Objective o explore the effect and mechanisms of transmembrane 4 super family (TM4SF) in digestive system cancer. Methods Articles were reviewed to discuss the biological characteristics of TM4SF in digestive system cancer. Results TM4SF played an important role in migration and invasion of digestive system cancer, including pancreatic cancer, gastric cancer, colorectal cancer, hepatic cancer, esophageal cancer, and so on. TM4SF modulated the cell biological activities by microdomains which were fixed on cell membrane, such as adhesion, migration, invasion, and proliferation. Conclusion TM4SF may be used to predict the metastasis and prognosis of digestive system cancer and may be the targets of therapy of it in the future.
Abstract: Objective To observe the expression of integrinlinked kinase (ILK) and matrix metalloproteinases9 (MMP9) in human nonsmall cell lung cancer (NSCLC) and investigate the correlation of ILK and MMP9 expression with the prognosis of NSCLC. Methods The expression of ILK and MMP9 in 75 specimens of NSCLC resected from January 2002 to January 2004 were detected by immunohistochemistry. According to the median of integral optical density (IOD), all patients were divided into the high or low ILK expression group and the high or low MMP-9 expression group. The relativity of ILK and MMP9 was determined, and the relationship of survival time with clinical features including expression of ILK and MMP-9 was compared by Logrank test. Results Both ILK and MMP-9 were expressed in NSCLC specimens. The expression between ILK and MMP-9 was positively correlated in 75 patients of our group (r=0.79, Plt;0.05). Patients with lower expression of ILK and MMP9 had a significantly longer survival time than those with higher expression of ILK and MMP-9 in the postoperative followup (χ2=15.067,14301,Plt;0.05). The survival time was not correlated with sex,age,smoking history or pathological type(χ2=0450,0078, 1.460, 1.623，Pgt;0.05), while tumor diameter, lymph node metastasis, TNM stage, the expression of ILK and MMP-9 significantly influenced the survival time (χ2=3.963, 15.169,20.529, 15.067，14.301，Plt;0.05). Conclusion The expression of ILK and MMP9 affects the prognosis of NSCLC. MMP-9 may advance infiltration and metastasis of tumor cells through ILK pathway. In summary, the expression of ILK and MMP9 may play an important role in the evaluation of prognosis for patients with NSCLC.
Objective To observe whether Cyclo-RGDfK (Arg-Gly-Asp-D-Phe-Lys) could enhance the adhesion of myofibroblast to decellularized scaffolds and upregulate the expression of Integrin αVβ3 gene. Methods Myofibroblast from the rat thoracic aorta was acquired by primary cell culture. The expression of Vimentin and α-smooth muscle actin(α-SMA) has been detected by immunoflurescent labeling. Decellularized valves have been randomly divided into three groups (each n=7). Group A (blank control): valves do not receive any pretreatment; Group B: valves reacted with linking agent NEthylN(3dimethylaminopropyl)carbodiimide hydrochloride (EDC) for 36 hours before being seeded; Experimental group: Cyclo-RGD peptide has been covalently immobilized onto the surface of scaffolds by linking agent EDC. The fifth generation of myofibroblast has been planted on the scaffolds of each group. The adhesion of myofibroblast to the scaffolds was evaluated by HE staining and electron scanning microscope. The expression of Integrin αVβ3 was quantified by halfquantitative reverse transcriptionpolymerase china reaction (RT-PCR). Results We can see that myofibroblast has exhibited b positive staining for Vimentin and α-SMA. Besides, it has been shown that the expression of Integrin αVβ3 was much higher in the experimental group than that of the group A and group B(Plt;0.05). There was no statistically difference in group A and group B (P=0.900). Conclusion RGD pretreatment does enhance the adhesive efficiency of seeding cells to the scaffolds and this effect may be related to the upregulation of Integrin αVβ3.
ObjectiveTo investigate the relationships between the expression of integrin β1 and activated cells in a partial-thickness articular cartilage injury model of adult rats. MethodForty-five male Sprague Dawley rats (aged 10 weeks and weighing 300-400 g) were randomly divided into operated group (n=15) , sham-operated group (n=15) , and control group (n=15) . Partial-thickness articular cartilage injury model was made by scarification in operated group, direct suture after opening of the knee joint was performed in sham-operated group, and no operation was done in control group. Five rats were sacrificed at 1, 7, and 14 days after operation respectively for macroscopic evaluation, HE staining, Safranin O staining, CD105, BrdU, CD105/integrin β1 immunofluorescence and double labeling staining. The histological score of HE staining, gray value of Safranin O staining and CD105-positive cells count were compared among groups at each time point. ResultsMacroscopic evaluation showed chondromalacia and cartilage fibrosis around the linear injury with aggravating tendency with time in operated group, but no chondromalacia and cartilage fibrosis in sham-operated and control groups. HE staining demonstrated a number of activated cells accumulating around the linear injury with nonuniform distribution in operated group, and uniform size and distribution in sham-operated and control groups. The histological scores at each time point in operated group were significantly higher than those in sham-operated group and control group (P<0.05) , but no significant difference was found between different time points in 3 groups (P>0.05) . Safranin O staining was nonuniform with hypochromasia around linear injury in operated group, but the staining was uniform in sham-operated group and control group. Gray value of Safranin O staining had no significant difference among groups and among different time points in the same group (P>0.05) . BrdU-positive and CD105-positive cells distributed unevenly around the linear injury in operated group, uniform distribution was observed in sham-operated group and control group. CD105-positive cells count in operated group was significantly higher than those in sham-operated group and control group at each time point (P<0.05) ; CD105-positive cells increased significantly with time in operated group (P<0.05) . CD105/integrinβ1-positive cells were observed around the linear injury in operated group, but was not observed in sham-operated group and control group. ConclusionsThe partial-thickness articular cartilage injury model is successfully established in rats, and cartilage injury could not be repaired completely in the model. The activated cells aggregation around the linear injury can be observed, but there is no obvious relationships between activated cells and cartilage matrix. These activated cells are in proliferation and could express both CD105 and integrin β1.
【Abstract】Objective To observe the changeable expressions of vascular endothelial growth factor (VEGF) and integrin β3 during the angiogenetic process of granulation tissue. Methods mRNA and protein of VEGF and integrin β3 in human normal subcutaneous tissue, proliferative granulation tissue and mature granulation tissue were observed by RT-PCR and immunohistochemistry staining. Results The expressions VEGF and integrin β3 were low in normal subcutaneous tissue and were much higher in proliferative granulation tissue. When the granulation tissue was mature, the expression was decreased again. Conclusion VEGF and integrin β3 are important regulating factors in ngiogenesis.
OBJECTIVE: To study the expression of type I collagen and its receptor system-integrin alpha 2 beta 1 in different passages of osteoblasts. METHODS: The expression of type I collagen and integrin alpha 2 beta 1 in the primary, sixth and fifteenth passage of osteoblasts were detected by S-P immunohistological staining technique, and their mRNA expression by quantity RT-PCR technique. RESULTS: Type I collagen and integrin alpha 2 beta 1 were expressed in different passages of osteoblasts and there was no significant difference among three passages by immunohistological technique. Their mRNA expression was gradually decreased with subculture. CONCLUSION: Type I collagen promotes the adhesion and phenotype expression of osteoblasts through its receptor-integrin alpha 2 beta 1. The reductive expression of type I collagen-receptor system will decline the phenotype of osteoblasts.
Objective To observe the expression of integrin αVβ3 in vascular endothelium cultured in vitro at different time points under different level of shear stress. Methods（1）We established a vascular culture system in vitro which could provide steady flow with different level of shear stress, and tested the flow stability when loading different level of shear stress. （2） A total of 50 rabbits were randomly divided into low shear stress group （5 dyn/cm2, n=25）and normal shear stress group（20 dyn/cm2, n=25）. Rabbits in each group were further randomly divided into five different time points as 2 h, 4 h, 8 h, 16 h and 24 h（n=5 at each time point）. The descending aorta of rabbits were harvested and cultured in the vascular culture system in vitro under different level of shear stress. The expression sites and intensity of αVβ3-Integrin in vascular endothelium were examined at 5 different time points in both groups by immunohistochemical staining. Results The vascular culture system in vitro was stable in providing laminar flow with different level of shear stress required for the experiment. Vascular endothelium expressions of αVβ3-Integrin in the low shear stress group were in high level at all the 5 time points and reached its summit at 16 h, when the mean optical density（MOD）value was （1.995±0.194）×10-2. In the normal shear stress group, the MOD value decreased time-dependently at the 5 time points. The MOD values at 2 h （0.059±0.005）×10-2 and 4 h（0. 049±0.002）×10-2 were significantly higher than those at other time points （P＜ 0.05）. The αVβ3-Integrin MOD values of the low shear stress group were significantly higher than those of the normal shear stress group at all the 5 respective time points （P=0.000）. Conclusion Low shear stress can significantly promote the expression of αVβ3-Integrin while normal shear stress decreases the expression of αVβ3-Integrin in vascular endothelium cultured in vitro.
ObjectiveTo investigate the value of integrin αvβ3 targeted microPET/CT imaging with 68Ga-NODAGA-RGD2 as radiotracer for the detection of osteosarcoma and theranostics of osteosarcoma lung metastasis.MethodsThe 68Ga-NODAGA-RGD2 and 177Lu-NODAGA-RGD2 were prepared via one-step method and their stability and integrin αvβ3 binding specificity were investigated in vitro. Forty-one nude mice were injected with human MG63 osteosarcoma to established the animal model bearing subcutaneous osteosarcoma (n=21), osteosarcoma in tibia (n=5), and osteosarcoma pulmonary metastatic (n=15). The microPET-CT imaging was carried out in 3 animal models at 1 hour after tail vein injection of 68Ga-NODAGA-RGD2. Biodistribution study of 68Ga-NODAGA-RGD2 was performed in animal model bearing subcutaneous osteosarcoma at 10, 60, and 120 minutes. The animal model bearing pulmonary metastatic osteosarcoma was injected with 177Lu-NODAGA-RGD2 at 7 weeks after model establishment to observe the therapeutic effect of pulmonary metastatic osteosarcoma. Histological and immunohistochemistry examinations were also done to confirm the establishment of animal model and integrin β3 expression in animal models bearing subcutaneous osteosarcoma and bearing pulmonary metastatic osteosarcoma.Results68Ga-NODAGA-RGD2 and 177Lu-NODAGA-RGD2 had good stability in vitro with the 50% inhibitory concentration value of (5.0±1.1) and (6.5±0.8) nmol/L, respectively. The radiochemical purity of 68Ga-NODAGA-RGD2 at 1, 4, and 8 hours was 98.5%±0.3%, 98.3%±0.5%, and 97.9%±0.4%; while the radiochemical purity of 177Lu-NODAGA-RGD2 at 1, 7, and 14 days was 99.3%±0.7%, 98.7%±1.2%, and 96.0%±2.8%. 68Ga-NODAGA-RGD2 microPET-CT showed that the accumulation of 68Ga-NODAGA-RGD2 in animal models bearing subcutaneous osteosarcoma and osteosarcoma in tibia and in lung metastasis as small as 1-2 mm in diameter of animal model bearing pulmonary metastatic osteosarcoma. Biodistribution study of 68Ga-NODAGA-RGD2 in animal model bearing subcutaneous osteosarcoma revealed rapid clearance from blood with tumor peak uptake of (3.85±0.84) %ID/g at 120 minutes. The distribution of 177Lu-NODAGA-RGD2 in lung metastasis was similar with 68Ga-NODAGA-RGD2. The number and size of osteosarcoma metastasis decreased at 2 weeks after 177Lu-NODAGA-RGD2 administration and integrin targeting specificity was confirmed by pathology examination.Conclusion68Ga-NODAGA-RGD2 was potential for positive imaging and early detection of osteosarcoma and metastasis. Targeted radiotherapy with 177Lu-NODAGA-RGD2 was one potential alternative for osteosarcoma lung metastasis.
Objective To evaluate the role for integrins in tumor angiogenesis. MethodsLiteratures in recent years were reviewed. ResultsIntegrins played an important role in tumor angiogenesis and integrins had a close relation to vascular growth factors. Conclusion Inhibitors of integrins will be a promising way to cure tumors.
Integrins is a family of multi-functional cell-adhesion molecules, heterodimeric receptors that connect extracellular matrix to actin cytoskeleton in the cell cortex, thus regulating various physiological and pathological processes. Risuteganib (Luminate®) is a novel broad-spectrum integrin inhibitor. Based on multiple biological functions of anti-angiogenesis, vitreolysis, and neuroprotection, risuteganib is hopeful in treating several fundus diseases such as diabetic macular edema, vitreomacular traction, and non-exudative age-related macular degeneration. By far, risuteganib has successfully met the endpoints for three phase 2 studies and is preparing to enter the phase 3 of diabetic macular edema clinical trials. Overall the risuteganib is safe with no serious ocular or systemic adverse events. Given the unique mechanism of action and longer duration of efficacy, intravitreal injection of risuteganib has the potential to serve as a primary therapy, or adjunctive therapy to anti-VEGF agents.