Lung cancer is a highly vascular tumors, over the past ten years, anti-angiogenes is has been proved to be an effective and highly promising combinational treatment. The data of the combination of anti-angiogenesis with chemotherapy, targeted therapy, immunotherapy has been constantly updating. Advanced lung cancer patients, no matter different groups or different stages of the disease, are benefited from anti-angiogenes. In this paper, based on the clinical status and unsolved problems, combined with the latest clinical and translational research data, we reviewed the current anti-angiogenesis treatment of lung cancer.
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Angiogenesis Inhibitors/therapeutic use* ; Humans ; Immunotherapy ; Lung Neoplasms/pathology* ; Molecular Targeted Therapy ; Neovascularization, Pathologic/drug therapy*

High-mobility group box 1 (HMGB1) is a non-histone nuclear protein in most eukaryocytes. Inside the nucleus, HMGB1 plays an important role in several DNA events such as DNA repair, transcription, telomere maintenance, and genome stability. While outside the nucleus, it fulfils more complicated functions, including promoting cell proliferation, inflammation, angiogenesis, immune tolerance and immune escape, which may play a pro-tumoral role.Meanwhile, HMGB1 acts as an anti-tumoral protein by regulating immune cell recruitment and inducing immunogenic cell death (ICD) during the carcinogenesis process. Therefore, abnormal expression of HMGB1 is associated with oncogenesis, development, and metastasis of cancer, which may play a dual role of pro-tumor and anti-tumor.
Carcinogenesis ; Cell Proliferation ; HMGB1 Protein/metabolism* ; Humans ; Neoplasms/pathology* ; Neovascularization, Pathologic

OBJECTIVE: To explore the effect of lenalidomide on human fibroblast-like synovial cells (HFLS) and the therapeutic efficacy on hemophilic arthropathy in hemophilia A mice model. METHODS: In vitro, to remodel the inflammatory environment of synovial tissue after hemorrhage, ferric citrate and recombinant TNF-α were added into the cell culture medium of HFLS. Cell Counting Kit-8 (CCK-8), Enzyme-linked immunosorbent assay (ELISA), Quantitative Real-time PCR (RT-qPCR) and flow cytometry were employed for detection of the effects of lenalidomide on the proliferation ability, pro-inflammatory cytokines release and apoptosis of HFLS cells. In vivo, hemophilia arthropathy was remodeled in hemophilia A mice by induction of hemarthrosis. A series of doses of lenalidomide (0.1, 0.3 and 1.0 g/kg) was administrated intra-articularly. Tissues of knee joints were collected on the 14th day after administration, and the protective effect of lenalidomide on arthritis in hemophilia A mice were evaluated by RT-qPCR and histological grading. RESULTS: In vitro, compared with the untreated control group, lenalidomide could significantly inhibit the proliferation of HFLS cells (P<0.05), and the effect was the most significant when the concentration was 0.01 μmol/L (P<0.001). Compared with the control group, lenalidomide could significantly inhibit the expression levels of TNF-α, IL-1β, IL-6 and IFN-γ in HFLS cells (P<0.05). The flow cytometry results showed that lenalidomide could enhance the apoptotis of HFLS cells (P<0.05). The results of RT-qPCR showed that lenalidomide could significantly reduce the mRNA expression levels of TNF-α, IL-1β, IL-6,MCP-1 and VEGF in the joint tissues (P<0.05). Histological results showed that compared with the injured group, lenalidomide could significantly reduce the pathological sequela after hemarthrosis induction, e.g. synovial thickening and neo-angiogenesis in the synovium. The protection displayed a dose-response pattern roughly. CONCLUSION In vitro, lenalidomide can inhibit the proliferation of HFLS cells, promote their apoptosis, and inhibit the expression of pro-inflammatory cytokines. In vivo, lenalidomide can significantly decrease the expression of pro-inflammatory cytokines in the joints of mice, and prevent the development of inflammation and neo-angiogenesis. The results provide a theoretical and experimental basis for the clinical application of lenalidomide in the treatment of hemophilic arthropathy.
Animals ; Arthritis ; Cytokines/metabolism* ; Hemarthrosis/pathology* ; Hemophilia A/genetics* ; Humans ; Interleukin-6 ; Lenalidomide ; Mice ; Neovascularization, Pathologic ; RNA, Messenger ; Sincalide ; Tumor Necrosis Factor-alpha ; Vascular Endothelial Growth Factor A

Breast cancer is the most common cancer in the world, and 5-year survival rate of metastatic breast cancer is about 20%. The treatment of metastatic breast cancer is mainly chemotherapy, endocrine therapy and targeted therapy. However, after multiline treatment, patients with MBC especially the triple negative breast cancer face the problem of drug resistance. Tumor angiogenesis theory suggests that blocking angiogenesis can inhibit tumor growth and migration. Based on this, angiogenesis treatment strategy is proposed. Antiangiogenic drugs mainly include biological macromolecular drugs targeting vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) and small molecule VEGFR inhibitors. Angiogenesis is known to play a key role in the growth and metastasis of breast cancer. Therefore, anti-angiogenetic therapy has potential in metastatic breast cancer patients. Since the approval of tumor drug indications by NPMA in China is often later than the release of the latest research data, the National Health Commission issued "the guiding principles for the clinical application of new antitumor drugs" in 2020. The principle pointed out that under special circumstances such as the absence of better treatment, medical institutions should manage the usage of drugs that are not clearly defined in the instructions but have evidence-based data. Based on the latest research progress in breast cancer, the consensus writing expert group collated published reports, international academic conferences, conducted analysis, discussion and summary, collected data on the use of small molecule anti-vascular targeting drugs for advanced breast cancer, and formulated "expert consensus on the application of small molecule anti-angiogenic drugs in the treatment of advanced breast cancer" . For clinicians' reference only.
Angiogenesis Inhibitors/therapeutic use* ; Breast Neoplasms/pathology* ; Consensus ; Female ; Humans ; Neovascularization, Pathologic/pathology* ; Off-Label Use ; Vascular Endothelial Growth Factor A/metabolism*

OBJECTIVE: To isolate tumor stem-like cells from human epithelial ovarian cancer SKOV3 cells and explore their role in the formation of vascularization mimicry (VM). METHODS: SKOV3 cells were passaged to the 7th generation by suspension culture in serum-free medium, and the percentages of CD133- and CD117-positive cells in the 1st, 3rd, 5th and 7th generations were analyzed using flow cytometry. The proliferative activity of the cells sorted from the 7th generation SKOV3 cells was assessed with colony formation assay. A three-dimensional cell culture model was established to compare the ability of VM formation between the sorted cells and the parental SKOV3 cells. The expression levels of matrix metalloproteinases-2 (MMP-2) and MMP-9 in the two groups were detected using real-time PCR and Western blotting. RESULTS: Some SKOV3 cells formed typical cell spheres with suspension growth in serum-free medium and were passaged to the 7th generation. Flow cytometry revealed that the percentage of CD133-positive cells increased with cell passaging. The cloning efficiency of the sorted cells was significantly higher than that of the parental SKOV3 cells (50.33% 5.33%, < 0.001). The VM formation ability of the sorted cells was stronger than that of the parental SKOV3 cells in the three-dimensional cell culture system. RT-PCR and Western blotting showed that the expression levels of MMP-2 and MMP-9 were significantly higher in the 7th passage cells than in the parental cells ( < 0.05). CONCLUSIONS The sorted cells from SKOV3 cells cultured in serum-free medium exhibit biological properties of tumor stem cells with strong VM formation ability, suggesting their role in VM formation.
Carcinoma, Ovarian Epithelial ; pathology ; Cell Line, Tumor ; Cell Movement ; Female ; Humans ; Matrix Metalloproteinase 2 ; metabolism ; Matrix Metalloproteinase 9 ; metabolism ; Neoplastic Stem Cells ; cytology ; Neovascularization, Pathologic ; pathology ; Ovarian Neoplasms ; pathology

Integrin is a large family of cell adhesion molecules (CAMs) which involves in the interaction of cells/cells and cells/ extracellular matrix (ECM) to mediate cell proliferation, differentiation, adhesion, migration, etc. In recent years, aberrant expression of integrin has been clearly found in many tumor studies, indicating that integrin is closely related to tumor formation and development. Meanwhile, it has effects on tumor cell differentiation, cell migration, proliferation and tumor neovascularization. The study of drugs targeting integrins is of great significance for the clinical treatment of tumors. Because of its important role in tumorigenesis and development, integrin has become a promising target for the treatment of cancer. This review summarizes the role of integrin in tumor development and the current state of integrin inhibitors to provide a valuable reference for subsequent research.
Antineoplastic Agents ; pharmacology ; therapeutic use ; Biological Products ; pharmacology ; therapeutic use ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Extracellular Matrix ; metabolism ; Humans ; Integrins ; antagonists & inhibitors ; classification ; genetics ; metabolism ; Neoplasms ; drug therapy ; pathology ; Neovascularization, Pathologic ; drug therapy ; pathology ; Signal Transduction ; drug effects

Prostate cancer is a complex, heterogeneous disease that mainly affects the older male population with a high-mortality rate. The mechanisms underlying prostate cancer progression are still incompletely understood. Beta-adrenergic signaling has been shown to regulate multiple cellular processes as a mediator of chronic stress. Recently, beta-adrenergic signaling has been reported to affect the development of aggressive prostate cancer by regulating neuroendocrine differentiation, angiogenesis, and metastasis. Here, we briefly summarize and discuss recent advances in these areas and their implications in prostate cancer therapeutics. We aim to provide a better understanding of the contribution of beta-adrenergic signaling to the progression of aggressive prostate cancer.
Cell Differentiation/genetics* ; Disease Progression ; Humans ; Male ; Neoplasm Metastasis ; Neovascularization, Pathologic/pathology* ; Neuroendocrine Cells/pathology* ; Prostatic Neoplasms/pathology* ; Receptors, Adrenergic, beta ; Signal Transduction

Angiogenesis Inhibitors ; pharmacology ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; blood supply ; pathology ; Humans ; Lung Neoplasms ; blood supply ; pathology ; Neovascularization, Pathologic ; drug therapy ; therapy ; Societies, Medical

The aim of this paper was to observe the effect of gambogenic acid on angiogenesis of lung cancer and its preliminary mechanism. After culturing lung adenocarcinoma A549 cells, the conditioned medium was treated with gambogenic acid and then used to culture human umbilical vein endothelial cells (HUVECs) to establish the indirect contact cell co-culture system. A two-dimensional culture model of HUVEC was established with matrigel to observe the effect of gambogenic acid on angiogenesis. DAPI staining was used to observe the morphological changes in HUVEC cells after treatment with gambogenic acid under the fluorescence microscope. Annexin V-FITC/PI staining and flow cytometry analysis were used to determine gambogenic acid's effect on HUVEC cell apoptosis rate. The protein expressions of PI3K, p-PI3K, Akt, p-Akt were measured by Western blot. PTEN-siRNA was transfected into cells, and RT-PCR was used to detect the expression levels of PI3K and Akt genes. Gambogenic acid can significantly inhibit angiogenesis, and its inhibitory effect was dose-dependent. DAPI staining showed apoptotic morphological features of HUVEC cells under fluorescence microscope. Annexin V-FITC/PI staining showed that gambogenic acid induced apoptosis in HUVECs. The results of Western blot showed that the expressions of p-PI3K and p-Akt protein were down-regulated with gambogenic acid, while the expressions of PI3K and Akt protein was insignificant. The results of RT-PCR indicated that the expressions of PI3K and Akt protein were up-regulated by PTEN siRNA. Gambogenic acid can inhibit angiogenesis in lung cancer in vitro, and the mechanism of inhibiting angiogenesis may be related to the PI3K/Akt signaling pathway.
A549 Cells ; Apoptosis ; Coculture Techniques ; Human Umbilical Vein Endothelial Cells ; drug effects ; Humans ; Lung Neoplasms ; drug therapy ; pathology ; Neovascularization, Pathologic ; pathology ; PTEN Phosphohydrolase ; genetics ; Phosphatidylinositol 3-Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Transfection ; Xanthenes ; pharmacology

BACKGROUNDThe autologous saphenous vein is the most common conduit for coronary artery bypass grafting, but the vein graft disease will occur. This study used Matrigel basement membrane matrix with many different growth factors to promote vasa vasorum neovascularization and extenuate the hypoxia to improve remodeling.

METHODSThis study observed the hypoxia and thickness of the vein grafts at different times. Normal veins and vein grafts with 15 min of ischemia one day postoperatively were harvested in the neck of rabbits. Paired vein grafts with 15 min ischemia bilaterally (control vs. Matrigel basement membrane matrix) were performed and harvested at 2, 6, and 12 weeks postoperatively. The rabbits were randomly divided into four postoperative groups (six rabbits in each group): Group 1, one day postoperatively; Group 2, 2 weeks postoperatively; Group 3, 6 weeks postoperatively; and Group 4, 12 weeks postoperatively. The dimensions of vessel wall were captured, and the mean thicknesses of intima, media, and adventitia were measured. The hypoxia-inducible factor (HIF)-1α and HIF-2α labeling indices of intima, media, and adventitia were also measured.

RESULTSIn Group 1, the labeling index of HIF-1α was high in the normal vein and decreased significantly in the vein graft one day postoperatively (intima: 80 ± 3% vs. 12 ± 1%, P = 0.01; media: 67 ± 5% vs. 11 ± 1%, P = 0.01; adventitia: 40 ± 10% vs. 7 ± 2%, P = 0.03). The labeling index of HIF-2α had similar trend as HIF-1α (intima: 80 ± 10% vs. 10 ± 5%, P = 0.02; media: 60 ± 14% vs. 12 ± 2%, P = 0.01; adventitia: 45 ± 20% vs. 10 ± 4%, P = 0.03). Compared with the control vein grafts, vein grafts with Matrigel basement membrane matrix had lower labeling indices of HIF-1α and HIF-2α in media and adventitia at Group 2 (HIF-1α: 34 ± 5% vs. 20 ± 4%, P = 0.04 for media; 23 ± 3% vs. 11 ± 2%, P = 0.03 for adventitia; HIF-2α: 37 ± 6% vs. 21 ± 4%, P = 0.03 for media; 24 ± 4% vs. 13 ± 2%, P = 0.04 for adventitia) and Group 3 (HIF-1α: 33 ± 4% vs. 7 ± 2%, P = 0.04 for media; 13 ± 3% vs. 3 ± 1%, P = 0.02 for adventitia; HIF-2α: 27 ± 4% vs. 12 ± 3%, P = 0.02 for media; 19 ± 2% vs. 6 ± 1%, P = 0.02 for adventitia). There were no differences in mean thickness of intima, media, and adventitia between bilateral vein grafts at 2, 6, and 12 weeks postoperatively.

CONCLUSIONSThis study indicated that promoting vasa vasorum neovascularization of vein grafts extenuated hypoxia, but did not influence the intimal hyperplasia of the wall.

Animals ; Basic Helix-Loop-Helix Transcription Factors ; metabolism ; Hyperplasia ; pathology ; Hypoxia-Inducible Factor 1 ; metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Neovascularization, Pathologic ; pathology ; Postoperative Period ; Rabbits ; Saphenous Vein ; pathology ; Tunica Intima ; pathology ; Vasa Vasorum ; pathology