole limpet haemocyanin (KLH) instilled intravesically improves the local cellular response within the bladder wall of patients suffering from superficial bladder carcinoma. PATIENTS AND METHODS: Twelve patients (10 men and two women, mean age 67 years, range 42-85) with superficial carcinomas of the bladder were treated for 6 consecutive weeks and then monthly for 1 year with 20 mg KLH in 20 mL saline instilled intravesically after complete resection of the tumours. Biopsies were taken for immunohistochemical examination before treatment and again 6 weeks, 3, 6 and 9 months after treatment. Six patients with no evidence of cystitis or malignant bladder disease acted as a control group. Immunofluorescent staining of the biopsies was performed using monoclonal antibodies to the T-cell markers CD4 and CD8, and to CD14 (monocytes), CDw15 (granulocytes), CD19 B-cells (Pan-B), CD68 (macrophages) and HLA-DR. Anti-KLH antibody-producing plasma cells were detected using a standard technique. A semiquantitative analysis of locally infiltrating cell types was performed. RESULTS: After treatment with KLH the increase of CD8+ suppressor cells was less pronounced than that of CD4+ helper cells. The T-helper/inducer to T-suppressor/cytotoxic cell ratio thus altered from 0.8:2.0 before treatment to 1.6:2.3 afterwards. Hence, the number of T-helper cells had increased considerably, whereas there was only a moderate increase in the number of T-suppressor cells. This cellular ratio could be detected for 9 months after KLH therapy. The numbers of activated HLA-DR+ immune cells in the submucosa and among urothelial cells also increased after KLH instillation. The degree of mononuclear cell infiltration of the submucosa increased considerably, but granulocyte infiltration was only moderate. Lymph follicles with enhanced B-lymphocyte counts were also detected. CONCLUSION: Immune-cell infiltration into the urothelium and enhanced activation (expression of class II antigens) suggests distinct processes of cellular antigen recognition, which could be detected for up to 9 months after the beginning of KLH therapy. This may represent a basic functional mechanism of KLH therapy.

Administration, Intravesical↗
PubMed2026

Hypoxia-inducible factor-1α promotes the malignant progression of cervical cancer cells by regulating lactate dehydrogenase A-mediated glycolysis.

BACKGROUND: Enhanced glycolysis is a hallmark of metabolic reprogramming in cervical cancer and plays a key role in tumor progression. Hypoxia-inducible factor-1α (HIF-1α), a core regulator of glycolytic metabolism, remains incompletely characterized in cervical cancer. This study aimed to investigate the expression pattern and clinical significance of HIF-1α in cervical cancer, and to explore its association with malignant biological behavior and lactate dehydrogenase A (LDHA)-related glycolytic metabolism in cervical cancer cells. METHODS: The expression level, clinicopathological features, immune infiltration correlation, and prognostic value of HIF-1α in cervical cancer were analyzed based on the The Cancer Genome Atlas (TCGA) database. HIF-1α overexpression and knockdown models were established in HeLa and Caski cells. Cell viability and invasive ability were assessed by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect changes in LDHA expression. Lactate production was measured using a lactate assay kit, and intracellular reactive oxygen species (ROS) levels were determined by flow cytometry. RESULTS: Bioinformatics analysis showed that HIF-1α was highly expressed in cervical cancer and was closely associated with patient age, menopausal status, immune cell infiltration, and poor prognosis. Kaplan-Meier survival analysis demonstrated that patients with high HIF-1α expression had significantly worse overall survival (OS) than those with low expression. In vitro functional experiments further confirmed that HIF-1α overexpression significantly enhanced the viability and invasive ability of HeLa and Caski cells, whereas HIF-1α knockdown produced the opposite effects. HIF-1α overexpression was associated with increased messenger RNA (mRNA) and protein expression levels of LDHA, a key glycolytic molecule, along with increased lactate production and elevated intracellular ROS levels. CONCLUSIONS: HIF-1α is aberrantly highly expressed in cervical cancer and may enhance glycolytic activity by upregulating LDHA expression, thereby promoting the proliferation and invasion of cervical cancer cells. These findings suggest that HIF-1α could serve as a potential diagnostic, prognostic, and therapeutic target biomarker for cervical cancer.

Hypoxia-inducible factor-1α (HIF-1α)↗
PubMed2026

Prognostic significance of DNA damage response-related markers in esophageal squamous cell carcinoma using machine learning approaches.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) lacks reliable prognostic biomarkers. Homologous recombination deficiency (HRD) has been implicated in genomic instability across multiple cancers, but its prognostic significance in ESCC remains unexplored. This study aimed to evaluate HRD score as a prognostic biomarker and develop a machine learning-based predictive model for ESCC. METHODS: Transcriptomic and clinical data from 78 ESCC patients were obtained from The Cancer Genome Atlas (TCGA) and randomly split into training (70%) and test (30%) cohorts. Prognostic models were constructed using 112 machine learning algorithm combinations based on DNA damage response (DDR)-related genes. Gene set enrichment analysis (GSEA), somatic mutation profiling, and immune cell infiltration estimation via CIBERSORT were performed to characterize HRD-associated molecular features. RESULTS: High HRD scores were significantly associated with poorer overall survival (P<0.05). Among 112 algorithm combinations, the survival support vector machine (Survival-SVM) model demonstrated optimal performance [training concordance index (C-index): 0.741; test C-index: 0.708], identifying six hub genes: PARP1, MBD4, TELO2, NSMCE3, SMUG1, and BABAM1. A nomogram incorporating risk score (RS) and clinical variables achieved strong predictive accuracy for 1- to 3-year survival [area under the curve (AUC) >0.7]. High-HRD tumors exhibited distinct mutational patterns (TP53 and TTN) and enriched glutathione metabolism and cytochrome P450 pathways. Immune infiltration analysis revealed significant differences in plasma cell and neutrophil infiltration between risk groups (P<0.05), suggesting HRD-associated immune microenvironment remodeling. CONCLUSIONS: We developed a novel HRD-based prognostic model incorporating six DDR-related genes that demonstrates robust predictive performance in ESCC. HRD score is identified as an independent prognostic factor associated with genomic instability, immune microenvironment alterations, and clinical outcomes. These findings provide a theoretical basis for personalized treatment strategies, including potential applications of PARP inhibitors and immunotherapy in ESCC.

Esophageal squamous cell carcinoma (ESCC)↗
PubMed2026

Integrated transcriptomic and functional characterization of Claudin-1 reveals its oncogenic and immunomodulatory roles in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, driven by its invasive nature and lack of effective biomarkers. Disruption of the epithelial barrier, mediated by tight junction components, is a critical yet underexplored contributor to PDAC progression. Claudins, integral regulators of tight junction integrity, display altered expression across cancers, but their prognostic and immunomodulatory roles in PDAC remain unclear. We performed an integrative analysis of 177 RNA-Seq datasets from TCGA and GTEx to characterize Claudin family alterations in PDAC. Differential expression, copy number variation, methylation, and co-expression networks were analyzed alongside clinical and survival data. Prognostic significance was assessed using Kaplan - Meier and Cox regression analyses, while immune cell infiltration was examined using deconvolution algorithms. Functional validation of Claudin-1 was conducted in Capan-1 cells using CRISPR/Cas9 knockout, followed by proliferation, wound-healing, and Western blot assays. Ten Claudin genes were significantly dysregulated, with Claudin-1 and Claudin-4 frequently amplified and associated with advanced stage and poor survival. High Claudin-1 expression correlated with reduced immune infiltration, indicating an immune-excluded phenotype characterized by immune cells retained in the tumor stroma but largely absent from the tumor parenchyma. Claudin-1 knockout markedly inhibited proliferation, migration, and EMT, evidenced by downregulation of Snail and Slug and restoration of E-cadherin expression. This integrative transcriptomic and functional study identifies Claudin-1 as a key driver of PDAC aggressiveness and immune modulation. These findings establish Claudin-1 as a promising prognostic biomarker and therapeutic target for restoring epithelial integrity and counteracting immune evasion in pancreatic cancer.

Humans↗
PubMed2000

Fas ligand is expressed in normal breast epithelial cells and is frequently up-regulated in breast cancer.

Fas (CD95/Apo-1) is a cell membrane receptor that upon binding by its ligand (FasL), triggers a signal resulting in apoptotic cell death. Fas is produced by breast epithelial cells, but its contribution to breast tissue homeostasis is unknown. This study investigated whether FasL is synthesized in the breast. By reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry, FasL expression was analysed in normal and malignant human breast epithelial cell lines, normal breast tissue, benign breast disease (fibrocystic changes, fibroadenoma), and breast cancer (ductal carcinoma in situ; invasive ductal, lobular, mucinous and medullary carcinomas). The results demonstrate expression of FasL by normal breast epithelial cells and show a marked increase of FasL protein in the majority of breast carcinomas, compared with normal breast tissue and benign breast disease. By western blot analysis, soluble FasL was detected in culture supernatants of one of three normal breast epithelial cell lines and in all four breast cancer cell lines tested. The expression of Fas protein was more heterogeneous in benign and malignant breast tissue, with expression levels ranging from weak to strong, but breast cancer cells frequently exhibited a weaker Fas expression than surrounding residual normal breast epithelial cells. In vitro, two out of three normal breast epithelial cell lines were sensitive to cell death induction by an agonistic anti-Fas antibody. Co-treatment with cycloheximide, an inhibitor of protein translation, rendered the resistant cell line sensitive. In contrast, two out of four breast cancer cell lines were resistant to the anti-Fas antibody and this resistance could not be reversed by cycloheximide. These results suggest that increased expression of FasL may confer an advantage on breast cancer cells, possibly by eliminating tumour-infiltrating immune cells, and/or by facilitating tissue destruction during invasion.

Adenocarcinoma↗
PubMed2003

Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas.

The present study has analysed the distribution and phenotype of dendritic cells (DCs) in primary cutaneous melanomas and sentinel lymph nodes by immunohistochemistry. In primary melanomas, an increase of DCs was found in the epidermis and the peritumoural area. Intraepidermal DCs were mostly CD1a(+)/Langerin(+) Langerhans cells. Peritumoural DCs included a large population of DC-SIGN(+)/mannose-receptor(+)/CD1a(-) DCs, a small subset of CD1a(+) DCs, and, remarkably, plasmacytoid monocytes/plasmacytoid DCs (PM/PDCs). The PM/PDCs, most likely recruited by SDF-1 secreted by melanoma cells, produced type I interferon (IFN-I), but the expression of the IFN-alpha inducible protein MxA was extremely variable and very limited in the majority of cases. All DC subsets were predominantly immature. The peritumoural area also contained a minor subset of mature CD1a(+) DCs. However, the small amount of local interleukin (IL)-12 p40 mRNA and the naïve phenotype of 20-50% of peritumoural T-lymphocytes are consistent with poor T-cell stimulation or erroneous recruitment. In sentinel lymph nodes, notable expansion of mature CD1a(+)/Langerin(+) DCs was observed. The paucity of intratumoural DCs and the predominant immature phenotype of peritumoural dermal DCs indicate defective maturation of primary cutaneous melanoma-associated DCs, resulting in lack of T-cell priming. These results may explain why melanoma cells grow despite the presence of infiltrating immune cells.

Aged↗
PubMed1999

Costimulatory markers in muscle of patients with idiopathic inflammatory myopathies and in cultured muscle cells.

In an attempt to understand the mechanisms of cell injury in the inflammatory myopathies, we analyzed the expression of costimulatory molecules, CTLA4, CD28, CD86, CD40, and CD154 as well as HLA class I, HLA class II, and ICAM-I in normal muscle and in muscle biopsies from patients with polymyositis (PM) or dermatomyositis (DM). By immunohistochemical staining, DM and PM biopsies showed the presence of CTLA4, CD28, CD86, and CD40 on inflammatory cells. More strikingly, however, low levels of CTLA4 and CD28 were observed on muscle cells. The expression of CTLA4 and CD28 on nonlymphoid cells has not been previously reported. These unexpected findings were confirmed in cultured normal human myoblasts: various proinflammatory cytokines induced the expression of CTLA4 and CD28 on normal human muscle cells. The sequences of the cDNAs were found to be identical to the sequences for these molecules in T cells. The data suggest a novel complexity in the network of cellular interactions between the infiltrated immune cells and the muscle cells in which the normal relationship between infiltrating inflammatory cells and target tissue is under a previously unrecognized set of controls.

Abatacept↗
PubMed1992

Tubulointerstitial nephritis.

Tubulointerstitial nephritis (TIN) describes a range of pathological processes that are at least partly responsible for the progression of renal disease of nearly all aetiologies. TIN is frequently the most important pathological manifestation of progressive glomerulonephritis, obstructive uropathy, reflux nephropathy and cystic diseases, although it may also present as a primary disease process associated with infection, drug use or other immunologically mediated disease. Recent clinical and laboratory research has increased our knowledge of tubulointerstitial structure, physiological function and tubulointerstitial response to injury. This review presents a classification of TIN in which acute and chronic tubulointerstitial diseases are recognized as forming a continuum. Primary TIN and TIN associated with glomerulonephritis, obstructive nephropathy and chronic progressive renal disease are discussed from both clinical and pathogenic aspects. It is argued that chronic TIN is a disease process in which inflammation is accompanied by a destructive tubulopathy and fibrogenesis. In acute TIN there is a cessation and reversal of this process. It is suggested that most forms of TIN have an immunological basis because of the presence of immune cell infiltrates, the occurrence of TIN in several immune diseases and immunological animal models of TIN. However, to date TIN has not been convincingly modified in patients by immune manipulation. Experimental evidence suggesting an important pathogenic role for proteinuria and antigenuria, and the renal tubule cell acting as an antigen-presenting cell is discussed.

Acute Disease↗
PubMed2005

Molecular and cellular mechanisms in vascular injury in hypertension: role of angiotensin II.

PURPOSE OF REVIEW: Emerging evidence indicates that hypertension is a vascular disease associated with inflammation, induced through redox-sensitive mechanisms that are regulated by angiotensin II. This review focuses on the role of inflammation, oxidative stress and angiotensin II in vascular injury and discusses implications of these processes in hypertension. RECENT FINDINGS: The dogma that hypertension is primarily a consequence of hemodynamic alterations has changed over the recent past, with compelling evidence that high blood pressure is linked to vascular damage, oxidative stress and inflammation. Of the many factors implicated in hypertensive vascular disease, angiotensin II appears to be one of the most important. Angiotensin II, a multifunctional peptide regulating vascular contraction, growth and fibrosis, has recently been identified as proinflammatory mediator. Angiotensin II increases vascular permeability, promotes recruitment of inflammatory cells into tissues, and directly activates infiltrating immune cells, which further contribute to the inflammatory process. Moreover, angiotensin II participates in tissue repair and remodeling, by stimulating cell growth and fibrosis. Many of these processes are mediated through increased generation of reactive oxygen species (oxidative stress). SUMMARY: Inflammation, oxidative stress and hypertension are closely interrelated. Here we discuss the (patho)physiology of vascular inflammation in hypertension, focusing specifically on the role of angiotensin II and reactive oxygen species. By understanding molecular and cellular mechanisms of hypertensive vascular disease will allow for more targeted therapy and hopefully improved management and treatment of patients with hypertension.

Angiotensin II↗
PubMed2005

Modulation of monocyte matrix metalloproteinase-2 by breast adenocarcinoma cells.

INTRODUCTION: The presence of monocyte and macrophage cells in growing breast tumors, and the positive relationship between the degree of immune cell infiltration and tumor growth, suggest a possible paracrine growth regulatory function of immune cells in breast cancer. METHOD: To better understand the interaction between monocytes and breast cancer cells, in vitro matrix metalloproteinase and tissue inhibitor of metalloproteinase activity was assessed from the THP-1 myeloid cell line in response to conditioned media from two breast cancer cell lines, MCF-7 and MDA-MB-231. RESULTS: Enzymography and immunoblotting revealed increased MMP-2 as well as increased levels of TIMP-1 and TIMP-2. Furthermore, a significant increase in the invasive potential of MCF-7 and MDA-MB-231 cells was noted in response to THP-1 cell-conditioned media. CONCLUSION: These data demonstrate that monocyte cells in the breast tumor microenvironment play an important role in the modulation of MMPs, which may have a significant effect on the control of tumor growth and metastatic spread.

Adenocarcinoma↗
PubMed2006

Selective ablation of matrix metalloproteinase-2 exacerbates experimental colitis: contrasting role of gelatinases in the pathogenesis of colitis.

The matrix metalloproteinases (MMPs), MMP-2 and MMP-9, share structural and substrate similarities and are up-regulated during human as well as animal models of inflammatory bowel disease. We recently demonstrated that epithelial-derived MMP-9 is an important mediator of inflammation and tissue damage in colitis. In this study, we examined the role of MMP-2 in acute colitis. Colitis was induced using two models, administration of dextran sodium sulfate (DSS) and Salmonella enterica subsp. serovar Typhimurium (S.T.). Bone marrow chimeras were performed using bone marrow cells from wild-type (WT) and MMP-2(-/-) mice. Colitis was evaluated by clinical symptoms, myeloperoxidase assay, and histology. MMP-2 protein expression and activity were up-regulated in WT mice treated with DSS or S.T. MMP-2(-/-) mice were highly susceptible to the development of colitis induced by DSS (or S.T.) compared with WT. During inflammation, MMP-2 expression was increased in epithelial cells as well as in the infiltrating immune cells. Bone marrow chimera demonstrated that mucosa-derived MMP-2 was required for its protective effects toward colitis. Furthermore, we demonstrate that severe colitis in MMP-2(-/-) is not due to a compensatory increase in MMP-9. Finally, we show that MMP-2 regulates epithelial barrier function. In contrast to MMP-9, mucosa-derived MMP-2 may be a critical host factor that is involved in the prevention or cessation of the host response to luminal pathogens or toxins, an important aspect of healing and tissue resolution. Together, our data suggest that a critical balance between the two gelatinases determines the outcome of inflammatory response during acute colitis.

Acute Disease↗
PubMed1994

Cellular aspects of myositis.

Polymyositis, dermatomyositis, and inclusion-body myositis are characterized by muscle cell infiltration and specific alterations on or within muscle fibers. Infiltrating immune cells (ie, T or B lymphocytes, macrophages, and natural killer cells) have distinctive distributions in these conditions: increased presence of CD8+/MHC I-restricted T lymphocytes at endomysial sites in polymyositis and more B than T lymphocytes perivascularly in muscles of dermatomyositis patients. Muscle-infiltrating T lymphocytes mainly express alpha beta T cell receptors (TCRs) in polymyositis; they also express TCRs characterized by oligoclonal V beta repertoire, with a consensus motif indicating a conventional antigen as target of the immune attack. In inclusion-body myositis, TCRs with oligoclonal V beta also are found, but no consensus motif has been identified, suggesting possible superantigen involvement in lymphocyte recruitment. Sequence analysis of TCRs in these lymphocytes has provided insight into the probable nature of the antigenic stimulus and into recruitment of these cells to the inflammation sites. T cell- or natural killer cell-mediated cytotoxic agents have been characterized by messenger RNA or protein expression in these inflammatory myopathies, and the roles of other cytokines in the inflammation processes have been determined. In vivo and in vitro studies on muscle cells have assessed their functions as target cells or antigen-presenting cells. Combined molecular and cellular immunology studies on effector and target cells are expected to clarify the pathogenetic mechanisms underlying these inflammatory myopathies in the near future.

Humans↗
PubMed2002

Significance of changes in local immunity in patients with hepatocellular carcinoma after percutaneous microwave coagulation therapy.

OBJECTIVE: To assess the local immune response in patients with hepatocellular carcinoma after percutaneous microwave coagulation therapy (PMCT). METHODS: Seventy-eight patients with hepatocellular carcinoma underwent PMCT. Both cancerous and adjacent liver tissue were taken before, and 3, 17 and 30 days after PMCT using ultrasound-guided liver biopsy. Specimens were stained by immunohistochemical techniques for detecting CD3, CD45RO, CD56, CD68, and CD20 positive cells. RESULTS: A few CD3, CD45RO, CD56, CD68 and CD20 positive cells were observed in the cancer stroma and surrounding sinusoids in liver tissue pre-PMCT. The number of immunocytes, except for CD20 positive cells, was significantly increased both within the cancer and the adjacent liver tissue, with a larger increase in tumor tissue at day 3 post-PMCT compared with pre-PMCT. These immunocytes were enlarged in size. The number of CD3, CD45RO and CD56 positive cells peaked at day 17 and CD68 positive cells peaked at days 3 post-PMCT. At day 30 post-PMCT, this increase still existed. These infiltrating immunocytes distributed in the parenchyma of the tumor, and within the lumen of small blood vessels after PMCT. In addition, more infiltrated immune cells were seen in cancer cell spaces. CONCLUSIONS: A change in immunocyte infiltration takes place in number, configuration and location after patients with HCC are treated with percutaneous microwave coagulation, suggesting that local immune function is enhanced post-PMCT.

Adult↗