Abstract
As angiogenesis was recognized as a core hallmark of cancer growth and survival, several strategies have been implemented to target the tumour vasculature. Yet to date, attempts have rarely been so diverse, ranging from vessel growth inhibition and destruction to vessel normalization, reprogramming and vessel growth promotion. Some of these strategies, combined with standard of care, have translated into improved cancer therapies, but their successes are constrained to certain cancer types. This Review provides an overview of these vascular targeting approaches and puts them into context based on our subsequent improved understanding of the tumour vasculature as an integral part of the tumour microenvironment with which it is functionally interlinked. This new knowledge has already led to dual targeting of the vascular and immune cell compartments and sets the scene for future investigations of possible alternative approaches that consider the vascular link with other tumour microenvironment components for improved cancer therapy.
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References
Aird, W. C. Spatial and temporal dynamics of the endothelium. J. Thromb. Haemost. 3, 1392–1406 (2005).
Rajendran, P. et al. The vascular endothelium and human diseases. Int. J. Biol. Sci. 9, 1057–1069 (2013).
Durand, M. J. & Gutterman, D. D. Diversity in mechanisms of endothelium-dependent vasodilation in health and disease. Microcirculation 20, 239–247 (2013).
Carman, C. V. & Martinelli, R. T lymphocyte–endothelial interactions: emerging understanding of trafficking and antigen-specific immunity. Front. Immunol. 6, 603 (2015).
Augustin, H. G. & Koh, G. Y. Organotypic vasculature: from descriptive heterogeneity to functional pathophysiology. Science 357, eaal2379 (2017).
Oria, V. O. & Erler, J. T. Tumor angiocrine signaling: novel targeting opportunity in cancer. Cells 12, 2510 (2023).
Sun, R., Kong, X., Qiu, X., Huang, C. & Wong, P. P. The emerging roles of pericytes in modulating tumor microenvironment. Front. Cell Dev. Biol. 9, 676342 (2021).
Jiang, Z. et al. Pericytes in the tumor microenvironment. Cancer Lett. 556, 216074 (2023).
van Splunder, H., Villacampa, P., Martínez-Romero, A. & Graupera, M. Pericytes in the disease spotlight. Trends Cell Biol. 34, 58–71 (2023).
Wong, P. P. et al. Cancer burden is controlled by mural cell-β3-integrin regulated crosstalk with tumor cells. Cell 181, 1346–1363.e1321 (2020). On the basis of previous findings of pericyte-derived signals in the regulation of cancer cells, this paper identifies a central role for mural cell β3-integrin in pericyte-derived paracrine regulation, coined here pericrine signalling.
Singhal, M. & Augustin, H. G. Beyond angiogenesis: exploiting angiocrine factors to restrict tumor progression and metastasis. Cancer Res. 80, 659–662 (2020).
Jakab, M. et al. Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency. Nat. Cancer 5, 716–730 (2024). This study provides evidence for endothelial-cell-derived WNT signalling in determining whether metastasizing tumour cells proliferate intravascularly or extravasate.
Rivera, L. B. & Bergers, G. Angiogenesis. Targeting vascular sprouts. Science 344, 1449–1450 (2014).
Katayama, Y. et al. Tumor neovascularization and developments in therapeutics. Cancers 11, 316 (2019).
Welti, J., Loges, S., Dimmeler, S. & Carmeliet, P. Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J. Clin. Invest. 123, 3190–3200 (2013).
Liu, Z. L., Chen, H. H., Zheng, L. L., Sun, L. P. & Shi, L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct. Target. Ther. 8, 198 (2023).
Bergers, G. & Benjamin, L. E. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 3, 401–410 (2003).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).
Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).
Baluk, P., Hashizume, H. & McDonald, D. M. Cellular abnormalities of blood vessels as targets in cancer. Curr. Opin. Genet. Dev. 15, 102–111 (2005). This review details the multiple structural and functional abnormalities of tumour blood vessels.
Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).
Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986). This seminal paper was the first to describe the tumour stroma as a wound that never heals.
Nagy, J. A., Chang, S. H., Dvorak, A. M. & Dvorak, H. F. Why are tumour blood vessels abnormal and why is it important to know? Br. J. Cancer 100, 865–869 (2009).
Zeng, Q. et al. Understanding tumour endothelial cell heterogeneity and function from single-cell omics. Nat. Rev. Cancer 23, 544–564 (2023).
Palikuqi, B. et al. Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis. Nature 585, 426–432 (2020).
Gomez-Salinero, J. M., Itkin, T. & Rafii, S. Developmental angiocrine diversification of endothelial cells for organotypic regeneration. Dev. Cell 56, 3042–3051 (2021).
Koch, P. S., Lee, K. H., Goerdt, S. & Augustin, H. G. Angiodiversity and organotypic functions of sinusoidal endothelial cells. Angiogenesis 24, 289–310 (2021).
Liebner, S. et al. Functional morphology of the blood–brain barrier in health and disease. Acta Neuropathol. 135, 311–336 (2018).
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971). This seminal paper describes the concept of blocking tumour vessel growth to abrogate tumour propagation.
Folkman, J. Angiogenesis: an organizing principle for drug discovery. Nat. Rev. Drug Discov. 6, 273–286 (2007).
Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).
Kerbel, R. & Folkman, J. Clinical translation of angiogenesis inhibitors. Nat. Rev. Cancer 2, 727–739 (2002).
Gasparini, G., Longo, R., Toi, M. & Ferrara, N. Angiogenic inhibitors: a new therapeutic strategy in oncology. Nat. Clin. Pract. Oncol. 2, 562–577 (2005).
Qin, S. et al. Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J. Hematol. Oncol. 12, 27 (2019).
Kim, K. J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362, 841–844 (1993).
Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov. 3, 391–400 (2004).
Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004). This was the first study demonstrating that addition of bevacizumab to fluorouracil-based combination chemotherapy had significant and clinically meaningful improvements in survival among patients with metastatic colorectal cancer.
Giantonio, B. J. et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J. Clin. Oncol. 25, 1539–1544 (2007).
Sandler, A. et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542–2550 (2006).
Ramaswamy, B. et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin. Cancer Res. 12, 3124–3129 (2006).
Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007).
Yang, J. C. et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427–434 (2003).
Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014).
Wenger, K. J. et al. Bevacizumab as a last-line treatment for glioblastoma following failure of radiotherapy, temozolomide and lomustine. Oncol. Lett. 14, 1141–1146 (2017).
Reardon, D. A. et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol. 6, 1003–1010 (2020).
Jin, R. et al. Real-world outcomes among patients with metastatic colorectal cancer treated first line with a bevacizumab biosimilar (bevacizumab-awwb). Ther. Adv. Med. Oncol. 15, 17588359231182386 (2023).
Good, D. J. et al. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc. Natl Acad. Sci. USA 87, 6624–6628 (1990).
Clamp, A. R. & Jayson, G. C. The clinical potential of antiangiogenic fragments of extracellular matrix proteins. Br. J. Cancer 93, 967–972 (2005).
Walia, A. et al. Endostatin’s emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications. Biochim. Biophys. Acta 1850, 2422–2438 (2015).
Kulke, M. H. et al. Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J. Clin. Oncol. 24, 3555–3561 (2006).
Folkman, J. Antiangiogenesis in cancer therapy — endostatin and its mechanisms of action. Exp. Cell Res. 312, 594–607 (2006).
Sun, Y. et al. Results of phase III trial of rh-endostatin (YH-16) in advanced non-small cell lung cancer (NSCLC) patients. J. Clin. Oncol. 23, 7138–7138 (2005).
Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60, 1878–1886 (2000). This was the first study describing continuous low-dose chemotherapy as a form of anti-angiogenic therapy, coined metronomic chemotherapy.
Klement, G. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105, R15–R24 (2000).
Chen, Y. et al. Promotion of tumor progression induced by continuous low-dose administration of antineoplastic agent gemcitabine or gemcitabine combined with cisplatin. Life Sci. 306, 120826 (2022).
Kikuchi, H. et al. Low-dose metronomic cisplatin as an antiangiogenic and anti-inflammatory strategy for cancer. Br. J. Cancer 130, 336–345 (2024).
Zheng, X., Kuai, J. & Shen, G. Low-dose metronomic gemcitabine pretreatments overcome the resistance of breast cancer to immune checkpoint therapy. Immunotherapy 15, 429–442 (2023).
Kerbel, R. S. & Shaked, Y. The potential clinical promise of ‘multimodality’ metronomic chemotherapy revealed by preclinical studies of metastatic disease. Cancer Lett. 400, 293–304 (2017).
Vasudev, N. S. & Reynolds, A. R. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 17, 471–494 (2014).
Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).
Pàez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009). This report describes pro-invasive and metastasis-promoting effects of anti-vascular endothelial growth factor therapies in mouse models of pancreatic neuroendocrine tumours and glioblastoma.
Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603 (2008).
Casanovas, O., Hicklin, D. J., Bergers, G. & Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299–309 (2005).
Hauschild, A. et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J. Clin. Oncol. 27, 2823–2830 (2009).
Kelly, W. K. et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J. Clin. Oncol. 30, 1534–1540 (2012).
Kim, K. B. et al. BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J. Clin. Oncol. 30, 34–41 (2012).
Miller, K. D. et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J. Clin. Oncol. 23, 792–799 (2005).
Miles, D. W. et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol. 28, 3239–3247 (2010).
Kindler, H. L. et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J. Clin. Oncol. 28, 3617–3622 (2010).
Ribatti, D., Annese, T., Ruggieri, S., Tamma, R. & Crivellato, E. Limitations of anti-angiogenic treatment of tumors. Transl. Oncol. 12, 981–986 (2019).
Goveia, J. et al. An integrated gene expression landscape profiling approach to identify lung tumor endothelial cell heterogeneity and angiogenic candidates. Cancer Cell 37, 421 (2020).
Zhao, Q. et al. Single-cell transcriptome analyses reveal endothelial cell heterogeneity in tumors and changes following antiangiogenic treatment. Cancer Res. 78, 2370–2382 (2018).
Bergers, G., Javaherian, K., Lo, K. M., Folkman, J. & Hanahan, D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284, 808–812 (1999).
Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).
Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003).
Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277–1289 (2018).
Zhao, Q. et al. Heterogeneity and chimerism of endothelial cells revealed by single-cell transcriptome in orthotopic liver tumors. Angiogenesis 23, 581–597 (2020).
Sun, Z. et al. Single-cell RNA sequencing reveals gene expression signatures of breast cancer-associated endothelial cells. Oncotarget 9, 10945–10961 (2017).
Cooke, V. G. et al. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21, 66–81 (2012).
Keskin, D. et al. Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep. 10, 1066–1081 (2015).
Nisancioglu, M. H., Betsholtz, C. & Genové, G. The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor-a blockade. Cancer Res. 70, 5109–5115 (2010).
Nolla, K., Benjamin, D. J. & Cella, D. Patient-reported outcomes in metastatic renal cell carcinoma trials using combinations versus sunitinib as first-line treatment. Nat. Rev. Urol. 20, 420–433 (2023).
Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).
Cantelmo, A. R. et al. Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell 30, 968–985 (2016). This paper describes how targeting tumour endothelial cell metabolism can induce vessel normalization and improve chemotherapy.
Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192–197 (2015).
Andonegui-Elguera, M. A. et al. An overview of vasculogenic mimicry in breast cancer. Front. Oncol. 10, 220 (2020).
Luo, Q. et al. Vasculogenic mimicry in carcinogenesis and clinical applications. J. Hematol. Oncol. 13, 19 (2020).
Ribatti, D., Annese, T. & Tamma, R. Vascular co-option in resistance to anti-angiogenic therapy. Front. Oncol. 13, 1323350 (2023).
Hinnen, P. & Eskens, F. A. Vascular disrupting agents in clinical development. Br. J. Cancer 96, 1159–1165 (2007). This review describes the original principles of vessel disruption for cancer therapy and its first applications in the clinic.
Siemann, D. W. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer Treat. Rev. 37, 63–74 (2011).
Smolarczyk, R., Czapla, J., Jarosz-Biej, M., Czerwinski, K. & Cichoń, T. Vascular disrupting agents in cancer therapy. Eur. J. Pharmacol. 891, 173692 (2021).
Chaplin, D. J. & Dougherty, G. J. Tumour vasculature as a target for cancer therapy. Br. J. Cancer 80, 57–64 (1999).
Singh, S. B. Discovery, synthesis, activities, structure–activity relationships, and clinical development of combretastatins and analogs as anticancer drugs. A comprehensive review. Nat. Prod. Rep. 41, 298–322 (2024).
Dark, G. G. et al. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res. 57, 1829–1834 (1997).
Abotaleb, M. et al. Flavonoids in cancer and apoptosis. Cancers 11, 28 (2018).
Khan, H. et al. Flavonoids nanoparticles in cancer: Treatment, prevention and clinical prospects. Semin. Cancer Biol. 69, 200–211 (2021).
Ellerby, H. M. et al. Anti-cancer activity of targeted pro-apoptotic peptides. Nat. Med. 5, 1032–1038 (1999).
Jahanban-Esfahlan, R. et al. RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice. Sci. Rep. 7, 8126 (2017).
Ran, S., Huang, X., Downes, A. & Thorpe, P. E. Evaluation of novel antimouse VEGFR2 antibodies as potential antiangiogenic or vascular targeting agents for tumor therapy. Neoplasia 5, 297–307 (2003).
Daei Farshchi Adli, A., Jahanban-Esfahlan, R., Seidi, K., Samandari-Rad, S. & Zarghami, N. An overview on vadimezan (DMXAA): the vascular disrupting agent. Chem. Biol. Drug Des. 91, 996–1006 (2018).
Grisham, R., Ky, B., Tewari, K. S., Chaplin, D. J. & Walker, J. Clinical trial experience with CA4P anticancer therapy: focus on efficacy, cardiovascular adverse events, and hypertension management. Gynecol. Oncol. Res. Pract. 5, 1–10 (2018).
Tsang, W. et al. Clinical application of tumor vascular disrupting therapy: a systematic review and meta-analysis. Onco Targets Ther. 14, 5085–5093 (2021).
Gill, J. H., Rockley, K. L., De Santis, C. & Mohamed, A. K. Vascular disrupting agents in cancer treatment: cardiovascular toxicity and implications for co-administration with other cancer chemotherapeutics. Pharmacol. Ther. 202, 18–31 (2019).
Seidi, K., Jahanban-Esfahlan, R. & Zarghami, N. Tumor rim cells: from resistance to vascular targeting agents to complete tumor ablation. Tumour Biol. 39, 1010428317691001 (2017).
Shaked, Y. et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313, 1785–1787 (2006). This study demonstrates that vascular disruption induces the recruitment of endothelial progenitor cells at the tumour rim as a resistance mechanism, providing a rationale for combining vascular disrupting agents with anti-angiogenic therapies.
Liang, W., Ni, Y. & Chen, F. Tumor resistance to vascular disrupting agents: mechanisms, imaging, and solutions. Oncotarget 7, 15444–15459 (2016).
Drzyzga, A. et al. The proper administration sequence of radiotherapy and anti-vascular agent-DMXAA is essential to inhibit the growth of melanoma tumors. Cancers 13, 3924 (2021).
Song, W. et al. Solid tumor therapy using a cannon and pawn combination strategy. Theranostics 6, 1023–1030 (2016).
Pérez-Pérez, M. J. et al. Blocking blood flow to solid tumors by destabilizing tubulin: an approach to targeting tumor growth. J. Med. Chem. 59, 8685–8711 (2016).
Nguyen, L., Fifis, T. & Christophi, C. Vascular disruptive agent OXi4503 and anti-angiogenic agent sunitinib combination treatment prolong survival of mice with CRC liver metastasis. BMC Cancer 16, 533 (2016).
Wang, Y. et al. Co-administration of combretastatin A4 nanoparticles and sorafenib for systemic therapy of hepatocellular carcinoma. Acta Biomater. 92, 229–240 (2019).
Monk, B. J. et al. Randomized phase II evaluation of bevacizumab versus bevacizumab plus fosbretabulin in recurrent ovarian, tubal, or peritoneal carcinoma: an NRG oncology/gynecologic oncology group study. J. Clin. Oncol. 34, 2279–2286 (2016).
Garon, E. B. et al. A randomized phase II trial of the tumor vascular disrupting agent CA4P (fosbretabulin tromethamine) with carboplatin, paclitaxel, and bevacizumab in advanced nonsquamous non-small-cell lung cancer. Onco Targets Ther. 9, 7275–7283 (2016).
Horsman, M. R., Wittenborn, T. R., Nielsen, P. S. & Elming, P. B. Tumors resistant to checkpoint inhibitors can become sensitive after treatment with vascular disrupting agents. Int. J. Mol. Sci. 21, 4778 (2020).
Zhao, B. et al. Co-administration of combretastatin A4 nanoparticles and anti-PD-L1 for synergistic therapy of hepatocellular carcinoma. J. Nanobiotechnol. 19, 124 (2021).
Smolarczyk, R. et al. Combination of anti-vascular agent — DMXAA and HIF-1α inhibitor — digoxin inhibits the growth of melanoma tumors. Sci. Rep. 8, 7355 (2018).
Liang, J. et al. Nanoparticle-enhanced chemo-immunotherapy to trigger robust antitumor immunity. Sci. Adv. 6, eabc3646 (2020).
Li, H. et al. Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis. Nat. Commun. 12, 2773 (2021).
Gu, J. et al. Tumor vascular destruction and cGAS-STING activation induced by single drug-loaded nano-micelles for multiple synergistic therapies of cancer. Small 19, e2303517 (2023).
Zheng, C. et al. Lenvatinib- and vadimezan-loaded synthetic high-density lipoprotein for combinational immunochemotherapy of metastatic triple-negative breast cancer. Acta Pharm. Sin. B 12, 3726–3738 (2022).
Rauca, V. F. et al. Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression. Sci. Rep. 11, 22102 (2021).
Zhang, Y. et al. An intelligent vascular disrupting dendritic nanodevice incorporating copper sulfide nanoparticles for immune modulation-mediated combination tumor therapy. Small 19, e2301914 (2023).
Temizoz, B. et al. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation. Front. Immunol. 15, 1353336 (2024).
Jassar, A. S. et al. Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. Cancer Res. 65, 11752–11761 (2005).
Weiss, J. M. et al. The STING agonist DMXAA triggers a cooperation between T lymphocytes and myeloid cells that leads to tumor regression. Oncoimmunology 6, e1346765 (2017).
Ran, S., Downes, A. & Thorpe, P. E. Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res. 62, 6132–6140 (2002).
DeRose, P., Thorpe, P. E. & Gerber, D. E. Development of bavituximab, a vascular targeting agent with immune-modulating properties, for lung cancer treatment. Immunotherapy 3, 933–944 (2011).
Ran, S. et al. Antitumor effects of a monoclonal antibody that binds anionic phospholipids on the surface of tumor blood vessels in mice. Clin. Cancer Res. 11, 1551–1562 (2005).
He, J., Yin, Y., Luster, T. A., Watkins, L. & Thorpe, P. E. Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma. Clin. Cancer Res. 15, 6871–6880 (2009).
Ly, K. I. et al. Bavituximab decreases immunosuppressive myeloid-derived suppressor cells in newly diagnosed glioblastoma patients. Clin. Cancer Res. 29, 3017–3025 (2023).
Lee, J. et al. Phase 2 study of bavituximab (bavi), a first-in-class antibody targeting phosphatidylserine (PS), plus pembrolizumab (P) in advanced gastric or gastroesophageal junction (GEJ) cancer. J. Clin. Oncol. 41, e16023–e16023 (2023).
Hsiehchen, D. et al. The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial. Nat. Commun. 15, 2178 (2024).
Stupp, R. et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 15, 1100–1108 (2014).
Reynolds, A. R. et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat. Med. 15, 392–400 (2009).
Wong, P. P., Bodrug, N. & Hodivala-Dilke, K. M. Exploring novel methods for modulating tumor blood vessels in cancer treatment. Curr. Biol. 26, R1161–R1166 (2016).
Wong, P. P. et al. Dual-action combination therapy enhances angiogenesis while reducing tumor growth and spread. Cancer Cell 27, 123–137 (2015). This study identifies that exploiting the vascular-promoting features of low-dose cilengitide can be used to enhance the efficacy of gemcitabine treatment in mouse models of lung and pancreatic ductal adenocarcinoma.
Bridges, E. & Harris, A. L. Vascular-promoting therapy reduced tumor growth and progression by improving chemotherapy efficacy. Cancer Cell 27, 7–9 (2015).
Wei, Y. et al. MT1-MMP-activated liposomes to improve tumor blood perfusion and drug delivery for enhanced pancreatic cancer therapy. Adv. Sci. 7, 1902746 (2020).
Weinmüller, M. et al. Overcoming the lack of oral availability of cyclic hexapeptides: design of a selective and orally available ligand for the integrin αvβ3. Angew. Chem. Int. Ed. Engl. 56, 16405–16409 (2017).
Goto, W. et al. Eribulin promotes antitumor immune responses in patients with locally advanced or metastatic breast cancer. Anticancer Res. 38, 2929–2938 (2018).
Kashiwagi, S. et al. Mesenchymal–epithelial transition and tumor vascular remodeling in eribulin chemotherapy for breast cancer. Anticancer Res. 38, 401–410 (2018).
Nakai, S. et al. Eribulin suppresses clear cell sarcoma growth by inhibiting cell proliferation and inducing melanocytic differentiation both directly and via vascular remodeling. Mol. Cancer Ther. 19, 742–754 (2020).
Funahashi, Y. et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci. 105, 1334–1342 (2014).
Mills, G. B. & Moolenaar, W. H. The emerging role of lysophosphatidic acid in cancer. Nat. Rev. Cancer 3, 582–591 (2003).
Takara, K. et al. Lysophosphatidic acid receptor 4 activation augments drug delivery in tumors by tightening endothelial cell–cell contact. Cell Rep. 20, 2072–2086 (2017). This paper demonstrates that lysophosphatidic acid (LPA) improves drug delivery via the specific activation of the LPA4 receptor, ultimately enhancing vascular network formation.
Fukumura, D., Kashiwagi, S. & Jain, R. K. The role of nitric oxide in tumour progression. Nat. Rev. Cancer 6, 521–534 (2006).
Moncada, S. & Higgs, E. A. The discovery of nitric oxide and its role in vascular biology. Br. J. Pharmacol. 147, S193–S201 (2006).
Yin, M., Tan, S., Bao, Y. & Zhang, Z. Enhanced tumor therapy via drug co-delivery and in situ vascular-promoting strategy. J. Control. Rel. 258, 108–120 (2017). This study presents a possible combination therapy, which enhances blood vessel numbers and drug delivery to inhibit tumour propagation and spread.
Preuss, S. F., Grieshober, D. & Augustin, H. G. Systemic reprogramming of endothelial cell signaling in metastasis and cachexia. Physiology 38, 189–202 (2023).
Bishop, D., Schwarz, Q. & Wiszniak, S. Endothelial-derived angiocrine factors as instructors of embryonic development. Front. Cell Dev. Biol. 11, 1172114 (2023).
Kobayashi, H. et al. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat. Cell Biol. 12, 1046–1056 (2010).
Lee, H. J. et al. Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes. Nat. Commun. 14, 2754 (2023).
Ramasamy, S. K., Kusumbe, A. P., Wang, L. & Adams, R. H. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507, 376–380 (2014).
Rafii, S., Butler, J. M. & Ding, B. S. Angiocrine functions of organ-specific endothelial cells. Nature 529, 316–325 (2016). This review was one of the first to coin the phrase angiocrine signalling as a descriptor of paracrine and juxtacrine signals from endothelial cells in the control of tumour growth.
Hu, J. et al. Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science 343, 416–419 (2014).
Pasquier, J. et al. Angiocrine endothelium: from physiology to cancer. J. Transl. Med. 18, 52 (2020).
Alsina-Sanchis, E., Mülfarth, R. & Fischer, A. Control of tumor progression by angiocrine factors. Cancers 13, 2610 (2021).
Lu, J. et al. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23, 171–185 (2013).
Ghiabi, P. et al. Endothelial cells provide a notch-dependent pro-tumoral niche for enhancing breast cancer survival, stemness and pro-metastatic properties. PLoS ONE 9, e112424 (2014).
Pedrosa, A. R. et al. Endothelial Jagged1 antagonizes Dll4 regulation of endothelial branching and promotes vascular maturation downstream of Dll4/Notch1. Arterioscler. Thromb. Vasc. Biol. 35, 1134–1146 (2015).
Taylor, J. et al. Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia. Nat. Cancer 4, 1544–1560 (2023). This paper describes how NOTCH1 signalling from endothelial cells in white adipose tissue regulates the life-threatening condition cachexia.
Wieland, E. et al. Endothelial notch1 activity facilitates metastasis. Cancer Cell 31, 355–367 (2017).
Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355–366 (2010). This paper demonstrates that DNA-damaging therapies such as doxorubicin can modulate IL-6 secretion from endothelial cells, which in turn affects the efficacy of the therapy.
Tavora, B. et al. Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy. Nature 514, 112–116 (2014). This paper describes how endothelial cell focal adhesion kinase coordinates the production of paracrine angiocrine signals to protect tumour cells from DNA-damaging therapies.
Roy-Luzarraga, M. et al. Suppression of endothelial cell FAK expression reduces pancreatic ductal adenocarcinoma metastasis after gemcitabine treatment. Cancer Res. 82, 1909–1925 (2022).
Newport, E. et al. Elucidating the role of the kinase activity of endothelial cell focal adhesion kinase in angiocrine signalling and tumour growth. J. Pathol. 256, 235–247 (2022).
Roy-Luzarraga, M. et al. Association of low tumor endothelial cell pY397-focal adhesion kinase expression with survival in patients with neoadjuvant-treated locally advanced breast cancer. JAMA Netw. Open 3, e2019304 (2020).
Acharyya, S. et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).
Cao, Z. et al. Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance. Cancer Cell 25, 350–365 (2014).
Cao, Z. et al. Molecular checkpoint decisions made by subverted vascular niche transform indolent tumor cells into chemoresistant cancer stem cells. Cancer Cell 31, 110–126 (2017).
Viski, C. et al. Endosialin-expressing pericytes promote metastatic dissemination. Cancer Res. 76, 5313–5325 (2016). This paper describes the role of pericyte-derived endosialin (also known as CD248) in the promotion of metastasis in mouse models of breast cancer.
Hosaka, K. et al. Pericyte-fibroblast transition promotes tumor growth and metastasis. Proc. Natl Acad. Sci. USA 113, E5618–E5627 (2016).
Murgai, M. et al. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat. Med. 23, 1176–1190 (2017).
Zhang, C. et al. Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma. Cell Metab. 36, 778–792.e10 (2024).
Lechertier, T. et al. Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth. Nat. Commun. 11, 2810 (2020).
Lees, D. M., Reynolds, L. E., Pedrosa, A. R., Roy-Luzarraga, M. & Hodivala-Dilke, K. M. Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression. Angiogenesis 24, 471–482 (2021).
Brantley-Sieders, D. M. et al. Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium. Cancer Res. 71, 976–987 (2011).
Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).
Franses, J. W., Baker, A. B., Chitalia, V. C. & Edelman, E. R. Stromal endothelial cells directly influence cancer progression. Sci. Transl. Med. 3, 66ra65 (2011).
Inverso, D. et al. A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie-Wnt signaling axis in the liver. Dev. Cell 56, 1677–1693.e10 (2021).
Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005). This seminal paper describes the concept of tumour vessel normalization.
Stylianopoulos, T., Munn, L. L. & Jain, R. K. Reengineering the tumor vasculature: improving drug delivery and efficacy. Trends Cancer 4, 258–259 (2018).
Nia, H. T., Munn, L. L. & Jain, R. K. Physical traits of cancer. Science 370, eaaz0868 (2020).
Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31, 2205–2218 (2013).
Martin, J. D., Seano, G. & Jain, R. K. Normalizing function of tumor vessels: progress, opportunities, and challenges. Annu. Rev. Physiol. 81, 505–534 (2019).
Carmeliet, P. & Jain, R. K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov. 10, 417–427 (2011).
Goel, S. et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 91, 1071–1121 (2011).
Magnussen, A. L. & Mills, I. G. Vascular normalisation as the stepping stone into tumour microenvironment transformation. Br. J. Cancer 125, 324–336 (2021).
Van der Veldt, A. A. et al. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 21, 82–91 (2012). This study presents a lack of evidence of vessel normalization or an improvement in drug delivery in patients with non-small-cell lung cancer treated with bevacizumab, thus highlighting the importance of optimizing the dosing and scheduling of this drug to obtain an effective vessel-normalizing strategy.
Zhang, Z. et al. ‘γδT cell–IL17A–neutrophil’ axis drives immunosuppression and confers breast cancer resistance to high-dose anti-VEGFR2 therapy. Front. Immunol. 12, 699478 (2021).
Choi, Y. & Jung, K. Normalization of the tumor microenvironment by harnessing vascular and immune modulation to achieve enhanced cancer therapy. Exp. Mol. Med. 55, 2308–2319 (2023).
Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012).
Chauhan, V. P. et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat. Nanotechnol. 7, 383–388 (2012).
Bruning, U. et al. Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation. Cell Metab. 28, 866–880.e815 (2018).
Conradi, L. C. et al. Tumor vessel disintegration by maximum tolerable PFKFB3 blockade. Angiogenesis 20, 599–613 (2017).
Shan, Y. et al. Targeting tumor endothelial hyperglycolysis enhances immunotherapy through remodeling tumor microenvironment. Acta Pharm. Sin. B 12, 1825–1839 (2022).
Lorgis, V. et al. Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts. J. Neurooncol. 107, 351–358 (2012).
Kreisl, T. N. et al. Continuous daily sunitinib for recurrent glioblastoma. J. Neurooncol. 111, 41–48 (2013).
Levin, V. A., Chan, J., Datta, M., Yee, J. L. & Jain, R. K. Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab. J. Neurooncol. 134, 325–330 (2017).
Suminokura, J. et al. Potential efficacy of weekly low-dose administration of bevacizumab as a combination therapy for platinum-resistant ovarian carcinoma: a retrospective analysis. BMC Cancer 22, 176 (2022).
Garcia, A. A. et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J. Clin. Oncol. 26, 76–82 (2008).
Defferrari, C. et al. A case series of low dose bevacizumab and chemotherapy in heavily pretreated patients with epithelial ovarian cancer. J. Ovarian Res. 5, 17 (2012).
Bauer, N. et al. Therapy-induced modulation of tumor vasculature and oxygenation in a murine glioblastoma model quantified by deep learning-based feature extraction. Sci. Rep. 14, 2034 (2024).
Li, W., Quan, Y. Y., Li, Y., Lu, L. & Cui, M. Monitoring of tumor vascular normalization: the key points from basic research to clinical application. Cancer Manag. Res. 10, 4163–4172 (2018).
Park, J.-S., Park, I. & Koh, G. Y. in Tumor Angiogenesis: A Key Target for Cancer Therapy (ed. Dieter, M.) 51–71 (Springer International Publishing, 2019).
Sorensen, A. G. et al. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res. 72, 402–407 (2012). This study provides direct clinical evidence that vascular normalization can increase tumour perfusion and help improve the survival of patients with glioblastoma.
Batchelor, T. T. et al. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc. Natl Acad. Sci. USA 110, 19059–19064 (2013).
Emblem, K. E. et al. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat. Med. 19, 1178–1183 (2013).
Heist, R. S. et al. Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer. Proc. Natl Acad. Sci. USA 112, 1547–1552 (2015).
Ueda, S. et al. In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br. J. Cancer 114, 1212–1218 (2016).
Ueda, S., Saeki, T., Osaki, A., Yamane, T. & Kuji, I. Bevacizumab induces acute hypoxia and cancer progression in patients with refractory breast cancer: multimodal functional imaging and multiplex cytokine analysis. Clin. Cancer Res. 23, 5769–5778 (2017).
Rigamonti, N. et al. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 8, 696–706 (2014). This study demonstrates that tumour resistance to anti-VEGFA therapy enhances ANG2–TIE2 signalling, which can be reversed by ANG2 blockade.
Casazza, A. et al. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene 33, 1743–1754 (2014).
Martin, J. D., Fukumura, D., Duda, D. G., Boucher, Y. & Jain, R. K. Reengineering the tumor microenvironment to alleviate hypoxia and overcome cancer heterogeneity. Cold Spring Harb. Perspect. Med. 6, a027094 (2016).
Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014).
Fan, P. et al. Alleviating hypoxia to improve cancer immunotherapy. Oncogene 42, 3591–3604 (2023).
Rivera, L. B. & Bergers, G. Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends Immunol. 36, 240–249 (2015).
Barsoum, I. B., Smallwood, C. A., Siemens, D. R. & Graham, C. H. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 74, 665–674 (2014).
Du, R. et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).
De Palma, M., Biziato, D. & Petrova, T. V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457–474 (2017).
Missiaen, R., Mazzone, M. & Bergers, G. The reciprocal function and regulation of tumor vessels and immune cells offers new therapeutic opportunities in cancer. Semin. Cancer Biol. 52, 107–116 (2018).
Hua, Y. & Bergers, G. Tumors vs. chronic wounds: an immune cell’s perspective. Front. Immunol. 10, 2178 (2019).
Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475, 226–230 (2011).
Liu, A. et al. Hypoxia-activated prodrug and antiangiogenic therapies cooperatively treat pancreatic cancer but elicit immunosuppressive G-MDSC infiltration. JCI Insight 9, e169150 (2024).
Motz, G. T. & Coukos, G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat. Rev. Immunol. 11, 702–711 (2011).
Mazzone, M. & Bergers, G. Regulation of blood and lymphatic vessels by immune cells in tumors and metastasis. Annu. Rev. Physiol. 81, 535–560 (2019).
Huinen, Z. R., Huijbers, E. J. M., van Beijnum, J. R., Nowak-Sliwinska, P. & Griffioen, A. W. Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat. Rev. Clin. Oncol. 18, 527–540 (2021).
Lieu, C. H. et al. The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer. PLoS ONE 8, e77117 (2013).
Rivera, L. B. et al. Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Cell Rep. 11, 577–591 (2015).
Schmid, M. C. et al. PI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation. Nat. Commun. 13, 1768 (2022).
Shojaei, F. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat. Biotechnol. 25, 911–920 (2007).
Yang, S. et al. Neutrophil extracellular traps promote angiogenesis in gastric cancer. Cell Commun. Signal. 21, 176 (2023).
Sun, C., Mezzadra, R. & Schumacher, T. N. Regulation and function of the PD-L1 checkpoint. Immunity 48, 434–452 (2018).
Allen, E. et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl. Med. 9, eaak9679 (2017). This study provides evidence that anti-PDL1 therapy sensitizes tumours to anti-angiogenic therapy, and conversely, anti-angiogenic therapy can improve anti-PDL1 treatment through the formation of intratumoural high endothelial venules that facilitate enhanced cytotoxic T lymphocyte infiltration and activity.
Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl. Med. 9, eaak9670 (2017). This study revealed that the antitumour effects of dual blockade of ANG2 and VEGFA were partly dependent on cytotoxic T lymphocytes but blunted by upregulation of PDL1, whereas addition of PD1 blockade to the therapeutic regimen improved tumour growth control in different mouse tumour models.
Motz, G. T. & Coukos, G. Deciphering and reversing tumor immune suppression. Immunity 39, 61–73 (2013).
Huang, X. et al. Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. J. Exp. Med. 207, 505–520 (2010).
Mazanet, M. M. & Hughes, C. C. B7-H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J. Immunol. 169, 3581–3588 (2002).
Nambiar, D. K. et al. Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. J. Clin. Invest. 129, 5553–5567 (2019).
Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014). This study describes an FAS ligand-dependent mechanism of the tumour endothelium in forming an immune barrier.
Kabir, A. U. et al. Dual role of endothelial Myct1 in tumor angiogenesis and tumor immunity. Sci. Transl. Med. 13, eabb6731 (2021).
Khan, K. A. & Kerbel, R. S. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat. Rev. Clin. Oncol. 15, 310–324 (2018).
Gabrilovich, D. I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2, 1096–1103 (1996). This study demonstrates that VEGFA directly blocks dendritic cell maturation.
Gavalas, N. G. et al. VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2. Br. J. Cancer 107, 1869–1875 (2012).
Wada, J. et al. The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. Anticancer Res. 29, 881–888 (2009).
Terme, M. et al. VEGFA–VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 73, 539–549 (2013).
Huang, Y. et al. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood 110, 624–631 (2007).
Dirkx, A. E. et al. Tumor angiogenesis modulates leukocyte–vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res. 63, 2322–2329 (2003).
Tromp, S. C. et al. Tumor angiogenesis factors reduce leukocyte adhesion in vivo. Int. Immunol. 12, 671–676 (2000).
Lee, W. S., Yang, H., Chon, H. J. & Kim, C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular–immune crosstalk to potentiate cancer immunity. Exp. Mol. Med. 52, 1475–1485 (2020).
Di Tacchio, M. et al. Tumor vessel normalization, immunostimulatory reprogramming, and improved survival in glioblastoma with combined inhibition of PD-1, angiopoietin-2, and VEGF. Cancer Immunol. Res. 7, 1910–1927 (2019).
Park, H. R. et al. Angiopoietin-2-dependent spatial vascular destabilization promotes T-cell exclusion and limits immunotherapy in melanoma. Cancer Res. 83, 1968–1983 (2023).
Martinez-Usatorre, A. et al. Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Sci. Transl. Med. 13, eabd161 (2021).
Carretero, R. et al. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8+ T cells. Nat. Immunol. 16, 609–617 (2015).
Vaios, E. J., Winter, S. F., Muzikansky, A., Nahed, B. V. & Dietrich, J. Eosinophil and lymphocyte counts predict bevacizumab response and survival in recurrent glioblastoma. Neurooncol. Adv. 2, vdaa031 (2020).
Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017).
Schmid, M. C. & Varner, J. A. Myeloid cells in the tumor microenvironment: modulation of tumor angiogenesis and tumor inflammation. J. Oncol. 2010, 201026 (2010).
Benguigui, M. et al. Bv8 blockade sensitizes anti-PD1 therapy resistant tumors. Front. Immunol. 13, 903591 (2022).
Itatani, Y. et al. Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer. Proc. Natl Acad. Sci. USA 117, 21598–21608 (2020).
Yang, H. et al. STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade. J. Clin. Invest. 129, 4350–4364 (2019).
Sato, M. et al. Angiogenic inhibitor pre-administration improves the therapeutic effects of immunotherapy. Cancer Med. 12, 9760–9773 (2023).
Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).
McDermott, D. F. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24, 749–757 (2018).
Powles, T. et al. Efficacy and safety of atezolizumab plus bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with metastatic renal cell carcinoma in IMmotion150: a randomized phase 2 clinical trial. Eur. Urol. 79, 665–673 (2021).
Yi, M. et al. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol. Cancer 18, 60 (2019).
Granet-Vaissiere, E. et al. Combinations of anti-angiogenic agents and immune checkpoint inhibitors in renal cell carcinoma: best option? Cancers 15, 644 (2023).
Wu, F. T. H. et al. Pre- and post-operative anti-PD-L1 plus anti-angiogenic therapies in mouse breast or renal cancer models of micro- or macro-metastatic disease. Br. J. Cancer 120, 196–206 (2019).
Shigeta, K. et al. Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma. Hepatology 71, 1247–1261 (2020).
Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).
Socinski, M. A. et al. IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J. Thorac. Oncol. 16, 1909–1924 (2021).
Nogami, N. et al. IMpower150 final exploratory analyses for atezolizumab plus bevacizumab and chemotherapy in key NSCLC patient subgroups with EGFR mutations or metastases in the liver or brain. J. Thorac. Oncol. 17, 309–323 (2022).
Cheng, A. L. et al. IMbrave150: efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann. Oncol. 30, ix186–ix187 (2019).
Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).
Cheng, A. L. et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J. Hepatol. 76, 862–873 (2022).
Vogel, A., Meyer, T. & Saborowski, A. IMbrave050: the first step towards adjuvant therapy in hepatocellular carcinoma. Lancet 402, 1806–1807 (2023).
Hack, S. P. et al. IMbrave 050: a phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol. 16, 975–989 (2020).
Qin, S. et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1835–1847 (2023).
Jain, S., Chalif, E. J. & Aghi, M. K. Interactions between anti-angiogenic therapy and immunotherapy in glioblastoma. Front. Oncol. 11, 812916 (2021).
Nayak, L. et al. Randomized phase II and biomarker study of pembrolizumab plus bevacizumab versus pembrolizumab alone for patients with recurrent glioblastoma. Clin. Cancer Res. 27, 1048–1057 (2021).
Kuo, H. Y., Khan, K. A. & Kerbel, R. S. Antiangiogenic-immune-checkpoint inhibitor combinations: lessons from phase III clinical trials. Nat. Rev. Clin. Oncol. 21, 468–482 (2024).
Vella, G., Hua, Y. & Bergers, G. High endothelial venules in cancer: regulation, function, and therapeutic implication. Cancer Cell 41, 527–545 (2023). This review describes intratumoural high endothelial venules found in multiple human and mouse cancers and the comprehensive analyses of high endothelial venule-modulating signals and therapies.
Vella, G., Guelfi, S. & Bergers, G. High endothelial venules: a vascular perspective on tertiary lymphoid structures in cancer. Front. Immunol. 12, 736670 (2021).
Asrir, A. et al. Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell 40, 318–334.e319 (2022). This study reveals, using intravital microscopy, that intratumoural high endothelial venules are the main sites of lymphocyte arrest and extravasation into immune checkpoint blockade-treated tumours.
Streeter, P. R., Rouse, B. T. & Butcher, E. C. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J. Cell Biol. 107, 1853–1862 (1988).
Rosen, S. D. Ligands for L-selectin: homing, inflammation, and beyond. Annu. Rev. Immunol. 22, 129–156 (2004).
Girard, J. P., Moussion, C. & Forster, R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat. Rev. Immunol. 12, 762–773 (2012).
Ruddle, N. H. Regulation, maintenance, and remodeling of high endothelial venules in homeostasis, inflammation, and cancer. Curr. Opin. Physiol. 36, 100705 (2023).
Veerman, K., Tardiveau, C., Martins, F., Coudert, J. & Girard, J.-P. Single-cell analysis reveals heterogeneity of high endothelial venules and different regulation of genes controlling lymphocyte entry to lymph nodes. Cell Rep. 26, 3116–3131.e5 (2019).
Hua, Y. et al. Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1(+) T lymphocyte niches through a feed-forward loop. Cancer Cell 40, 1600–1618.e10 (2022). This study describes the regulation and function of intratumoural high endothelial venules, which provide a niche for TCF1+CD8+ progenitor cells that can differentiate into effector cells.
Martinet, L. et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 71, 5678–5687 (2011). This study identified for the first time that high endothelial venules are found in melanoma and breast, ovarian, colon and lung tumours and are associated with lymphocytes and correlate with a good prognosis.
Sautès-Fridman, C., Petitprez, F., Calderaro, J. & Fridman, W. H. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat. Rev. Cancer 19, 307–325 (2019).
Schumacher, T. N. & Thommen, D. S. Tertiary lymphoid structures in cancer. Science 375, eabf9419 (2022).
Fridman, W. H. et al. Tertiary lymphoid structures and B cells: an intratumoral immunity cycle. Immunity 56, 2254–2269 (2023).
Ye, D. et al. High endothelial venules predict response to PD-1 inhibitors combined with anti-angiogenesis therapy in NSCLC. Sci. Rep. 13, 16468 (2023).
Vanhersecke, L. et al. Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression. Nat. Cancer 2, 794–802 (2021).
Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).
Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).
Shen, H. et al. Alterations of high endothelial venules in primary and metastatic tumors are correlated with lymph node metastasis of oral and pharyngeal carcinoma. Cancer Biol. Ther. 15, 342–349 (2014).
Bekkhus, T. et al. Remodeling of the lymph node high endothelial venules reflects tumor invasiveness in breast cancer and is associated with dysregulation of perivascular stromal cells. Cancers 13, 211 (2021).
Ramachandran, M. et al. Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma. Cancer Cell 41, 1134–1151.e10 (2023).
Johansson-Percival, A. et al. De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors. Nat. Immunol. 18, 1207–1217 (2017). The study demonstrated that LIGHT targeted to tumours with a vascular targeting peptide in combination with immune checkpoint blockade generated an accumulation of intratumoural effector and memory T cells, which in turn provided mice with a survival benefit; the addition of an anti-tumour vaccine to this therapeutic regimen enabled maximal therapeutic efficacy to be achieved.
He, B. et al. Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules. J. Pathol. 245, 209–221 (2018).
Wang, Z. et al. DC101, an anti-VEGFR2 agent, promotes high-endothelial venule formation and immune infiltration versus SAR131675 and fruquintinib. Biochem. Biophys. Res. Commun. 661, 10–20 (2023).
Chelvanambi, M., Fecek, R. J., Taylor, J. L. & Storkus, W. J. STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment. J. Immunother. Cancer 9, e001906 (2021).
Liang, J. et al. Verteporfin inhibits PD-L1 through autophagy and the STAT1–IRF1–TRIM28 signaling axis, exerting antitumor efficacy. Cancer Immunol. Res. 8, 952–965 (2020).
Lauder, S. N. et al. Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3. J. Immunother. Cancer 8, e000693 (2020).
Faget, J. et al. Neutrophils and snail orchestrate the establishment of a pro-tumor microenvironment in lung cancer. Cell Rep. 21, 3190–3204 (2017).
Chaurio, R. A. et al. TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures. Immunity 55, 115–128.e9 (2022).
Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).
Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211.e10 (2019).
Vats, K. et al. Sensory nerves impede the formation of tertiary lymphoid structures and development of protective antimelanoma immune responses. Cancer Immunol. Res. 10, 1141–1154 (2022).
Gaceb, A. & Paul, G. in Pericyte Biology — Novel Concepts (ed. Birbrair, A.) 139–163 (Springer International Publishing, 2018).
De Palma, M. & Hanahan, D. Milestones in tumor vascularization and its therapeutic targeting. Nat. Cancer 5, 827–843 (2024).
Amersfoort, J., Eelen, G. & Carmeliet, P. Immunomodulation by endothelial cells — partnering up with the immune system? Nat. Rev. Immunol. 22, 576–588 (2022).
Pober, J. S. & Sessa, W. C. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol. 7, 803–815 (2007).
Zhou, T. et al. Microvascular endothelial cells engulf myelin debris and promote macrophage recruitment and fibrosis after neural injury. Nat. Neurosci. 22, 421–435 (2019).
Lohse, A. W. et al. Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells. Gastroenterology 110, 1175–1181 (1996).
Limmer, A. et al. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat. Med. 6, 1348–1354 (2000).
Stamatiades, E. G. et al. Immune monitoring of trans-endothelial transport by kidney-resident macrophages. Cell 166, 991–1003 (2016).
Carmeliet, P. Blood vessels and nerves: common signals, pathways and diseases. Nat. Rev. Genet. 4, 710–720 (2003).
Carmeliet, P. & Ruiz de Almodovar, C. VEGF ligands and receptors: implications in neurodevelopment and neurodegeneration. Cell Mol. Life Sci. 70, 1763–1778 (2013).
Hanahan, D. & Monje, M. Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer Cell 41, 573–580 (2023).
Zahalka, A. H. et al. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science 358, 321–326 (2017).
Hondermarck, H. & Jobling, P. The sympathetic nervous system drives tumor angiogenesis. Trends Cancer 4, 93–94 (2018).
Huang, D. et al. Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression. Nat. Cell Biol. 24, 230–241 (2022).
James, J. M. & Mukouyama, Y. S. Neuronal action on the developing blood vessel pattern. Semin. Cell Dev. Biol. 22, 1019–1027 (2011).
Holash, J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998 (1999).
Pichol-Thievend, C. et al. VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance. Nat. Commun. 15, 3602 (2024).
Donnem, T. et al. Non-angiogenic tumours and their influence on cancer biology. Nat. Rev. Cancer 18, 323–336 (2018). This review details the biology of non-angiogenic tumours and their implications for cancer treatment.
Kuczynski, E. A., Vermeulen, P. B., Pezzella, F., Kerbel, R. S. & Reynolds, A. R. Vessel co-option in cancer. Nat. Rev. Clin. Oncol. 16, 469–493 (2019).
García-Gómez, P. & Valiente, M. Vascular co-option in brain metastasis. Angiogenesis 23, 3–8 (2020).
Valiente, M. et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014).
Fan, J. et al. Integrin β4 signaling promotes mammary tumor cell adhesion to brain microvascular endothelium by inducing ErbB2-mediated secretion of VEGF. Ann. Biomed. Eng. 39, 2223–2241 (2011).
Yao, H. et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature 560, 55–60 (2018).
Carrera-Aguado, I. et al. The inhibition of vessel co-option as an emerging strategy for cancer therapy. Int. J. Mol. Sci. 25, 921 (2024).
Lu, K. V. et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22, 21–35 (2012).
Depner, C. et al. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. Nat. Commun. 7, 12329 (2016).
Haeger, A. et al. Collective cancer invasion forms an integrin-dependent radioresistant niche. J. Exp. Med. 217, e20181184 (2020).
Haj-Shomaly, J. et al. T cells promote metastasis by regulating extracellular matrix remodeling following chemotherapy. Cancer Res. 82, 278–291 (2022).
Teuwen, L. A. et al. Tumor vessel co-option probed by single-cell analysis. Cell Rep. 35, 109253 (2021). This report describes that single-cell RNA sequencing revealed a largely similar transcriptome between co-opted tumour endothelial cells and pericytes and their healthy counterparts, underscoring the observation that co-opted tumour vessels are distinct from angiogenic tumour vessels.
Leenders, W. P. et al. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin. Cancer Res. 10, 6222–6230 (2004).
Kuczynski, E. A. et al. Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma. J. Natl Cancer Inst. 108, djw030 (2016).
Bridgeman, V. L. et al. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J. Pathol. 241, 362–374 (2017).
Frentzas, S. et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat. Med. 22, 1294–1302 (2016). This study reveals that vessel co-option in human liver metastases is a clinically relevant mechanism of resistance to anti-angiogenic therapy.
Kuczynski, E. A. & Reynolds, A. R. Vessel co-option and resistance to anti-angiogenic therapy. Angiogenesis 23, 55–74 (2020).
Latacz, E. et al. Pathological features of vessel co-option versus sprouting angiogenesis. Angiogenesis 23, 43–54 (2020).
Cuypers, A., Truong, A. K., Becker, L. M., Saavedra-García, P. & Carmeliet, P. Tumor vessel co-option: the past & the future. Front. Oncol. 12, 965277 (2022).
Rada, M., Hassan, N., Lazaris, A. & Metrakos, P. The molecular mechanisms underlying neutrophil infiltration in vessel co-opting colorectal cancer liver metastases. Front. Oncol. 12, 1004793 (2022).
Acknowledgements
S.G. and G.B. are supported by grants from the Flemish government FWO (G072021N to S.G. and G0I2922N and G0A1122N to G.B.). K.H.-D. is supported through HEFCE funding from Queen Mary University of London with relevant scientific funding support from CRUK Programme Grant (CRUK DRCNPG-May21/100004), Barts Charity (MGU0601) Medical Research Council (MR/V009621/1) and Worldwide Cancer Research (19-0108).
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K.H.-D. is a consultant for Ellipesis, RGD-Science and Vasodynamics. G.B. is a consultant for Mestag. S.G. declares no competing interests.
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Glossary
- Anergy
-
In the context of T cells, it is a tolerance mechanism in which the lymphocyte is functionally inactivated following an antigen encounter. In the context of endothelial cells, it is a state in which endothelial cells no longer respond to inflammatory cytokines.
- Angiocrine
-
Derived from endothelial cells.
- Biosimilar
-
Non-generic versions of brand-name drugs that may offer more affordable treatment options to patients.
- Metronomic chemotherapy
-
Continuous and dose-dense administration of chemotherapeutic drugs.
- Mural cells
-
Pericytes and smooth muscle cells that surround and support blood vessels.
- Pericrine
-
Derived from pericytes.
- Pericytes
-
Mural cells covering blood microvessels, including capillaries.
- Secondary lymphoid organs
-
Encapsulated structures in which lymphocytes mount adaptive immune responses.
- Stalk cells
-
Endothelial cells that trail tip cells, proliferate and elongate the vascular sprout.
- Tertiary lymphoid structures
-
Ectopic lymphoid tissues that drive antigen-specific immune responses at sites of chronic inflammation.
- Tip cells
-
Migratory endothelial cells with long filopodia at the tip of the vascular sprout.
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Guelfi, S., Hodivala-Dilke, K. & Bergers, G. Targeting the tumour vasculature: from vessel destruction to promotion. Nat Rev Cancer 24, 655–675 (2024). https://doi.org/10.1038/s41568-024-00736-0
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DOI: https://doi.org/10.1038/s41568-024-00736-0