Role Of CD44 Research Articles

CD44(+) tumor cells promote early angiogenesis in head and neck squamous cell carcinoma

The role of CD44 in progression of head and neck squamous cell carcinoma (HNSCC) has been controversial. The goal of this study was to study the effects of CD44(+) tumor cells on the initial stages of tumor angiogenesis and to evaluate CD44 as a potential marker of tumor angiogenesis. The CD44 gene expression was studied using the Cancer Genome Atlas (TCGA) Head and Neck Cancer data base. Expression levels of CD44 and of microvascular density (MVD) markers were assessed by immunohistochemistry performed with tissue microarrays in a cohort of 49 HNSCC patients, 11 patients with dysplasia and 12 control oral mucosa tissues. The 4-nitroquinoline-1-oxide oral carcinogenesis mouse model was used to study CD44 expression during carcinogenesis. Gelatin sponges seeded with CD44(+), CD44(-) and unsorted cancer cells suspended in Matrigel were implanted in NOD/SCID mice into a dorsal skinfold chamber and compared to non-seeded sponges as controls. Angiogenic response was assessed by intravital microscopy. In the TCGA analysis, CD44 gene expression correlated with various pro-angiogenic genes. In human HNSCC tissues, CD44 expression was upregulated and was associated with blood vessels, although no correlation between MVD and CD44 expression was found. During oral carcinogenesis CD44 expression was upregulated. In dorsal skinfold chambers, CD44(+) cells showed a significantly higher MVD than CD44(-) or unsorted cells (p < 0.001). The results indicate that CD44(+) cells contain pro-angiogenic factors and stimulate tumor angiogenesis in HNSCC. Thus, CD44 might emerge as a potential angiogenic biomarker and a therapeutic target for anti-angiogenic therapies.

Endoglin-based assessment of neoangiogenesis in sporadic VIII cranial nerve schwannoma

Although the diagnosis and treatment of sporadic vestibular schwannoma has improved in recent years, no factors capable of predicting its growth have been identified as yet. Endoglin (CD105) is a proliferation-associated protein expressed in angiogenic endothelial cells, and a potential prognostic indicator for several solid tumors. The aim of the present study was primarily to investigate the expression and role of CD105 in a series of sporadic vestibular nerve schwannomas.In 71 consecutive cases of vestibular schwannoma, vessel cross-sectional area and density were calculated from immunohistochemically assessed CD105 expression using image analysis to correlate them with: (i) tumor dimensions; and (ii) tumor growth rate measured on high-resolution contrast-enhanced MRI (ceMRI).Based on assessments of CD105 expression, a significant positive correlation was identified between vessel cross-sectional area and tumor size at the time of surgery (p = 0.0024), and between vessel density and tumor size (p = 0.013). Vessel cross-sectional area (p = 0.0006) and vessel density (p = 0.003) were significantly greater in tumors measuring ≥10 mm in size than in those <10 mm. Conversely, when tumor growth rate could be calculated from two or more ceMRI (38 cases), there was no significant correlation between tumor growth rate and cross-sectional vessel area or vessel density as assessed with CD105.Further investigations are needed to ascertain the feasibility of: (i) using circulating endoglin assay to monitor tumor growth; and (ii) targeting neoangiogenesis with anti-endoglin antibodies in sporadic vestibular schwannoma.

The Role of CD44 and RHAMM in Endometrial (Endometrioid Type) Cancer: An Immunohistochemical Study.

Hyaluronan controls cell migration, differentiation, and proliferation, and it is involved in tumor invasion. The extracellular matrix containing hyaluronan regulates cell behavior via cell surface receptors such as CD44 and receptor for hyaluronan-mediated motility (RHAMM, CD168). We investigated the expression of CD44 and RHAMM in tissue samples of endometrial cancer and the relation of their expression with clinicopathologic parameters of patients. In order to evaluate the value of CD44 and RHAMM as prognostic factors, we investigated the relation of their expression with patients' survival. Our results demonstrated a statistically significant correlation with the depth of myometrial invasion, lymphovascular invasion (LVSI), The International Federation of Gynecology and Obstetrics stage of disease, and, in the case of RHAMM expression, a significant correlation with histologic tumor grade as well. CD44 expression was present in the cell membrane in all cases, but in a proportion of tumors in the cytoplasm as well. In this group of patients, we noticed a significantly greater number of cases with deeper myometrial invasion and LVSI. Finally, we sorted out the group of tumors with simultaneous strong CD44 and strong RHAMM expression, and found a statistically significant correlation with the depth of myometrial invasion and LVSI. Using an univariate analysis, we demonstrated that, in our sample of patients, CD44 expression showed a statistically significant influence on patients' 5-year survival. However, using a multivariate Cox regression analysis, neither CD44 nor RHAMM confirmed themselves as independent prognostic factors.

Lack of the hyaluronan receptor CD44 affects the course of bacterial otitis media and reduces leukocyte recruitment to the middle ear

BackgroundCD44 is a multifunctional molecule that plays major roles in both leukocyte recruitment and tissue proliferation. Since mucosal hyperplasia and leukocyte infiltration of the middle ear cavity are major features of otitis media, we evaluated the role of CD44 in the pathophysiology and course of this disease in a mouse model of middle ear infection. Expression of genes related to CD44 function were evaluated using gene arrays in wild-type mice. The middle ears of mice deficient in CD44 were inoculated with non-typeable Haemophilus influenzae. Histopathology and bacterial clearance were compared to that seen in wild-type controls.ResultsWe observed strong up-regulation of CD44 and of genes related to its role in leukocyte extravasation into the middle ear, during the course of acute otitis media. Mice deficient in CD44 exhibited reduced early mucosal hyperplasia and leukocyte recruitment, followed by delayed resolution of infection and persistent inflammation.ConclusionsCD44 plays an important role in OM pathogenesis by altering the mucosal growth and neutrophil enlistment. Targeted therapies based on CD44 could be useful adjuncts to the treatment of middle ear infections.

A New crucial role for complement receptor CD46 in chromatin packaging and direct gene regulation

Abstract Chromatin is the condensed form of DNA ‘packaged’ by positively charged histones in the nucleus. Post-translational modifications of histones regulate nucleosome dynamics, chromatin accessibility and gene expression. Signals mediated by autocrine activation of the human-specific complement regulator/receptor CD46 during T cell receptor stimulation are vital to Th1 induction in CD4+ T cells. CD46 is expressed in different isoforms that arise through alternative-splicing of a single gene - with two distinct cytoplasmic tails: CYT-1 or CYT-2. CYT-1 nuclear translocation is critical for the expression of genes that are involved in the metabolic adaptations underlying Th1 activity. Because CD46-CYT-1 lacks direct DNA-binding domains, we hypothesized that CYT-1 interacts with transcription factor (TF) activator and/or repressor complexes to control gene expression. ChIP-seq analyses of human CD4+ T cells using anti-CYT-1 antibody revealed 327 genes as direct CD46-CYT-1 targets and five conserved TF-binding motifs allowing us to define CYT-1-interacting TFs in T cells. Interestingly, pathway analysis of CYT-1-regulated genes identified broad nucleosome regulation as top ‘CYT-1 activity’. Indeed, we confirmed that CYT-1 directly regulates the expression and post-translational modification of core histones including H3 and H4 at lysine (4, 8, 9, 12, 20 and 27) in a time-dependent manner. Such CD46-driven nucleosome regulation was aberrant in T cells from CD46-deficient patients, explaining now mechanistically their inability to mount Th1 responses. These data define a novel role for CD46 in chromatin packaging and support our notion that intracellular/autocrine complement regulates basic cell-physiological processes.

CD44s Assembles Hyaluronan Coat on Filopodia and Extracellular Vesicles and Induces Tumorigenicity of MKN74 Gastric Carcinoma Cells.

CD44 is a multifunctional adhesion molecule typically upregulated in malignant, inflamed and injured tissues. Due to its ability to bind multiple ligands present in the tumor microenvironment, it promotes multiple cellular functions related to tumorigenesis. Recent data has shown that CD44 and its principal ligand hyaluronan (HA) are carried by extracellular vesicles (EV) derived from stem and tumor cells, but the role of CD44 in EV shedding has not been studied so far. To answer this question, we utilized CD44-negative human gastric carcinoma cell line MKN74 manipulated to stably express CD44 standard form (CD44s). The effect of CD44s expression on HA metabolism, EV secretion, morphology and growth of these cells was studied. Interestingly, HAS2 and HYAL2 expression levels were significantly upregulated in CD44s-expressing cells. Cell-associated HA levels were significantly increased, while HA levels in the culture medium of CD44s-positive cells was lower compared to CD44s-negative MOCK cells. CD44s expression had no significant effect on the proliferation capacity of cells, but cells showed diminished contact inhibition. Superresolution imaging revealed that CD44s and HA were accumulated on filopodia and EVs secreted from CD44s-positive cells, but no differences in total numbers of secreted EV between CD44s-negative and -positive cells was detected. In 3D cultures, CD44s-expressing cells had an enhanced invasion capacity in BME gel and increased spheroidal growth when cultured in collagen I gel. No significant differences in mitotic activity, tumor size or morphology were detected in CAM assays. However, a significant increase in HA staining coverage was detected in CD44s-positive tumors. Interestingly, CD44s-positive EVs embedded in HA-rich matrix were detected in the stromal areas of tumors. The results indicate that CD44s expression significantly increases the HA binding capacity of gastric cancer cells, while the secreted HA is downregulated. CD44s is also carried by EVs secreted by CD44s-expressing cells. These findings highlight the potential usefulness of CD44s and its ligands as multipurpose EV biomarkers, because they are upregulated in inflammatory, injured, and cancer cells and accumulate on the surface of EVs secreted in these situations.

CD151 confers metastatic potential to clear cell sarcoma of the soft tissue in animal model.

Cluster of differentiation 151 (CD151) is a potent therapeutic target for regulating tumor metastasis. In the present study, the role of CD151 in clear cell sarcoma of soft tissue was examined using a xenoplanted tumor model, which had high rates of metastasis. A clear cell sarcoma cell line, HS-MM, which was transplanted to the aponeuroses of the thighs, the most affected sites of human clear cell sarcoma, exhibited robust lymphatic invasion and nodal metastasis in SCID-beige mice. Serial in vivo passaging of peritoneally disseminated tumor cells accelerated the metastatic activity, which was accompanied by increased CD151 expression, and were designated as HS-MMhigh. Notably, inoculation of anti-CD151 antibody significantly suppressed the lymphatic invasion, peritoneal dissemination and distant metastasis of the present clear cell sarcoma model without affecting local tumor growth at the transplantation site. Small interfering RNA (siRNA)-mediated downregulation of CD151 did not alter cell proliferation, but significantly inhibited Matrigel invasion activity of HS-MMhigh cells. Downregulation of CD151 impaired matrix metalloproteinase-9 activity and phosphorylation of SMAD3 protein in HS-MMhigh cells. The present results suggest that CD151 may contribute to invasion and metastasis of clear cell sarcoma of soft tissue. Therefore, CD151 may serve as a potent target to regulate metastasis of clear cell sarcoma.

Knockdown of CD44 inhibits the alteration of osteoclast function induced by simulated microgravity

Mechanical forces are essential to maintain skeletal homeostasis, and microgravity exposure leads to bone loss. During space flight, bone mineral density is decreased because of the inactivation of osteoblast and activation of osteoclast. However, the underlying molecular mechanism is still not clear. CD44 acts as a cellular surface adhesion molecule, which plays an important role in signal transduction between cells. Numerous studies have shown that CD44 plays diverse roles in promoting pre-osteoclast fusion. However, the role of CD44 in the alteration of osteoclast function induced by simulated microgravity remains to be fully elucidated. In this work, we utilized a ground-based, microgravity-simulation system, the Rotating Wall Vessel Bioreactor (RWVB). Using the RWVB, we demonstrated that simulated microgravity enhanced osteoclast function, meantime CD44 mRNA and protein levels were significantly increased. To verify the effects of CD44 on alteration of osteoclast function induced by simulated microgravity, specific siRNAs targeting CD44 were transfected. The results showed knockdown of CD44 inhibited the alteration of osteoclast function induced by simulated microgravity. Moreover, we found that clinorotation activated the NF-κB/NFATc1-mediated signaling pathway, which was downregulated after knockdown of CD44. Our study provided evidence that CD44 positively regulated osteoclast function and therapeutic suppression of CD44 may counteract bone loss induced by simulated microgravity.

Structure, function and role of CD44 in neoplasia.

CD44 is a group of protein molecules which perform a variety of functions. Their wide range of functions are mainly based on their multiple variations in their molecular structure. Furthermore, they are distributed in various tissues of the human body. They have a unique property of cell adhesion, which can lead to interaction between two different cells or a cell and its pericellular matrix. CD44 as a cell surface adhesive molecule helps in aggregation and migration of tumor cells. CD44 plays an important role in cancer of bladder, liver, lungs, pancreas, etc. Expression profile of CD44 has been seen in the epithelia of the lip, tongue, gingiva, hard palate, floor of the mouth, buccal mucosa and pharynx. The relationship between the expression of CD44 v6 and regional lymph node metastasis has been studied immunohistochemically. The expression of CD44 v6 was apparently downregulated in oral squamous cell carcinoma, but not in normal oral mucosa. Carcinomas expressing lower levels of CD44 v6 exhibited more frequent regional lymph node metastasis. No significant relation was found between the expression of CD44 v6 in primary and metastatic lesions. Still, the precise function of CD44 in the metastatic process and the degree of involvement in human malignancies is yet to be established.

The Role of CD44 in Modulating Radiosensitivity In Vitro

The Role of CD44 in Modulating Radiosensitivity In Vitro

CD9 Tetraspanin: A New Pathway for the Regulation of Inflammation?

CD9 belongs to the tetraspanin superfamily. Depending on the cell type and associated molecules, CD9 has a wide variety of biological activities such as cell adhesion, motility, metastasis, growth, signal transduction, differentiation, and sperm–egg fusion. This review focuses on CD9 expression by hematopoietic cells and its role in modulating cellular processes involved in the regulation of inflammation. CD9 is functionally very important in many diseases and is involved either in the regulation or in the mediation of the disease. The role of CD9 in various diseases, such as viral and bacterial infections, cancer and chronic lung allograft dysfunction, is discussed. This review focuses also on its interest as a biomarker in diseases. Indeed CD9 is primarily known as a specific exosome marker however, its expression is now recognized as an anti-inflammatory marker of monocytes and macrophages. It was also described as a marker of murine IL-10-competent Breg cells and IL-10-secreting CD9+ B cells were associated with better allograft outcome in lung transplant patients, and identified as a new predictive biomarker of long-term survival. In the field of cancer, CD9 was both identified as a favorable prognostic marker or as a predictor of metastatic potential depending on cancer types. Finally, this review discusses strategies to target CD9 as a therapeutic tool. Because CD9 can have opposite effects depending on the situation, the environment and the pathology, modulating CD9 expression or blocking its effects seem to be a new promising therapeutic strategy.

The Role of CD44 AND SOX-2 Cancer Stem cell Markers in The Development and Progression of Mucoepidermoid Carcinoma and Primary Squamous Cell Carcinoma of Salivary Glands

One of the greatest difficulties to reach a successful treatment of mucoepidermoid carcinoma(MEC) and primary squamous cell carcinoma (PSSC) of salivary glands is the resistance to differenttherapeutic procedures which advocate the existence of a subpopulation of cancer stem cell (CSC).In salivary gland tumors the hypothesis of cancer stem cell has not been fully understood.Aim: To assess the expression of cancer stem cell markers CD44 and SOX2 in low and highgradesMEC and PSSC and to determine whether the expression of these markers can be used topredict tumor aggressiveness.Materials and Methods: 4μm sections were prepared from paraffin-embedded blocks of16 samples of MEC and 16 samples of PSSC of salivary glands (8 low-grade and 8 high- gradecarcinomas for each of them). Staining of each specimen with hematoxylin and eosin, CD44 andSOX2 was done.Results: All lesions of MEC and PSSC showed membranous CD44 and nuclear SOX2expression. CD44 and SOX 2 expression were significantly higher in high-grade tumors than inlow-grade tumors. A strong positive correlation between CD44 and SOX2 expression was detected.Conclusion: Cancer stem cells can be identified in MEC and PSS C using CD44 and SOX 2markers and may participate in tumor aggressiveness. The present study also suggests that patientswith MEC and PSS C may benefit from therapies that comprise a combination of the two markers.

A novel critical role for CD46 in chromatin packaging and direct gene regulation

A novel critical role for CD46 in chromatin packaging and direct gene regulation

Abstract B57: Adhesion and beyond: CD44 in ovarian cancer spheroids

Abstract Epithelial ovarian carcinoma (EOC) metastasis is characterized by the shedding of malignant cells from the surface of the primary tumor and their implantation onto the peritoneal surface lining the abdominal cavity in addition to more distant sites. This shedding of malignant cells from the primary site results as either single cells or free-floating multicellular aggregates, known as spheroids, in the ascites. Although single cells and spheroids may potentially seed metastases, considerable evidence now suggests that the aggregation of cells is important for anchorage-independent cell survival and growth, and spheroid formation may represent an important intermediate survival mechanism to facilitate EOC dissemination. Recent studies have uncovered human transmembrane cell adhesion molecule CD44 standard (CD44s) isoform expression correlating with high-grade and advanced-stage ovarian carcinoma. Moreover, it has also been suggested that CD44s may be an important mediator of ovarian cancer cell implantation in the peritoneal cavity, enhancing the metastatic potential of ovarian cancer cells. Thus, we investigated the functional significance of CD44 standard by means of in vitro culture experiments with ovarian cancer spheroids. After characterizing 8 EOC cell lines, a spectrum of CD44 expression was observed and two cell lines with high CD44s (ES-2 and SKOV-3) and two cell lines low in CD44s (OVCAR-4 and OVSAHO) were chosen for further testing. Interestingly, the high CD44s-expressing cell lines formed larger spheroids that adhered significantly faster to a monolayer of primary mesothelial cells. Stable knockdown of CD44 using CRISPR/Cas9 in these 2 cell lines reduced spheroid formation, suggesting that differential expression of CD44 standard plays a role in cell-cell adhesion. When ES-2 CD44-/- cells were injected i.p. into athymic nude mice, decreased ascites production and mesentery tumor burden were observed as well as increased overall survival. However, CD44 knockdown also significantly increased metastasis to the lung, suggesting a suppressive role for CD44 in EOC metastasis as well. These in vivo data imply that CD44 enhances the metastatic potential in ovarian cancer spheroids influencing peritoneal tumor growth while suppressing metastasis to lung tissue. Citation Format: Joelle D. Sacks, Hilal Gurler Main, Goda G. Muralidhar, Osama Elfituri, Hao-Liang Xu, Andre A. Kajdacsy-Balla, Maria V. Barbolina. Adhesion and beyond: CD44 in ovarian cancer spheroids. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B57.

Tetraspanin CD82 affects migration, attachment and invasion of rheumatoid arthritis synovial fibroblasts

Tetraspanins function as membrane adaptors altering cell-cell fusion, antigen presentation, receptor-mediated signal transduction and cell motility via interaction with membrane proteins including other tetraspanins and adhesion molecules such as integrins....

Expression of adhesion molecules on granulocytes and monocytes following myocardial infarction in rats drinking white wine.

Neutrophils and monocytes through their CD15s, CD11b and CD44 adhesion molecules are implicated in the initiation and resolution of cardiac inflammation as well as in healing processes after the myocardial infarction (MI). The aim of this study was to determine the effect of white wine consumption on granulocyte and monocyte CD15s, CD11b, and CD44 expression 24h after the surgically inflicted MI. Granulocytes and monocytes were analyzed by flow cytometry, using whole blood of male Sprague–Dawley rats that consumed white wine for 4 weeks. This group was compared with water only drinking controls, sham animals (subject to surgery without myocardial infarction) and baseline group (intact animals that received no intervention prior to being sacrificed). Sham animals did not differ from baseline animals in CD11b+CD44+ percentage and CD44+ median fluorescence intensity. Wine drinking was associated with striking increase in CD44 expression on monocyte subpopulations. Its expression was three and fourfold increased on monocytes and large monocytes, respectively, relative to the water only drinking controls. Because of known role of CD44 on suppression of post-infarction inflammation, its upregulation on granulocytes and monocytes may significantly contribute to the microenvironment favourable for the cardiac regeneration.

Risk stratification of gastrointestinal stromal tumors by CtBP2 and CD44 analysis.

48 Background: C-terminal binding protein 2 (CtBP2) is an oncogenic transcription factor that promotes cancer stem cell (CSC) growth and self-renewal, and controls pathways for tumor initiation, progression, and response to therapy. Expression of CtBP2 is linked to aggressive behavior in ovarian cancer, while genetic or pharmacologic targeting of CtBP2 disrupts CSC growth and self-renewal. CD44 is a cell surface marker that has been linked to CSC populations in many solid tumors, though data is conflicting on its role as tumor suppressor or oncogene. Gastrointestinal stromal tumors (GIST) is an increasingly common malignancy where risk stratification is essential for guiding post-surgical adjuvant therapy. We hypothesized that CtBP2 and CD44 staining would enhance risk stratification of GIST which currently relies on purely non-molecular clinicopathologic criteria. Methods: We identified 149 GIST cases from 1990 to 2016 in the Virginia Commonwealth University Medical Center pathology archive. Clinical data for 121 patients was available. The Armed Forces Institute of Pathology (AFIP) criteria (Miettinen's criteria) was used to risk stratify GISTs using the size, site, and mitotic index of the primary tumor. Immunohistochemistry for CtBP2 and CD44 was then performed on GIST samples with adequate tumor (86, CD44; 87, CtBP2). Stains were scored 0 (negative) to 3 (maximum) by two independent pathologists. Statistical analysis (χ2) correlating AFIP risk category with CD44 and CtBP2 staining was performed using PRISM6. Results: Moderate and high risk GISTs, based on AFIP criteria, significantly correlated with high CtBP2 expression (score = 3, p = 0.046) and low CD44 expression (score = 0-2, p = 0.034). Conclusions: CD44 and CtBP2 staining can be used to risk stratify GIST, and may enhance and complement current clinical risk stratification systems. Our data also suggests a potential tumor suppressive role of CD44 in GIST. Additionally, based on our findings, investigation of therapeutics that target CtBP2 in GISTs should be pursued.

CD44 Predicts Early Recurrence in Pancreatic Cancer Patients Undergoing Radical Surgery.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of digestive cancer. Recurrence within one year after surgery is inevitable in most PDAC patients. Recently, cluster of differentiation 44 (CD44) has been shown to be associated with tumor initiation, metastasis and prognosis. This study aimed to explore the correlation of CD44 expression with clinicopathological factors and the role of CD44 in predicting early recurrence (ER) in PDAC patients after radical surgery. PDAC patients who underwent radical resection between January 1999 and March 2015 were enrolled in this study. Tumor recurrence within 6 months after surgery was defined as ER. Immunohistochemical staining was performed with anti-CD44 antibodies. The association between clinicopathological parameters and CD44 expression was analyzed. Predictors for ER were also assessed with univariate and multivariate analyses. Overall, 155 patients were included in this study. Univariate analysis revealed CA19-9 levels (p=0.014), CD44 histoscores (H-scores; p=0.002), differentiation (p=0.010), nodal status (p=0.005), stage (p=0.003), vascular invasion (p=0.007), lymphatic invasion (p<0.001) and perineural invasion (p=0.042) as risk factors for ER. In multivariate analysis, high CA19-9 levels and CD44 H-scores and poor differentiation independently predicted ER. High CA19-9 levels, CD44 H-scores and poor differentiation are independent predictors for ER in PDAC patients undergoing radical resection. Therefore, the determination of CD44 expression might help in identifying patients at a high risk of ER for more aggressive treatment after radical surgery.

Comparison of microvessel density using CD34 and CD105 in oral submucous fibrosis and its correlation with clinicopathological features: An immunohistochemical study.

To compare immunohistochemical expression of CD34 and CD105 in oral submucous fibrosis (OSF) and normal oral mucosa (NOM) and correlate with clinicopathological features of OSF. Total of thirty clinically diagnosed and histologically confirmed cases of OSF and 15 NOM were included in the study. Tissues sections were immunostained using CD34 and CD105 antibodies. Twenty-eight cases (93.33%) were positive for CD34, and only 12 cases (40%) were positive for CD105 in OSF. In NOM all cases were positive for CD34 and only one case was positive for CD105. CD34 and CD105 significantly expressed in moderately advanced OSF when compared to very early, early, and advanced cases. It was found that the microvessel density (MVD) in NOM was significantly higher as compared to OSF and MVD decreased with advanced OSF. MVD was higher in CD34 when compared to CD105. MVD decreased with disease progression in OSF using both the markers. The role of CD34 in determining the premalignant nature of OSF could not be ascertained, since all endothelial cells were positive for CD34, whereas CD105 appeared to be more specific as it is associated with hypoxia-induced angiogenesis which is occurring in OSF due to hyalinization suggesting, CD105 to be more specific marker to determine neoangiogenesis in OSF. Thus further follow-up study of the cases positive for CD105 is required to determine the true nature of angiogenesis in OSF patients.

Tetraspanin CD9 Limits Mucosal Healing in Experimental Colitis.

Tetraspanins are a family of proteins with four transmembrane domains that associate between themselves and cluster with other partner proteins, conforming a distinct class of membrane domains, the tetraspanin-enriched microdomains (TEMs). These TEMs constitute macromolecular signaling platforms that regulate key processes in several cellular settings controlling signaling thresholds and avidity of receptors. In this study, we investigated the role of CD9, a tetraspanin that regulates major biological processes such as cell migration and immunological responses, in two mouse models of colitis that have been used to study the pathogenesis of inflammatory bowel disease (IBD). Previous in vitro studies revealed an important role in the interaction of leukocytes with inflamed endothelium, but in vivo evidence of the involvement of CD9 in inflammatory diseases is scarce. Here, we studied the role of CD9 in the pathogenesis of colitis in vivo. Colitis was induced by administration of dextran sodium sulfate (DSS), a chemical colitogen that causes epithelial disruption and intestinal inflammation. CD9−/− mice showed less severe colitis than wild-type counterparts upon exposure to DSS (2% solution) and enhanced survival in response to a lethal DSS dose (4%). Decreased neutrophil and macrophage cell infiltration was observed in colonic tissue from CD9−/− animals, in accordance with their lower serum levels of TNF-α, IL-6, and other proinflammatory cytokines in the colon. The specific role of CD9 in IBD was further dissected by transfer of CD4+ CD45RBhi naive T cells into the Rag1−/− mouse colitis model. However, no significant differences were observed in these settings between both groups, ruling out a role for CD9 in IBD in the lymphoid compartment. Experiments with bone marrow chimeras revealed that CD9 in the non-hematopoietic compartment is involved in colon injury and limits the proliferation of epithelial cells. Our data indicate that CD9 in non-hematopoietic cells plays an important role in colitis by limiting epithelial cell proliferation. Future strategies to repress CD9 expression may be of therapeutic benefit in the treatment of IBD.