调控肿瘤微环境实现血管正常化的研究进展
Research Progress in the Regulation of Tumor Microenvironment for Vascular Normalization
DOI: 10.12677/ACM.2023.134883, PDF,   
作者: 李 璐:济宁医学院临床医学院,山东 济宁;刘艳荣*:济宁医学院附属医院病理科,山东 济宁
关键词: 肿瘤血管正常化肿瘤微环境血管生成Tumor Vascular Normalization Tumor Microenvironment Angiogenesis
摘要: 异常肿瘤血管导致低氧、低pH的恶性微环境形成,加剧肿瘤恶化、机体免疫抑制和治疗耐药,肿瘤血管已成为治疗的重要靶点。传统的抗血管生成疗法由于容易产生耐药仍存在争议。基于此,有学者提出肿瘤血管的正常化理论,即肿瘤血管生成回到更成熟和稳定的血管系统。肿瘤微环境(TME)在微血管的启动和发展中起着重要的作用。近年来,许多研究致力于通过TME提高肿瘤微血管正常化治疗效果。本文综述了基于肿瘤微环境在血管正常化中的靶向和重塑策略最新研究进展,并对其中存在的问题及未来的发展进行讨论。
Abstract: Abnormal tumor blood vessels lead to the formation of a malignant microenvironment with low ox-ygen and low pH, which aggravates tumor deterioration, immunosuppression and drug resistance. Tumor blood vessels have become an important target for treatment. Traditional anti- angiogenesis therapy is still controversial due to drug resistance. Based on this, some scholars have proposed the normalization theory of tumor blood vessels, that is, to achieve tumor angiogenesis back to a more mature and stable vascular system. Tumor microenvironment (TME) plays an important role in the initiation and development of microvessels. In recent years, many studies have focused on improv-ing the therapeutic effect of tumor microvascular normalization by TME. This article reviews the latest research progress of targeting and remodeling strategies based on tumor microenvironment in vascular normalization, and discusses the existing problems and future development.
文章引用:李璐, 刘艳荣. 调控肿瘤微环境实现血管正常化的研究进展[J]. 临床医学进展, 2023, 13(4): 6274-6282. https://doi.org/10.12677/ACM.2023.134883

参考文献

[1] Lugano, R., Ramachandran, M. and Dimberg, A. (2020) Tumor Angiogenesis: Causes, Consequences, Challenges and Opportunities. Cellular and Molecular Life Sciences, 77, 1745-1770. [Google Scholar] [CrossRef] [PubMed]
[2] Montemagno, C. and Pagès, G. (2020) Resistance to An-ti-Angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs. Frontiers in Cell and Devel-opmental Biology, 8, Article 584. [Google Scholar] [CrossRef] [PubMed]
[3] Yang, T., Xiao, H., Liu, X., et al. (2021) Vascular Normalization: A New Window Opened for Cancer Therapies. Frontiers in Oncology, 11, Article 719836. [Google Scholar] [CrossRef] [PubMed]
[4] Viallard, C. and Larrivée, B. (2017) Tumor Angiogenesis and Vas-cular Normalization: Alternative Therapeutic Targets. Angiogenesis, 20, 409-426. [Google Scholar] [CrossRef] [PubMed]
[5] Roma-Rodrigues, C., Mendes, R., Baptista, P.V. and Fernandes, A.R. (2019) Targeting Tumor Microenvironment for Cancer Therapy. International Journal of Molecular Sciences, 20, Article No. 840. [Google Scholar] [CrossRef] [PubMed]
[6] Jena, BC. and Mandal, M. (2021) The Emerging Roles of Exosomes in Anti-Cancer Drug Resistance and Tumor Progression: An Insight towards Tumor-Microenvironment Interaction. Bio-chimica et Biophysica Acta (BBA)-Reviews on Cancer, 1875, Article ID: 188488. [Google Scholar] [CrossRef] [PubMed]
[7] Yan, J., Zhang, N., Zhang, Z., et al. (2021) Redox-Responsive Polyethyleneimine/Tetrahedron DNA/Doxorubicin Nanocomplexes for Deep Cell/tissue Penetration to Overcome Multi-drug Resistance. Journal of Controlled Release, 329, 36-49. [Google Scholar] [CrossRef] [PubMed]
[8] Qin, S., Li, A., Yi, M., et al. (2019) Recent Advances on Anti-Angiogenesis Receptor Tyrosine Kinase Inhibitors in Cancer Therapy. Journal of Hematology & Oncology, 12, Article No. 27. [Google Scholar] [CrossRef] [PubMed]
[9] Yang, J.C., Haworth, L., Sherry, R.M., et al. (2003) A Random-ized Trial of Bevacizumab, an Anti-Vascular Endothelial Growth Factor Antibody, for Metastatic Renal Cancer. New England Journal of Medicine, 349, 427-434. [Google Scholar] [CrossRef
[10] Huang, M., Lin, Y., Wang, C., et al. (2022) New Insights into Anti-angiogenic Therapy Resistance in Cancer: Mechanisms and Therapeutic Aspects. Drug Resistance Updates, 64, Article ID: 100849. [Google Scholar] [CrossRef] [PubMed]
[11] Xu, X.-X., Chen, S.-Y., Yi, N.-B., et al. (2022) Research Pro-gress on Tumor Hypoxia-Associative Nanomedicine. Journal of Controlled Release, 350, 829-840. [Google Scholar] [CrossRef] [PubMed]
[12] Aventaggiato, M., Barreca, F., Sansone, L., et al. (2022) Sirtuins and Hypoxia in EMT Control. Pharmaceuticals, 15, Article No. 737. [Google Scholar] [CrossRef] [PubMed]
[13] Tang, M., Bolderson, E., O’Byrne, K.J. and Richard, D.J. (2021) Tumor Hypoxia Drives Genomic Instability. Frontiers in Cell and Developmental Biology, 9, Article 626229. [Google Scholar] [CrossRef] [PubMed]
[14] Janssens, L.K. and Stove, C.P. (2021) Sensing an Oxygen Sensor: Development and Application of Activity-Based Assays Directly Monitoring HIF Heterodimerization. Analytical Chem-istry, 93, 14462-14470. [Google Scholar] [CrossRef] [PubMed]
[15] Gunaratnam, L. and Bonventre, J.V. (2009) HIF in Kidney Disease and Development. Journal of the American Society of Nephrology, 20, 1877-1887. [Google Scholar] [CrossRef
[16] Kaur, B., Khwaja, F.W., Severson, E.A., et al. (2005) Hypoxia and the Hypoxia-Inducible-Factor Pathway in Glioma Growth and Angiogenesis. Neuro-Oncology, 7, 134-153. [Google Scholar] [CrossRef
[17] Wicks, E.E. and Semenza, G.L. (2022) Hypoxia-Inducible Fac-tors: Cancer Progression and Clinical Translation. Journal of Clinical Investigation, 132, e159839. [Google Scholar] [CrossRef
[18] Bauer, D., Visca, H., Weerakkody, A., et al. (2022) PET Imaging of Acid-ic Tumor Environment with 89Zr-Labeled pHLIP Probes. Frontiers in Oncology, 12, Article 882541. [Google Scholar] [CrossRef] [PubMed]
[19] Abumanhal-Masarweh, H., Koren, L., Zinger, A., et al. (2019) So-dium Bicarbonate Nanoparticles Modulate the Tumor Ph and Enhance the Cellular Uptake of Doxorubicin. Journal of Controlled Release, 296, 1-13. [Google Scholar] [CrossRef] [PubMed]
[20] Calorini, L., Peppicelli, S. and Bianchini, F. (2012) Extracellular Acidity as Favouring Factor of Tumor Progression and Metastatic Dissemination. Experimental Oncology, 34, 79-84.
[21] Végran, F., Boidot, R., Michiels, C., Sonveaux, P. and Feron, O. (2011) Lactate Influx through the Endo-thelial Cell Monocarboxylate Transporter MCT1 Supports an NF-κB/IL-8 Pathway that Drives Tumor Angiogenesis. Cancer Research, 71, 2550-2560. [Google Scholar] [CrossRef
[22] Chaussain, C., Boukpes-si, T., Khaddam, M., et al. (2013) Dentin Matrix Degradation by Host Matrix Metalloproteinases: Inhibition and Clinical Perspectives toward Regeneration. Frontiers in Physiology, 4, Article 308. [Google Scholar] [CrossRef] [PubMed]
[23] Zhen, Z., Tang, W., Wang, M., et al. (2017) Protein Nanocage Me-diated Fibroblast-Activation Protein Targeted Photoimmunotherapy to Enhance Cytotoxic T Cell Infiltration and Tumor Control. Nano Letters, 17, 862-869. [Google Scholar] [CrossRef] [PubMed]
[24] Madar, S., Goldstein, I. and Rotter, V. (2013) ‘Cancer Associat-ed Fibroblasts’—More than Meets the Eye. Trends in Molecular Medicine, 19, 447-453. [Google Scholar] [CrossRef] [PubMed]
[25] Luo, H., Tu, G., Liu, Z. and Liu, M. (2015) Cancer-Associated Fibroblasts: A Multifaceted Driver of Breast Cancer Progression. Cancer Letters, 361, 155-163. [Google Scholar] [CrossRef] [PubMed]
[26] Watnick, R.S. (2012) The Role of the Tumor Microenvironment in Regulating Angiogenesis. Cold Spring Harbor Perspectives in Medicine, 2, a006676. [Google Scholar] [CrossRef] [PubMed]
[27] Rizzolio, S., Giordano, S. and Corso, S. (2022) The Importance of Being CAFs (in Cancer Resistance to Targeted Therapies). Journal of Experimental & Clinical Cancer Research, 41, Article No. 319. [Google Scholar] [CrossRef] [PubMed]
[28] Wallace, J.A., Li, F., Balakrishnan, S., et al. (2013) Ets2 in Tu-mor Fibroblasts Promotes Angiogenesis in Breast Cancer. PLOS ONE, 8, e71533. [Google Scholar] [CrossRef] [PubMed]
[29] Wu, K., Lin, K., Li, X., et al. (2020) Redefining Tu-mor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment. Frontiers in Immunology, 11, Article 1731. [Google Scholar] [CrossRef] [PubMed]
[30] Riabov, V., Gudima, A., Wang, N., et al. (2014) Role of Tumor Associated Macrophages in Tumor Angiogenesis and Lymphangiogenesis. Frontiers in Physiology, 5, Article 75. [Google Scholar] [CrossRef] [PubMed]
[31] Zhang, J., Gao, J., Cui, J., et al. (2022) Tu-mor-Associated Macrophages in Tumor Progression and the Role of Traditional Chinese Medicine in Regulating TAMs to Enhance Antitumor Effects. Frontiers in Immunology, 13, Article 1026898. [Google Scholar] [CrossRef] [PubMed]
[32] Wu, H., Xu, J.-B., He, Y.-L., et al. (2012) Tumor-Associated Macrophages Promote Angiogenesis and Lymphangiogenesis of Gastric Cancer. Journal of Surgical Oncology, 106, 462-468. [Google Scholar] [CrossRef] [PubMed]
[33] Missiaen, R., Mazzone, M. and Bergers, G. (2018) The Reciprocal Function and Regulation of Tumor Vessels and Immune Cells Offers New Therapeutic Opportunities in Cancer. Semi-nars in Cancer Biology, 52, 107-116. [Google Scholar] [CrossRef] [PubMed]
[34] Martin, J.D., Seano, G. and Jain, R.K. (2019) Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges. Annual Review of Physiology, 81, 505-534. [Google Scholar] [CrossRef] [PubMed]
[35] Lee, W.S., Yang, H., Chon, H.J. and Kim, C. (2020) Combination of Anti-Angiogenic Therapy and Immune Checkpoint Blockade Normalizes Vascular-Immune Crosstalk to Potentiate Cancer Immunity. Experimental & Molecular Medicine, 52, 1475-1485. [Google Scholar] [CrossRef] [PubMed]
[36] Pezzuto, A. and Carico, E. (20180 Role of HIF-1 in Cancer Pro-gression: Novel Insights. A Review. Current Molecular Medicine, 18, 343-351.[CrossRef] [PubMed]
[37] Jung, H.-J., Seo, I., Jha, B.K., et al. (2014) Minocy-cline Inhibits Angiogenesis in Vitro through the Translational Suppression of HIF-1α. Archives of Biochemistry and Bi-ophysics, 545, 74-82. [Google Scholar] [CrossRef] [PubMed]
[38] Gupta, B., Chiang, L., Chae, K. and Lee, D.-H. (2013) Phenethyl Isothiocyanate Inhibits Hypoxia-Induced Accumulation of HIF-1α and VEGF Expression in Human Glioma Cells. Food Chemistry, 141, 1841-1846. [Google Scholar] [CrossRef] [PubMed]
[39] Park, J.J., Hwang, S.J., Park, J.-H. and Lee, H.-J. (2015) Chlorogenic Acid Inhibits Hypoxia-Induced Angiogenesis via Down-Regulation of the HIF-1α/AKT Pathway. Cellular Oncology, 38, 111-118. [Google Scholar] [CrossRef] [PubMed]
[40] Cheng, X., Zhang, X., Cheng, W., et al. (2014) Tumor-Specific Delivery of Histidine-Rich Glycoprotein Suppresses Tumor Growth and Metastasis by Anti-angiogenesis and Vessel Normalization. Current Gene Therapy, 14, 75-85. [Google Scholar] [CrossRef] [PubMed]
[41] David, J.M., Owens, T.A., Inge, L.J., Bremner, R.M. and Rajasekaran, A.K. (2014) Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypox-ia-Inducible Factor in Renal Cell Carcinoma. Molecular Cancer Therapeutics, 13, 788-799. [Google Scholar] [CrossRef
[42] Serocki, M., Bartoszewska, S., Janaszak-Jasiecka, A., et al. (2018) MiRNAs Regulate the HIF Switch during Hypoxia: A Novel Therapeutic Target. Angiogenesis, 21, 183-202. [Google Scholar] [CrossRef] [PubMed]
[43] Ando, H., Ikeda, A., Tagami, M., et al. (2022) Oral Administra-tion of Sodium Bicarbonate Can Enhance the Therapeutic Outcome of Doxil® via Neutralizing the Acidic Tumor Micro-environment. Journal of Controlled Release, 350, 414-420. [Google Scholar] [CrossRef] [PubMed]
[44] Parks, S.K. and Pouysségur, J. (2017) Targeting pH Regulating Proteins for Cancer Therapy—Progress and Limitations. Seminars in Cancer Biology, 43, 66-73. [Google Scholar] [CrossRef] [PubMed]
[45] Wiedmann, R.M., von Schwarzenberg, K., Palamidessi, A., et al. (2012) The V-ATPase-Inhibitor Archazolid Abrogates Tumor Metastasis via Inhibition of Endocytic Activation of the Rho-GTPase Rac1. Cancer Research, 72, 5976- 5987. [Google Scholar] [CrossRef
[46] Rath, S., Liebl, J., Fürst, R., Vollmar, A.M. and Zahler, S. (2014) Regulation of Endothelial Signaling and Migration by V-ATPase. Angiogenesis, 17, 587-601. [Google Scholar] [CrossRef] [PubMed]
[47] Fliedner, S.M., Yang, C., Thompson, E., et al. (2015) Potential Therapeutic Target for Malignant Paragangliomas: ATP Synthase on the Surface of Paraganglioma Cells. American Journal of Cancer Research, 5, 1558-1570.
[48] Zhou, X., Yan, T., Huang, C., et al. (2018) Melanoma Cell-Secreted Exosomal miR-155-5p Induce Proangiogenic Switch of Cancer-Associated Fibroblasts via SOCS1/JAK2/STAT3 Sig-naling Pathway. Journal of Experimental & Clinical Cancer Research, 37, Article No. 242. [Google Scholar] [CrossRef] [PubMed]
[49] Guan, J., Zhang, H., Wen, Z., et al. (2014) Retinoic Acid Inhibits Pancreatic Cancer Cell Migration and EMT through the Downregulation of IL-6 in Cancer Associated Fibroblast Cells. Cancer Letters, 345, 132-139 [Google Scholar] [CrossRef] [PubMed]
[50] Crawford, Y., Kasman, I., Yu, L., et al. (2009) PDGF-C Medi-ates the Angiogenic and Tumorigenic Properties of Fibroblasts Associated with Tumors Refractory to Anti-VEGF Treatment. Cancer Cell, 15, 21-34. [Google Scholar] [CrossRef] [PubMed]
[51] Nagasaki, T., Hara, M., Nakanishi, H., et al. (2014) Interleukin-6 Released by Colon Cancer-Associated Fibroblasts Is Critical for Tumour Angiogenesis: Anti-Interleukin-6 Receptor An-tibody Suppressed Angiogenesis and Inhibited Tumour–Stroma Interaction. British Journal of Cancer, 110, 469-478. [Google Scholar] [CrossRef] [PubMed]
[52] Zhou, F., Wang, M., Luo, T., Qu, J. and Chen, W.R. (2021) Pho-to-Activated Chemo-Immunotherapy for Metastatic Cancer Using a Synergistic Graphene Nanosystem. Biomaterials, 265, Article ID: 120421. [Google Scholar] [CrossRef] [PubMed]
[53] Cirri, P. and Chiarugi, P. (2011) Cancer Associated Fibro-blasts: The Dark Side of the Coin. American Journal of Cancer Research, 1, 482-497.
[54] Salmaninejad, A., Valilou, S.F., Soltani, A., et al. (2019) Tumor-Associated Macrophages: Role in Cancer Development and Therapeutic Implica-tions. Cellular Oncology, 42, 591-608. [Google Scholar] [CrossRef] [PubMed]
[55] Kioi, M., Vogel, H., Schultz, G., et al. (2010) Inhibition of Vasculogenesis, But Not Angiogenesis, Prevents the Recurrence of Glioblastoma after Irradiation in Mice. Journal of Clinical Investigation, 120, 694-705.
[56] Fu, L.-Q., Du, W.-L., Cai, M.-H., et al. (2020) The Roles of Tumor-Associated Macrophages in Tumor Angiogenesis and Metastasis. Cellular Immunology, 353, Article ID: 104119. [Google Scholar] [CrossRef] [PubMed]
[57] Nakanishi, Y., Nakatsuji, M., Seno, H., et al. (2011) COX-2 i Inhibition Alters the Phenotype of Tumor-Associated Macrophages From M2 to M1 in ApcMin/+ Mouse Polyps. Carcinogenesis, 32, 1333-13339. [Google Scholar] [CrossRef] [PubMed]
[58] Liu, Y., Zhao, L., Li, D., et al. (2013) Microvesicle-Delivery miR-150 Promotes Tumorigenesis by up-Regulating VEGF, and the Neutralization of miR-150 Attenuate Tumor Development. Protein & Cell, 4, 932-941. [Google Scholar] [CrossRef] [PubMed]
[59] Huang, H. (2018) Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances. Sensors, 18, Article No. 3249. [Google Scholar] [CrossRef] [PubMed]
[60] Li, Z., Zheng, Z., Li, C., et al. (2020) Therapeutic Drugs and Drug Deliv-ery Systems Targeting Stromal Cells for Cancer Therapy: A Review. Journal of Drug Targeting, 28, 714-726. [Google Scholar] [CrossRef
[61] Guo, Y., Wang, D., Song, Q., et al. (2015) Erythrocyte Membrane-Enveloped Polymeric Nanoparticles as Nanovaccine for Induction of Antitumor Immunity against Melanoma. ACS Nano, 9, 6918-6933. [Google Scholar] [CrossRef] [PubMed]
[62] Zhao, Y., Wang, H., Yang, Y., et al. (2020) Mannose-Modified Liposome Co-Delivery of Human Papillomavirus Type 16 E7 Peptide and CpG Oligodeoxynucleotide Adjuvant En-hances Antitumor Activity against Established Large TC-1 Grafted Tumors in Mice. International Journal of Nanomedi-cine, 15, 9571-9586. [Google Scholar] [CrossRef
[63] Chen, C.-A., Ho, C.-M., Chang, M.-C., et al. (2010) Metronomic Chemotherapy Enhances Antitumor Effects of Cancer Vaccine by Depleting Regulatory T Lympho-cytes and Inhibiting Tumor Angiogenesis. Molecular Therapy, 18, 1233- 1243. [Google Scholar] [CrossRef] [PubMed]
[64] Cao, M., Xu, Y., Youn, J.-I., et al. (2011) Kinase Inhibitor Sorafenib Modulates Immunosuppressive Cell Populations in a Murine Liver Cancer Model. Laboratory Investigation, 91, 598-608. [Google Scholar] [CrossRef] [PubMed]