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Regulation of tumor vessels has become one of the most common strategies for clinical anti-tumor therapy. In recent years, studies have found that the anti-tumor effect of limotherapy, which routinely inhibits tumor angiogenesis, is not ideal and may even deteriorate the tumor microenvironment, causing tumor resistance and distal metastasis and increasing the risk of tumor metastasis and recurrence. However, the proper use of anti-angiogenic drugs can promote the normalization of tumor vessels, improve the structure and function of tumor vessels, increase the number of functional vessels in the tumor, and reduce the number of ineffective vessels. It is beneficial to promote the penetration of anti-tumor drugs into the tumor, improve the microenvironment of tumor hypoxia and immunosuppression, and enhance the anti-tumor effect. Traditional Chinese medicine(TCM) has a long history of understanding the etiology and pathogenesis of tumors and has accumulated rich experience in tumor treatment, with significant clinical advantages and broad application prospects. In this study, from the perspective of bidirectional "soothing" or "blockage" regulation of tumor vessels, the commonly used molecular targets were sorted out, and the research status of anti-tumor regulation of tumor vessels by monomer-single herb-compound(herb pair) of TCM in recent years was summarized. The research on the anti-tumor effects of TCM compounds and active ingredients by regulating tumor vessels combined with other therapies was analyzed and sorted out, so as to provide ideas for the clinical application of TCM in regulating functions and anti-tumor effects of tumor vessels.
Subject(s)
Humans , Medicine, Chinese Traditional , Drugs, Chinese Herbal/therapeutic use , Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Tumor MicroenvironmentABSTRACT
@#The main treatment of head and neck cancer is comprehensive sequential treatment, but the 5-year overall survival rate is less than 50%. Strategies to further improve the curative effect of head and neck cancer are urgently needed in the clinic. Recombinant human vascular endostatin is an antiangiogenesis drug targeting vascular endothelial cells, which has a certain inhibitory effect on tumors. The treatment of malignant tumors by drugs alone is not significantly better than chemoradiation, but combined with radiotherapy and chemotherapy, it can increase the effect of radiotherapy and chemotherapy without drug resistance by changing the distribution of blood vessels, reducing oxygen and normalizing blood vessels. Head and neck tumor treatment has certain advantages. New tumor treatments are expected. The results of a literature review showed that the mechanism of action of recombinant human endostatin mainly includes regulating the matrix protein inside and outside the endothelial cells to influence neovascularization, acting on receptors related to the surface of endothelial cells, reversing abnormal neovascularization to achieve vascular normalization, inhibiting hypoxia inducible factor to improve the hypoxic status of the tumor area, and regulating the cell cycle to ensure the tumor cells are sensitive to radiation in the sensitive period, and vascular normalization can increase the effect of radiotherapy. This treatment has a good synergistic effect with radiotherapy and chemotherapy of head and neck tumors and has a good effect on advanced head and neck tumors.
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Tumor vasculature is characterized by aberrant structure and function, resulting in immune suppressive profiles of tumor microenvironment through limiting immune cell infiltration into tumors, endogenous immune surveillance and immune cell function. Vascular normalization as a novel therapeutic strategy tends to prune some of the immature blood vessels and fortify the structure and function of the remaining vessels, thus improving immune stimulation and the efficacy of immunotherapy. Interestingly, the presence of "immune‒vascular crosstalk" enables the formation of a positive feedback loop between vascular normalization and immune reprogramming, providing the possibility to develop new cancer therapeutic strategies. The applications of nanomedicine in vascular-targeting therapy in cancer have gained increasing attention due to its specific physical and chemical properties. Here, we reviewed the recent advances of effective routes, especially nanomedicine, for normalizing tumor vasculature. We also summarized the development of enhancing nanoparticle-based anticancer drug delivery
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Objective@#To evaluate the feasibility of intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DWI MRI) in the evaluation of tumor vascular normalization in a mouse model of colorectal cancer induced by recombinant human endostatin (rhES).@*Methods@#The CT26 colorectal cancer xenograft model of BALB/c mice were established and divided into rhES group and control group, with 20 mice in each group. The mice of rhES group were intravenously injected with rhES 5 mg·kg-1·d-1 once daily for 12 days, while the mice of the control group were intravenously injected with the same volume of 0.9% saline. 5 mice of rhES group and control group were randomly selected to perform IVIM-DWI MRI as following times: before treatment and four, eight, twelve days after treatment. The parameters of IVIM-DWI were recorded, including true diffusion coefficient(D), pseudo-diffusion coefficient (D*) and perfusion fraction (f). Meanwhile, microvessel density (MVD), pericyte coverage and tumor perfusion in tumor tissues were detected by immunofluorescence, respectively.@*Results@#The tumor volumes of control group and rhES group before treatment were (154.42±24.65) mm3 and (174.24±28.27)mm3, respectively, without statistically significant difference (P=0.440). From day 2 to day 12 after treatment, the tumor volume of rhES group was significantly smaller than that of control group (all P<0.05). There were no statistical significances of D value between the rhES group and control group before and after treatment (all P>0.05). The D* values of the rhES group were (10.940±2.834)×10-3mm2/s and (12.940±2.801)×10-3mm2/s in day 4 and 8 after treatment respectively, significantly higher than (6.980±1.554)×10-3mm2/s and (7.898±1.603)×10-3mm2/s of control group (P<0.05). Moreover, compared with control group, the D* value of rhES group was significantly lower in day 12 (6.848±1.460)×10-3mm2/s vs (9.950±2.596)×10-3mm2/s, (P<0.05). The f value of rhES group in day 8 was (0.226±0.021)%, significantly higher than (0.178±0.016)% of control group (P<0.01). The MVD of rhES group was significantly lower than that of control group (P<0.05), while the pericyte coverage and tumor perfusion of rhES group were significantly higher than those of control group in day 4 and 8 after treatment (all P<0.05). In addition, we found D* value of IVIM-DWI in rhES group was significantly related with MVD, pericyte coverage and tumor perfusion (r=-0.354, r=0.555, r=0.559, all P<0.05). Meanwhile, the f value in rhES group was also significantly related with MVD, pericyte coverage and tumor perfusion (r=-0.391, r=0.538, r=0.315, all P<0.05).@*Conclusions@#IVIM-DWI MRI can effectively evaluate the vascular normalization in rhES-induced CT26 colorectal tumor.The parameters D* and f are closely related to intratumorally microvessel density, pericyte coverage and perfusion, which can effectively monitor the occurrence of tumor vascular normalization time.
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AIM:To explore whether there is synergistic effect of recombinant human endostatin ( rh-Endo ) and paclitaxel (Pac) in the time window of vascular normalization and the role of magnetic resonance imaging (MRI) in early assessment of chemotherapy by observing the response of human triple -negative breast cancer ( TNBC) to Pac after vascular normalization in nude mice .METHODS:The human TNBC MDA-MB-231 cells were planted in the subcutaneous region of right lower abdomen of BALB/c-nu female nude mice .These nude mice were randomly divided into 4 groups (n=7).rh-Endo was given for 17 consecutive days in rh-Endo group and rh-Endo+Pac group.Pac was given on the 6th and 12th days in Pac group and rh-Endo+Pac group.The dosage of both drugs was 10 mg· kg-1· d-1(ip).On the day before the treatment and the 5th, 11th and 17th days after treatment, all the transplanted tumors were examined by MRI . All the mice were killed by cervical dislocation and their transplanted tumors were taken down for examinations after the last MRI on the 17th day.The changes of pathology, immunohistochemisty, microvessel density (MVD) and Ki67 expression were measured.RESULTS:On the 17th day, the volume of transplanted tumor in rh-Endo+Pac group was smaller than that in model group and rh-Endo group ( P<0.05 ) , and no difference between rh-Endo+Pac group and Pac group was found.On the 17th day, the tumor inhibitory rates in rh-Endo group, Pac group and rh-Endo+Pac group were 14.61%, 39.08%and 54.79%, respectively.The slow diffusion coefficient in Pac group was increased compared with model group , while it was decreased compared with rh-Endo+Pac group (P<0.05).No distant metastatic lesion in the tumor-bearing mice was observed .The necrotic rates in rh-Endo+Pac group and Pac group were higher than those in model group and rh-Endo group.The MVD in model group was higher than that in the other 3 groups.The MVD in rh-Endo+Pac group was decreased compared with Pac group and rh-Endo group .The Ki67 level in rh-Endo+Pac group was decreased compared with rh-Endo group , and no difference between rh-Endo+Pac group and Pac group was detected .CONCLUSION:In the time window of vascular normalization , the combination of Pac and rh-Endo has a significant antitumor effect on TNBC , but this study did not observe a significant synergistic effect of the 2 drugs.The change of slow diffusion coefficient can predict the therapeutic effect in advance .
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AIM:To explore whether there is synergistic effect of recombinant human endostatin ( rh-Endo ) and paclitaxel (Pac) in the time window of vascular normalization and the role of magnetic resonance imaging (MRI) in early assessment of chemotherapy by observing the response of human triple -negative breast cancer ( TNBC) to Pac after vascular normalization in nude mice .METHODS:The human TNBC MDA-MB-231 cells were planted in the subcutaneous region of right lower abdomen of BALB/c-nu female nude mice .These nude mice were randomly divided into 4 groups (n=7).rh-Endo was given for 17 consecutive days in rh-Endo group and rh-Endo+Pac group.Pac was given on the 6th and 12th days in Pac group and rh-Endo+Pac group.The dosage of both drugs was 10 mg· kg-1· d-1(ip).On the day before the treatment and the 5th, 11th and 17th days after treatment, all the transplanted tumors were examined by MRI . All the mice were killed by cervical dislocation and their transplanted tumors were taken down for examinations after the last MRI on the 17th day.The changes of pathology, immunohistochemisty, microvessel density (MVD) and Ki67 expression were measured.RESULTS:On the 17th day, the volume of transplanted tumor in rh-Endo+Pac group was smaller than that in model group and rh-Endo group ( P<0.05 ) , and no difference between rh-Endo+Pac group and Pac group was found.On the 17th day, the tumor inhibitory rates in rh-Endo group, Pac group and rh-Endo+Pac group were 14.61%, 39.08%and 54.79%, respectively.The slow diffusion coefficient in Pac group was increased compared with model group , while it was decreased compared with rh-Endo+Pac group (P<0.05).No distant metastatic lesion in the tumor-bearing mice was observed .The necrotic rates in rh-Endo+Pac group and Pac group were higher than those in model group and rh-Endo group.The MVD in model group was higher than that in the other 3 groups.The MVD in rh-Endo+Pac group was decreased compared with Pac group and rh-Endo group .The Ki67 level in rh-Endo+Pac group was decreased compared with rh-Endo group , and no difference between rh-Endo+Pac group and Pac group was detected .CONCLUSION:In the time window of vascular normalization , the combination of Pac and rh-Endo has a significant antitumor effect on TNBC , but this study did not observe a significant synergistic effect of the 2 drugs.The change of slow diffusion coefficient can predict the therapeutic effect in advance .
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Angiogenesis inhibitors can make tumor cells in a harsh environment by inhibiting tumor angiogenesis and effectively blocking the tumor progression.However,anti-angiogenic drugs have shown lots of limitations,such as short-term duration,numerous adverse reactions,benefiting only a minority of tumor types and so on.These limitations restrain the development of new drugs and limit the cancer therapies.Many studies have revealed that tumor cells can escape from anti-angiogenic treatments through a variety of ways and mechanisms.In this review,we focus on the reasons behind the failure in treatments,so as to propose solving strategies to improve the current anti-angiogenic drug efficacy and provide reference for new angiogenesis inhibitors and clinical medication.
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Therapeutic strategies targeting tumor angiogenesis have been approved for cancer therapy. Vasculature normalization induced by anti-angiogenic drugs can restore abnormal tumor vessels, and improve the tumor microenvironment characterized by hypoxia, extracellular acidosis, and high interstitial lfuid pressure, improve the cancer treatment results by chemoradiotherapy and immunotherapy.
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Objective: To observe the intervention of total flavonoids from Camptosorus sibiricus (TFCS) on lung cancer in mice and to study its possible antitumor mechanism. Methods: The lung cancer model induced by urethane was used to investigate the preventive action of TFCS on lung cancer, the passive pulmonary metastatic model of Lewis lung cancer was used to evaluate the effect of TFCS on tumor metastasis, the scavenger effect of TFCS on system microenvironment was observed in the recurrent tumor model of Lewis lung cancer, the effect of TFCS on lysyl oxidase (LOX) was investigated by Western blotting and immunohistochemical staining, and the vascular normalization function of TFCS was examined by capillary permeability in carcinogenetic lung tissues. Results: TFCS (30 and 100 mg/kg) could decrease the lung carcinogenesis induced by urethane and reduce the passive pulmonary metastasis and recurrence after tumor removal in Lewis lung cancer-bearing mice. TFCS (30 and 100 mg/kg) could also downregulate the expression of LOX in lung cancer tissue, prevent serum lipid peroxide formation in mice with tumor removal, and promote vascular normalization of lung cancer tissue. Conclusion: TFCS as an LOX inhibitor has a definite preventive action on lung cancer.
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Blood vessels are indispensible for tumor growth and metastasis.Traditional antiangiogenic strategy reduce the density and the supply of tumor blood vessels.Recent studies have shown that antiangiogenic therapy has transient and insufficient efficacy.Blockage of blood and oxygen supplies creates a hypoxic and acidic microenvironment in the tumor tissues,which fosters tumor cells to become more aggressive and metastatic.Tumor vascular normalization may be an alternative approach to treat cancers,normalize the disorganized tumor vasculature,rather than disrupting or blocking them,thus reduce tumor hypoxia as well as increase the efficacy of chemotherapy,radiotherapy and immunotherapy.
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Objective To investigate whether recombinant human endostatin can create a time window of vascular normalization prior to vascular pruning to alleviate hypoxia in Lewis lung carcinoma in mice. Methods Kinetic changes in morphology of tumor vasculature in response to recombinant human endostatin were detected under a confocal microscope with immunofluorescent staining in Lewis lung carcinomas in mice. The hypoxic cell fraction of different time was assessed with immunohistochemical staining . Effects on tumor growth were monitored as indicated in the growth curve of tumors . Results Compared with the control group vascularity of the tumors was reduced over time by recombinant human endostatin treatment and significantly regressed for 9 days. During the treatment, pericyte coverage increased at day 3, increased markedly at day 5, and fell again at day 7. The vascular basement membrane was thin and closely associated with endothelial cells after recombinant human endostatin treatment, but appeared thickened, loosely associated with endothelial cells in control tumors. The decrease in hypoxic cell fraction at day 5 after treatment was also found. Tumor growth was not accelerated 5 days after recombinant human endostatin treatment. Conclusions Recombinant human endostatin can normalize tumor vasculature within day 3 to 7, leading to improved tumor oxygenation. The results provide important experimental basis for combining recombinant human endostatin with radiation therapy in human tumors.