Angiogenesis and targeted therapy in the tumour microenvironment: From basic to clinical practice

Abstract

Angiogenesis, as a core marker of cancer survival and growth, is integral to the processes of tumour growth, invasion and metastasis. In recent years, targeted angiogenesis treatment strategies have gradually become an important direction in cancer treatment. Single-cell sequencing technology can provide new insights into targeted angiogenesis by providing a deeper understanding of the heterogeneity of tumour endothelial cells and exploring the interactions between endothelial cells and surrounding cells in the tumour microenvironment. Here, we systematically review the research progress in endothelial cell pathophysiology and its endothelial‒mesenchymal transition and illustrate the heterogeneity of endothelial cells from a single-cell perspective. Finally, we examine the contributions of different cell types within the tumour microenvironment in relation to tumour angiogenesis, as well as the latest progress and strategies in targeted angiogenesis therapy, hoping to provide useful insights into the clinical application of antiangiogenic treatment. Furthermore, a summary of the present progress in the development of potential angiogenesis inhibitors and the ongoing clinical trials for combination therapies is provided.

Keywords

angiogenesis / antiangiogenic therapy / cancer / EndMT / endothelial cells

References

[1] Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002; 29: 15-18.

[2] Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971; 285: 1182-1186.

[3] Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350: 2335-2342.

[4] Zeng Q, Mousa M, Nadukkandy AS, et al. Understanding tumour endothelial cell heterogeneity and function from single-cell omics. Nat Rev Cancer. 2023; 23: 544-564.

[5] Lopes-Coelho F, Martins F, Serpa J. Endothelial cells (ECs) metabolism: a valuable piece to disentangle cancer biology. Adv Exp Med Biol. 2020; 1219: 143-159.

[6] Krüger-Genge A, Blocki A, Franke RP, Jung F. Vascular endothelial cell biology: an update. Int J Mol Sci. 2019; 20: 4411.

[7] Pelosi E, Castelli G, Testa U. Endothelial progenitors. Blood Cells Mol Dis. 2014; 52: 186-194.

[8] De Val S, Chi NC, Meadows SM, et al. Combinatorial regulation of endothelial gene expression by ets and forkhead transcription factors. Cell. 2008; 135: 1053-1064.

[9] Chavkin NW, Genet G, Poulet M, et al. Endothelial cell cycle state determines propensity for arterial-venous fate. Nat Commun. 2022; 13: 5891.

[10] Hida K, Maishi N, Annan DA, Hida Y. Contribution of tumor endothelial cells in cancer progression. Int J Mol Sci. 2018; 19: 1272.

[11] Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci. 2020; 77: 1745-1770.

[12] Draoui N, de Zeeuw P, Carmeliet P. Angiogenesis revisited from a metabolic perspective: role and therapeutic implications of endothelial cell metabolism. Open Biol. 2017; 7: 170219.

[13] Fang J-H, Chen J-Y, Zheng J-L, et al. Fructose metabolism in tumor endothelial cells promotes angiogenesis by activating AMPK signaling and mitochondrial respiration. Cancer Res. 2023; 83: 1249-1263.

[14] Bloom SI, Islam MT, Lesniewski LA, Donato AJ. Mechanisms and consequences of endothelial cell senescence. Nat Rev Cardiol. 2023; 20: 38-51.

[15] Liu J, Chen S, Biswas S, et al. Glucose-induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs. Physiol Rep. 2020; 8: e14331.

[16] Kim S, Piao S, Lee I, et al. CR6 interacting factor 1 deficiency induces premature senescence via SIRT3 inhibition in endothelial cells. Free Radic Biol Med. 2020; 150: 161-171.

[17] Khor ES, Wong PF. The roles of MTOR and miRNAs in endothelial cell senescence. Biogerontology. 2020; 21: 517-530.

[18] Yan Li, Xie Xu, Niu B-X, et al. Involvement of miR-199a-3p/DDR1 in vascular endothelial cell senescence in diabetes. Eur J Pharmacol. 2021; 908: 174317.

[19] Liu Y, Yang J, Yang X, et al. H₂O₂ down-regulates SIRT7's protective role of endothelial premature dysfunction via microRNA-335-5p. Biosci Rep. 2022; 42: BSR20211775.

[20] Haston S, Gonzalez-Gualda E, Morsli S, et al. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell. 2023; 41: 1242-1260.

[21] Yu S, Cheng Yu, Li B, et al. M1 macrophages accelerate renal glomerular endothelial cell senescence through reactive oxygen species accumulation in streptozotocin-induced diabetic mice. Int Immunopharmacol. 2020; 81: 106294.

[22] Zeng M, Zhang X, Xing W, Wang Q, Liang G, He Z. Cigarette smoke extract mediates cell premature senescence in chronic obstructive pulmonary disease patients by up-regulating USP7 to activate p300-p53/p21 pathway. Toxicol Lett. 2022; 359: 31-45.

[23] Hwang HJ, Kim N, Herman AB, Gorospe M, Lee J-S. Factors and pathways modulating endothelial cell senescence in vascular aging. Int J Mol Sci. 2022; 23: 10135.

[24] Xiong J, Dong Lu, Lv Q, et al. Targeting senescence-associated secretory phenotypes to remodel the tumour microenvironment and modulate tumour outcomes. Clin Transl Med. 2024; 14: e1772.

[25] Wu Z, Uhl B, Gires O, Reichel CA. A transcriptomic pan-cancer signature for survival prognostication and prediction of immunotherapy response based on endothelial senescence. J Biomed Sci. 2023; 30: 21.

[26] Giacinti C, Giordano A. RB and cell cycle progression. Oncogene. 2006; 25: 5220-5227.

[27] Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007; 8: 729-740.

[28] Dong Z, Luo Y, Yuan Z, Tian Y, Jin T, Xu F. Cellular senescence and SASP in tumor progression and therapeutic opportunities. Mol Cancer. 2024; 23: 181.

[29] Miwa S, Kashyap S, Chini E, von Zglinicki T. Mitochondrial dysfunction in cell senescence and aging. J Clin Invest. 2022: 132: e158447.

[30] Lafargue A, Degorre C, Corre I, et al. Ionizing radiation induces long-term senescence in endothelial cells through mitochondrial respiratory complex II dysfunction and superoxide generation. Free Radic Biol Med. 2017; 108: 750-759.

[31] Huo J, Xu Z, Hosoe K, et al. Coenzyme Q10 prevents senescence and dysfunction caused by oxidative stress in vascular endothelial cells. Oxid Med Cell Longev. 2018; 2018: 3181759.

[32] Hwang HJ, Lee Y-R, Kang D, et al. Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells. Cancer Lett. 2020; 490: 100-110.

[33] Wang D, Xiao F, Feng Z, et al. Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence. Breast Cancer Res. 2020; 22: 103.

[34] Ma L, He X, Fu Y, Ge S, Yang Z. Senescent endothelial cells promote liver metastasis of uveal melanoma in single-cell resolution. J Transl Med. 2024; 22: 605.

[35] López-Otín C, Pietrocola F, Roiz-Valle D, Galluzzi L, Kroemer G. Meta-hallmarks of aging and cancer. Cell Metab. 2023; 35: 12-35.

[36] Chou Y-H, Lee Y-N, Su C-H, et al. Senescence induces miR-409 to down-regulate CCL5 and impairs angiogenesis in endothelial progenitor cells. J Cell Mol Med. 2024; 28: e18489.

[37] Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther. 2023; 8: 198.

[38] Dritsoula A, Camilli C, Moss SE, Greenwood J. The disruptive role of LRG1 on the vasculature and perivascular microenvironment. Front Cardiovasc Med. 2024; 11: 1386177.

[39] Camilli C, Hoeh AE, De Rossi G, Moss SE, Greenwood J. LRG1: an emerging player in disease pathogenesis. J Biomed Sci. 2022; 29: 6.

[40] O'connor MN, Kallenberg DM, Camilli C, et al. LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency. Med. 2021; 2: 1231-1252.e1210.

[41] Kwan YP, Teo MHY, Lim JCW, et al. LRG1 promotes metastatic dissemination of melanoma through regulating EGFR/STAT3 signalling. Cancers (Basel). 2021: 13: 3279.

[42] Hoefsmit EP, Völlmy F, Rozeman EA, et al. Systemic LRG1 expression in melanoma is associated with disease progression and recurrence. Cancer Res Commun. 2023; 3: 672-683.

[43] Ma W, Wang Y, Zhang R, et al. Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma. Nat Cancer. 2021; 2: 83-97.

[44] Vemuri K, De Alves Pereira B, Fuenzalida P, et al. CD93 maintains endothelial barrier function and limits metastatic dissemination. JCI Insight. 2024; 9: e169830.

[45] Yi L, Liang Y, Zhao Q, Wang H, Dong J. CX3CL1 induces vertebral microvascular barrier dysfunction via the Src/P115-RhoGEF/ROCK signaling pathway. Front Cell Neurosci. 2020; 14: 96.

[46] Zhang D, Li AM, Hu G, et al. PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T cell immunotherapy. Cell Metab. 2023; 35: 517-534.e518.

[47] Rossi M, Altea-Manzano P, Demicco M, et al. PHGDH heterogeneity potentiates cancer cell dissemination and metastasis. Nature. 2022; 605: 747-753.

[48] Ribatti D. Judah Folkman, a pioneer in the study of angiogenesis. Angiogenesis. 2008; 11: 3-10.

[49] Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000; 407: 249-257.

[50] Liu Z, Chen J, Ren Y, et al. Multi-stage mechanisms of tumor metastasis and therapeutic strategies. Signal Transduct Target Ther. 2024; 9: 270.

[51] Dou R, Liu K, Yang C, et al. EMT-cancer cells-derived exosomal miR-27b-3p promotes circulating tumour cells-mediated metastasis by modulating vascular permeability in colorectal cancer. Clin Transl Med. 2021; 11: e595.

[52] Zeng Z, Li Y, Pan Y, et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun. 2018; 9: 5395.

[53] Li K, Xue W, Lu Z, et al. Tumor-derived exosomal ADAM17 promotes pre-metastatic niche formation by enhancing vascular permeability in colorectal cancer. J Exp Clin Cancer Res. 2024; 43: 59.

[54] Roblek M, Protsyuk D, Becker PF, et al. CCL2 is a vascular permeability factor inducing CCR2-dependent endothelial retraction during lung metastasis. Mol Cancer Res. 2019; 17: 783-793.

[55] Chen X, Li Q, Fu X, et al. Tumor-derived EBV-miR-BART2-5p promotes nasopharyngeal carcinoma metastasis by inducing pre-metastatic endothelial cell pyroptosis. Mol Cancer Res. 2025; 23: 250-262.

[56] Nowak-Sliwinska P, Van Beijnum JR, Griffioen CJ, et al. Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy. Angiogenesis. 2023; 26: 279-293.

[57] Griffioen AW, Damen CA, Martinotti S, Blijham GH, Groenewegen G. Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res. 1996; 56: 1111-1117.

[58] Shao Y, Saredy J, Yang WY, et al. Vascular endothelial cells and innate immunity. Arterioscler Thromb Vasc Biol. 2020; 40: e138-e152.

[59] Motz GT, Santoro SP, Wang L-P, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med. 2014; 20: 607-615.

[60] Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996; 2: 1096-1103.

[61] Huinen ZR, Huijbers EJM, van Beijnum JR, Nowak-Sliwinska P, Griffioen AW. Anti-angiogenic agents—overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat Rev Clin Oncol. 2021; 18: 527-540.

[62] Wachholz GE, Akbari P, Huijbers EJM, Jalan P, Van Beijnum JR, Griffioen AW. Targeting endothelial cell anergy to improve CAR T cell therapy for solid tumors. Biochim Biophys Acta Rev Cancer. 2024; 1879: 189155.

[63] Woodward J. Crossing the endothelium: e-selectin regulates tumor cell migration under flow conditions. Cell Adh Migr. 2008; 2: 151-152.

[64] Ghajar CM, Peinado H, Mori H, et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013; 15: 807-817.

[65] Peinado H, Zhang H, Matei IR, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017; 17: 302-317.

[66] Li J, Wang D, Tang F, Ling X, Zhang W, Zhang Z. Pan-cancer integrative analyses dissect the remodeling of endothelial cells in human cancers. Natl Sci Rev. 2024; 11(9): nwae231.

[67] Pan X, Li X, Dong L, et al. Tumour vasculature at single-cell resolution. Nature. 2024; 632: 429-436.

[68] Zheng Y, Pan Y-Q, Liao K, et al. Pan-cancer landscape of tumour endothelial cells pinpoints insulin receptor as a novel antiangiogenic target and predicts immunotherapy response. Clin Transl Med. 2023; 13: e1501.

[69] Papait A, Romoli J, Stefani FR, et al. Fight the cancer, hit the CAF! Cancers (Basel). 2022; 14: 3570.

[70] Clere N, Renault S, Corre I. Endothelial-to-mesenchymal transition in cancer. Front Cell Dev Biol. 2020; 8: 747.

[71] Li Y, Lui KO, Zhou B. Reassessing endothelial-to-mesenchymal transition in cardiovascular diseases. Nat Rev Cardiol. 2018; 15: 445-456.

[72] Platel V, Faure S, Corre I, Clere N. Endothelial-to-mesenchymal transition (EndoMT): roles in tumorigenesis, metastatic extravasation and therapy resistance. J Oncol. 2019; 2019: 8361945.

[73] Unterleuthner D, Neuhold P, Schwarz K, et al. Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer. Angiogenesis. 2020; 23: 159-177.

[74] Liu T, Ma W, Xu H, et al. PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma. Nat Commun. 2018; 9: 3439.

[75] Nie L, Lyros O, Medda R, et al. Endothelial‒mesenchymal transition in normal human esophageal endothelial cells cocultured with esophageal adenocarcinoma cells: role of IL-1β and TGF-β2. Am J Physiol Cell Physiol. 2014; 307: C859-C877.

[76] Ghiabi P, Jiang J, Pasquier J, et al. Breast cancer cells promote a notch-dependent mesenchymal phenotype in endothelial cells participating to a pro-tumoral niche. J Transl Med. 2015; 13: 27.

[77] Fan C-S, Chen W-S, Chen L-L, et al. Osteopontin-integrin engagement induces HIF-1α-TCF12-mediated endothelial‒mesenchymal transition to exacerbate colorectal cancer. Oncotarget. 2018; 9: 4998-5015.

[78] Yang S, Wang S, Chen L, et al. Neutrophil extracellular traps delay diabetic wound healing by inducing endothelial-to-mesenchymal transition via the Hippo pathway. Int J Biol Sci. 2023; 19: 347-361.

[79] Adjuto-Saccone M, Soubeyran P, Garcia J, et al. TNF-α induces endothelial-mesenchymal transition promoting stromal development of pancreatic adenocarcinoma. Cell Death Dis. 2021; 12: 649.

[80] Yoshimatsu Y, Wakabayashi I, Kimuro S, et al. TNF-α enhances TGF-β-induced endothelial-to-mesenchymal transition via TGF-β signal augmentation. Cancer Sci. 2020; 111: 2385-2399.

[81] Fang JS, Hultgren NW, Hughes CCW. Regulation of partial and reversible endothelial-to-mesenchymal transition in angiogenesis. Front Cell Dev Biol. 2021; 9: 702021.

[82] Welch-Reardon KM, Wu N, Hughes CC. A role for partial endothelial-mesenchymal transitions in angiogenesis? Arterioscler Thromb Vasc Biol. 2015; 35: 303-308.

[83] Wang K, Chen X. Autophagic tumor-associated macrophages promote the endothelial mesenchymal transition in lung adenocarcinomas through the FUT4/p-ezrin pathway. J Thorac Dis. 2021; 13: 5973-5985.

[84] Mina SG, Huang P, Murray BT, Mahler GJ. The role of shear stress and altered tissue properties on endothelial to mesenchymal transformation and tumor-endothelial cell interaction. Biomicrofluidics. 2017; 11: 044104.

[85] Jiao K, Zhen J, Wu M, et al. 27-Hydroxycholesterol-induced EndMT acts via STAT3 signaling to promote breast cancer cell migration by altering the tumor microenvironment. Cancer Biol Med. 2020; 17: 88-100.

[86] Choi S-H, Kim A-R, Nam J-K, et al. Tumour-vasculature development via endothelial-to-mesenchymal transition after radiotherapy controls CD44v6(+) cancer cell and macrophage polarization. Nat Commun. 2018; 9: 5108.

[87] Wawro ME, Sobierajska K, Ciszewski WM, Niewiarowska J. Nonsteroidal anti-inflammatory drugs prevent vincristine-dependent cancer-associated fibroblasts formation. Int J Mol Sci. 2019: 20: 1941.

[88] Banerjee D, Barton SM, Grabham PW, et al. High-dose radiation increases Notch1 in tumor vasculature. Int J Radiat Oncol Biol Phys. 2020; 106: 857-866.

[89] Hata A, Chen YG. TGF-β signaling from receptors to Smads. Cold Spring Harb Perspect Biol. 2016; 8: a022061.

[90] Marín-Ramos NI, Jhaveri N, Thein TZ, Fayngor RA, Chen TC, Hofman FM. NEO212, a conjugate of temozolomide and perillyl alcohol, blocks the endothelial-to-mesenchymal transition in tumor-associated brain endothelial cells in glioblastoma. Cancer Lett. 2019; 442: 170-180.

[91] Yeon JH, Jeong HE, Seo H, et al. Cancer-derived exosomes trigger endothelial to mesenchymal transition followed by the induction of cancer-associated fibroblasts. Acta Biomater. 2018; 76: 146-153.

[92] Huang M, Liu T, Ma P, et al. c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma. J Clin Invest. 2016; 126: 1801-1814.

[93] Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 2007; 67: 10123-10128.

[94] Fan C-S, Chen L-L, Hsu T-A, et al. Endothelial-mesenchymal transition harnesses HSP90α-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma. J Hematol Oncol. 2019; 12: 138.

[95] Choi KJ, Nam JK, Kim JH, Choi SH, Lee YJ. Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage. Exp Mol Med. 2020; 52: 781-792.

[96] Wang Z, Kim SoY, Tu W, et al. Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment. Cell Metab. 2023; 35: 1209-1226.e1213.

[97] Fang Y, Cui W, Yang Y, Zhang X, Tian M, Xie Z, et al. Breaking the premetastatic niche barrier: the role of endothelial cells and therapeutic strategies. Theranostics. 2025.

[98] Kim J, Lee C, Kim I, et al. Three-dimensional human liver-chip emulating premetastatic niche formation by breast cancer-derived extracellular vesicles. ACS Nano. 2020; 14: 14971-14988.

[99] Yan L, Wang J, Cai X, et al. Macrophage plasticity: signaling pathways, tissue repair, and regeneration. MedComm (2020). 2024; 5: e658.

[100] Dallavalasa S, Beeraka NM, Basavaraju CG, et al. The role of tumor associated macrophages (TAMs) in cancer progression, chemoresistance, angiogenesis and metastasis—current status. Curr Med Chem. 2021; 28: 8203-8236.

[101] Kalucka J, Bierhansl L, Wielockx B, Carmeliet P, Eelen G. Interaction of endothelial cells with macrophages-linking molecular and metabolic signaling. Pflugers Arch. 2017; 469: 473-483.

[102] Fu L-Q, Du W-L, Cai M-H, Yao J-Y, Zhao Y-Y, Mou X-Z. The roles of tumor-associated macrophages in tumor angiogenesis and metastasis. Cell Immunol. 2020; 353: 104119.

[103] Wang R, Wu N-S, Wang Li, et al. A pan-cancer analysis of Wnt family member 7B in human cancers. Cancer Innov. 2024; 3: e139.

[104] Wang Z, Wu Z, Wang H, et al. An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development. Cell. 2023; 186: 4454-4471.e4419.

[105] Ronca R, Van Ginderachter JA, Turtoi A. Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: tumor allies and foes. Curr Opin Oncol. 2018; 30: 45-53.

[106] Crawford Y, Kasman I, Yu L, et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2009; 15: 21-34.

[107] Anderberg C, Li H, Fredriksson L, et al. Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res. 2009; 69: 369-378.

[108] Pietras K, Pahler J, Bergers G, Hanahan D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 2008; 5: e19.

[109] Kang S-Y, Halvorsen OJ, Gravdal K, et al. Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1. Proc Natl Acad Sci U S A. 2009; 106: 12115-12120.

[110] Tesi RJ. MDSC; the most important cell you have never heard of. Trends Pharmacol Sci. 2019; 40: 4-7.

[111] Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017; 5: 3-8.

[112] Vetsika EK, Koukos A, Kotsakis A. Myeloid-derived suppressor cells: major figures that shape the immunosuppressive and angiogenic network in cancer. Cells. 2019; 8: 1647.

[113] Itatani Y, Kawada K, Yamamoto T, Sakai Y. Resistance to anti-angiogenic therapy in cancer-alterations to anti-VEGF pathway. Int J Mol Sci. 2018; 19: 1232.

[114] Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol. 2018; 9: 978.

[115] Wang Y, Ding Y, Guo N, Wang SM. Key criminals of tumor pre-metastatic niche formation. Front Immunol. 2019; 10: 172.

[116] Binsfeld M, Muller J, Lamour V, et al. Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma. Oncotarget. 2016; 7: 37931-37943.

[117] Zöller M. Janus-faced myeloid-derived suppressor cell exosomes for the good and the bad in cancer and autoimmune disease. Front Immunol. 2018; 9: 137.

[118] Ostrand-Rosenberg S, Fenselau C. Myeloid-derived suppressor cells: immune-suppressive cells that impair antitumor immunity and are sculpted by their environment. J Immunol. 2018; 200: 422-431.

[119] Geis-Asteggiante L, Belew AT, Clements VK, et al. Differential content of proteins, mRNAs, and miRNAs suggests that MDSC and their exosomes may mediate distinct immune suppressive functions. J Proteome Res. 2018; 17: 486-498.

[120] Rivera LB, Bergers G. Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends Immunol. 2015; 36: 240-249.

[121] Johnson BW, Achyut BR, Fulzele S, Mondal AK, Kolhe R, Arbab AS. Delineating pro-angiogenic myeloid cells in cancer therapy. Int J Mol Sci. 2018; 19: 2565.

[122] Zhou Y, Cheng L, Liu L, Li X. NK cells are never alone: crosstalk and communication in tumour microenvironments. Mol Cancer. 2023; 22: 34.

[123] Thompson TW, Kim AB, Li PJ, et al. Endothelial cells express NKG2D ligands and desensitize antitumor NK responses. Elife. 2017; 6: e30881.

[124] Dondero A, Casu B, Bellora F, et al. NK cells and multiple myeloma-associated endothelial cells: molecular interactions and influence of IL-27. Oncotarget. 2017; 8: 35088-35102.

[125] Jun HW, Lee HK, Na IH, et al. The role of CCL2, CCL7, ICAM-1, and VCAM-1 in interaction of endothelial cells and natural killer cells. Int Immunopharmacol. 2022; 113: 109332.

[126] Jiang Z, Zhou J, Li L, et al. Pericytes in the tumor microenvironment. Cancer Lett. 2023; 556: 216074.

[127] Stratman AN, Schwindt AE, Malotte KM, Davis GE. Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood. 2010; 116: 4720-4730.

[128] Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005; 97: 512-523.

[129] Guo P, Hu Bo, Gu W, et al. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am J Pathol. 2003; 162: 1083-1093.

[130] Thies KA, Hammer AM, Hildreth BE, et al. Stromal platelet-derived growth factor receptor-β signaling promotes breast cancer metastasis in the brain. Cancer Res. 2021; 81: 606-618.

[131] Huang F-J, You W-K, Bonaldo P, Seyfried TN, Pasquale EB, Stallcup WB. Pericyte deficiencies lead to aberrant tumor vascularizaton in the brain of the NG2 null mouse. Dev Biol. 2010; 344: 1035-1046.

[132] Song N, Huang Y, Shi H, et al. Overexpression of platelet-derived growth factor-BB increases tumor pericyte content via stromal-derived factor-1alpha/CXCR4 axis. Cancer Res. 2009; 69: 6057-6064.

[133] Meng M-B, Zaorsky NG, Deng L, et al. Pericytes: a double-edged sword in cancer therapy. Future Oncol. 2015; 11: 169-179.

[134] Yonenaga Y, Mori A, Onodera H, et al. Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology. 2005; 69: 159-166.

[135] Liang W, Ferrara N. The complex role of neutrophils in tumor angiogenesis and metastasis. Cancer Immunol Res. 2016; 4: 83-91.

[136] De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017; 17: 457-474.

[137] Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer. 2016; 16: 431-446.

[138] Zhu T, Ge X, Gong S, et al. Prognostic value of lactate transporter SLC16A1 and SLC16A3 as oncoimmunological biomarkers associating tumor metabolism and immune evasion in glioma. Cancer Innov. 2022; 1: 229-239.

[139] Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest. 2008; 118: 3367-3377.

[140] Jablonska J, Leschner S, Westphal K, Lienenklaus S, Weiss S. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest. 2010; 120: 1151-1164.

[141] Qu X, Zhuang G, Yu L, Meng G, Ferrara N. Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: key role of Stat3 signaling. J Biol Chem. 2012; 287: 19574-19584.

[142] Gaudry M, Brégerie O, Andrieu V, El Benna J, Pocidalo M-A, Hakim J. Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood. 1997; 90: 4153-4161.

[143] Zhong C, Qu X, Tan M, Meng YG, Ferrara N. Characterization and regulation of bv8 in human blood cells. Clin Cancer Res. 2009; 15: 2675-2684.

[144] Shojaei F, Wu X, Zhong C, et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature. 2007; 450: 825-831.

[145] Ardi VC, Kupriyanova TA, Deryugina EI, Quigley JP. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A. 2007; 104: 20262-20267.

[146] Deryugina EI, Zajac E, Juncker-Jensen A, Kupriyanova TA, Welter L, Quigley JP. Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP-9 in the tumor microenvironment. Neoplasia. 2014; 16: 771-788.

[147] Aponte-López A, Muñoz-Cruz S. Mast cells in the tumor microenvironment. Adv Exp Med Biol. 2020; 1273: 159-173.

[148] Ammendola M, Leporini C, Marech I, et al. Targeting mast cells tryptase in tumor microenvironment: a potential antiangiogenetic strategy. Biomed Res Int. 2014; 2014: 154702.

[149] Ribatti D, Ranieri G. Tryptase, a novel angiogenic factor stored in mast cell granules. Exp Cell Res. 2015; 332: 157-162.

[150] Kabiraj A, Jaiswal R, Singh A, Gupta J, Singh A, Samadi FM. Immunohistochemical evaluation of tumor angiogenesis and the role of mast cells in oral squamous cell carcinoma. J Cancer Res Ther. 2018; 14: 495-502.

[151] Aponte-López A, Fuentes-Pananá EM, Cortes-Muñoz D, Muñoz-Cruz S. Mast cell, the neglected member of the tumor microenvironment: role in breast cancer. J Immunol Res. 2018; 2018: 2584243.

[152] Cimpean AM, Tamma R, Ruggieri S, Nico B, Toma A, Ribatti D. Mast cells in breast cancer angiogenesis. Crit Rev Oncol Hematol. 2017; 115: 23-26.

[153] Alda S, Ceausu RA, Gaje PN, Raica M, Cosoroaba RM. Mast cell: a mysterious character in skin cancer. Vivo. 2024; 38: 58-68.

[154] Micu GV, Stăniceanu F, Sticlaru LC, et al. Correlations between the density of tryptase positive mast cells (DMCT) and that of new blood vessels (CD105+) in patients with gastric cancer. Rom J Intern Med. 2016; 54: 113-120.

[155] Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015; 348: 74-80.

[156] Akbari P, Katsarou A, Daghighian R, et al. Directing CAR T cells towards the tumor vasculature for the treatment of solid tumors. Biochim Biophys Acta Rev Cancer. 2022; 1877: 188701.

[157] Taguchi K, Onoe T, Yoshida T, Yamashita Y, Tanaka Y, Ohdan H. Tumor endothelial cell-mediated antigen-specific T-cell suppression via the PD-1/PD-L1 pathway. Mol Cancer Res. 2020; 18: 1427-1440.

[158] Tian L, Goldstein A, Wang H, et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature. 2017; 544: 250-254.

[159] Denardo DG, Barreto JB, Andreu P, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009; 16: 91-102.

[160] Baer C, Squadrito ML, Laoui D, et al. Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity. Nat Cell Biol. 2016; 18: 790-802.

[161] Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010; 11: 889-896.

[162] Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol. 2011; 11: 702-711.

[163] Downs-Canner SM, Meier J, Vincent BG, Serody JS. B cell function in the tumor microenvironment. Annu Rev Immunol. 2022; 40: 169-193.

[164] Yang C, Lee H, Pal S, et al. B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS One. 2013; 8: e64159.

[165] Van De Veen W, Globinska A, Jansen K, et al. A novel proangiogenic B cell subset is increased in cancer and chronic inflammation. Sci Adv. 2020; 6: eaaz3559.

[166] Minami S, Matsumoto K, Nagashio R, et al. Analysis of autoantibodies related to tumor progression in sera from patients with high-grade non-muscle-invasive bladder cancer. Anticancer Res. 2017; 37: 6705-6714.

[167] Barbera-Guillem E, Nelson MB, Barr B, et al. B lymphocyte pathology in human colorectal cancer. Experimental and clinical therapeutic effects of partial B cell depletion. Cancer Immunol Immunother. 2000; 48: 541-549.

[168] Nyhus JK, Wolford CC, Friece CR, Nelson BM, Sampsel JW, Barbera-Guillem E. IgG-recognizing shed tumor-associated antigens can promote tumor invasion and metastasis. Cancer Immunol Immunother. 2001; 50: 361-372.

[169] Yasuma R, Cicatiello V, Mizutani T, et al. Intravenous immune globulin suppresses angiogenesis in mice and humans. Signal Transduct Target Ther. 2016; 1: 15002.

[170] He H, Wu J, Zang M, et al. CCR6(+) B lymphocytes responding to tumor cell-derived CCL20 support hepatocellular carcinoma progression via enhancing angiogenesis. Am J Cancer Res. 2017; 7: 1151-1163.

[171] Zhang Z, Zhu Y, Wang Z, Zhang T, Wu P, Huang J. Yin-yang effect of tumor infiltrating B cells in breast cancer: from mechanism to immunotherapy. Cancer Lett. 2017; 393: 1-7.

[172] Shen Y, Wang X, Liu Y, et al. STAT3‒YAP/TAZ signaling in endothelial cells promotes tumor angiogenesis. Sci Signal. 2021; 14: eabj8393.

[173] Kam NW, Wu KC, Dai W, et al. Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma. Angiogenesis. 2022; 25: 181-203.

[174] Blonska M, Agarwal NK, Vega F. Shaping of the tumor microenvironment: stromal cells and vessels. Semin Cancer Biol. 2015; 34: 3-13.

[175] Vincent FB, Saulep-Easton D, Figgett WA, Fairfax KA, Mackay F. The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev. 2013; 24: 203-215.

[176] Guelfi S, Hodivala-Dilke K, Bergers G. Targeting the tumour vasculature: from vessel destruction to promotion. Nat Rev Cancer. 2024; 24: 655-675.

[177] Ribatti D, Annese T, Ruggieri S, Tamma R, Crivellato E. Limitations of anti-angiogenic treatment of tumors. Transl Oncol. 2019; 12: 981-986.

[178] Magnussen AL, Mills IG. Vascular normalisation as the stepping stone into tumour microenvironment transformation. Br J Cancer. 2021; 125: 324-336.

[179] Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005; 307: 58-62.

[180] Bruning U, Morales-Rodriguez F, Kalucka J, et al. Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation. Cell Metab. 2018; 28: 866-880.e815.

[181] Conradi L-C, Brajic A, Cantelmo AR, et al. Tumor vessel disintegration by maximum tolerable PFKFB3 blockade. Angiogenesis. 2017; 20: 599-613.

[182] Maes H, Kuchnio A, Peric A, et al. Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell. 2014; 26: 190-206.

[183] Lv H, Zong Q, Chen C, et al. TET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer. Nat Commun. 2024; 15: 6.

[184] Smolarczyk R, Czapla J, Jarosz-Biej M, Czerwinski K, Cichoń T. Vascular disrupting agents in cancer therapy. Eur J Pharmacol. 2021; 891: 173692.

[185] 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. 2018; 91: 996-1006.

[186] Liu Z, Zhang Y, Shen N, Sun J, Tang Z, Chen X. Destruction of tumor vasculature by vascular disrupting agents in overcoming the limitation of EPR effect. Adv Drug Deliv Rev. 2022; 183: 114138.

[187] Takara K, Eino D, Ando K, et al. Lysophosphatidic acid receptor 4 activation augments drug delivery in tumors by tightening endothelial cell-cell contact. Cell Rep. 2017; 20: 2072-2086.

[188] Funahashi Y, Okamoto K, Adachi Y, et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci. 2014; 105: 1334-1342.

[189] Guo F, Cui J. Anti-angiogenesis: opening a new window for immunotherapy. Life Sci. 2020; 258: 118163.

[190] Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018; 15: 310-324.

[191] La Porta S, Roth L, Singhal M, et al. Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis. J Clin Invest. 2018; 128: 834-845.

[192] Leong A, Kim M. The angiopoietin-2 and TIE pathway as a therapeutic target for enhancing antiangiogenic therapy and immunotherapy in patients with advanced cancer. Int J Mol Sci. 2020; 21: 8689.

[193] Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018; 15: 325-340.

[194] Schmittnaegel M, Rigamonti N, Kadioglu E, et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med. 2017; 9: eaak9670.

[195] Johansson-Percival A, He B, Li Z-J, et al. De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors. Nat Immunol. 2017; 18: 1207-1217.

[196] Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med. 2017; 9: eaak9679.

[197] Yang H, Lee WS, Kong SJ, et al. STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade. J Clin Invest. 2019; 129: 4350-4364.

[198] Wang L, Luo Y, Ren S, et al. A phase 1b study of ivonescimab, a programmed cell death protein-1 and vascular endothelial growth factor bispecific antibody, as first- or second-line therapy for advanced or metastatic immunotherapy-naive NSCLC. J Thorac Oncol. 2024; 19: 465-475.

[199] Xing R, Gao J, Cui Q, Wang Q. Strategies to improve the antitumor effect of immunotherapy for hepatocellular carcinoma. Front Immunol. 2021; 12: 783236.

[200] Ciciola P, Cascetta P, Bianco C, Formisano L, Bianco R. Combining immune checkpoint inhibitors with anti-angiogenic agents. J Clin Med. 2020; 9: 675.

[201] Song Y, Fu Y, Xie Q, Zhu B, Wang J, Zhang B. Anti-angiogenic agents in combination with immune checkpoint inhibitors: a promising strategy for cancer treatment. Front Immunol. 2020; 11: 1956.

[202] Tang T, Huang X, Zhang G, Hong Z, Bai X, Liang T. Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy. Signal Transduct Target Ther. 2021; 6: 72.

[203] Hack SP, Zhu AX, Wang Y. Augmenting anticancer immunity through combined targeting of angiogenic and PD-1/PD-L1 pathways: challenges and opportunities. Front Immunol. 2020; 11: 598877.

[204] Deng L, Wei T, Zhang Y, et al. Ultra-pH-sensitive nanoparticle of gambogenic acid for tumor targeting therapy via anti-vascular strategy plus immunotherapy. Int J Pharm. 2024; 660: 124303.

[205] Tu J, Liang H, Li C, et al. The application and research progress of anti-angiogenesis therapy in tumor immunotherapy. Front Immunol. 2023; 14: 1198972.

[206] Chen D, Qu X, Shao J, Wang W, Dong X. Anti-vascular nano agents: a promising approach for cancer treatment. J Mater Chem B. 2020; 8: 2990-3004.

[207] Ying M, Chen G, Lu W. Recent advances and strategies in tumor vasculature targeted nano-drug delivery systems. Curr Pharm Des. 2015; 21: 3066-3075.

[208] Lahooti B, Akwii RG, Zahra FT, et al. Targeting endothelial permeability in the EPR effect. J Control Release. 2023; 361: 212-235.

[209] Qiao Qi, Liu X, Yang T, et al. Nanomedicine for acute respiratory distress syndrome: the latest application, targeting strategy, and rational design. Acta Pharm Sin B. 2021; 11: 3060-3091.

[210] Tee JK, Yip LX, Tan ES, et al. Nanoparticles' interactions with vasculature in diseases. Chem Soc Rev. 2019; 48: 5381-5407.

[211] Sakurai Y, Akita H, Harashima H. Targeting tumor endothelial cells with nanoparticles. Int J Mol Sci. 2019; 20: 5819.

[212] Liang Q, Zhou L, Li Y, Liu J, Liu Y. Nano drug delivery system reconstruct tumour vasculature for the tumour vascular normalisation. J Drug Target. 2022; 30: 119-130.

[213] Li Z, Di C, Li S, Yang X, Nie G. Smart nanotherapeutic targeting of tumor vasculature. Acc Chem Res. 2019; 52: 2703-2712.

[214] Chauhan VP, Stylianopoulos T, Martin JD, et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol. 2012; 7: 383-388.

[215] Jiang W, Huang Y, An Y, Kim BY. Remodeling tumor vasculature to enhance delivery of intermediate-sized nanoparticles. ACS Nano. 2015; 9: 8689-8696.

[216] Cun X, Chen J, Li M, et al. Tumor-associated fibroblast-targeted regulation and deep tumor delivery of chemotherapeutic drugs with a multifunctional size-switchable nanoparticle. ACS Appl Mater Interfaces. 2019; 11: 39545-39559.

[217] Wang B, Ding Y, Zhao X, et al. Delivery of small interfering RNA against Nogo-B receptor via tumor-acidity responsive nanoparticles for tumor vessel normalization and metastasis suppression. Biomaterials. 2018; 175: 110-122.

[218] Jiang Z, Xiong H, Yang S, et al. Jet-lagged nanoparticles enhanced immunotherapy efficiency through synergistic reconstruction of tumor microenvironment and normalized tumor vasculature. Adv Healthc Mater. 2020; 9: e2000075.

[219] Tang B, Ma W, Lin Y. Emerging applications of anti-angiogenic nanomaterials in oncotherapy. J Control Release. 2023; 364: 61-78.

[220] Liu Q, Zou J, Chen Z, He W, Wu W. Current research trends of nanomedicines. Acta Pharm Sin B. 2023; 13: 4391-4416.

[221] Teuwen LA, Draoui N, Dubois C, Carmeliet P. Endothelial cell metabolism: an update anno 2017. Curr Opin Hematol. 2017; 24: 240-247.

[222] Roy-Luzarraga M, Hodivala-Dilke K. Molecular pathways: endothelial cell FAK-A target for cancer treatment. Clin Cancer Res. 2016; 22: 3718-3724.

[223] Roy-Luzarraga M, Reynolds LE, de Luxán-Delgado B, et al. Suppression of endothelial cell FAK expression reduces pancreatic ductal adenocarcinoma metastasis after gemcitabine treatment. Cancer Res. 2022; 82: 1909-1925.

[224] Potenta S, Zeisberg E, Kalluri R. The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer. 2008; 99: 1375-1379.

[225] Tanabe K. Microtubule depolymerization by kinase inhibitors: unexpected findings of dual inhibitors. Int J Mol Sci. 2017; 18: 2508.

[226] Ciszewski WM, Wawro ME, Sacewicz-Hofman I, Sobierajska K. Cytoskeleton reorganization in EndMT—the role in cancer and fibrotic diseases. Int J Mol Sci. 2021; 22: 11607.

[227] Peerzada MN, Dar MS, Verma S. Development of tubulin polymerization inhibitors as anticancer agents. Expert Opin Ther Pat. 2023; 33: 797-820.

[228] Rodón J, Carducci M, Sepulveda-Sánchez JM, et al. Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. Invest New Drugs. 2015; 33: 357-370.

[229] Peng D, Fu M, Wang M, Wei Y, Wei X. Targeting TGF-β signal transduction for fibrosis and cancer therapy. Mol Cancer. 2022; 21: 104.

[230] Shi X, Young CD, Zhou H, Wang X. Transforming growth factor-β signaling in fibrotic diseases and cancer-associated fibroblasts. Biomolecules. 2020; 10: 1666.

[231] Deng Z, Fan T, Xiao C, et al. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther. 2024; 9: 61.

[232] Olejarz W, Kubiak-Tomaszewska G, Chrzanowska A, Lorenc T. Exosomes in angiogenesis and anti-angiogenic therapy in cancers. Int J Mol Sci. 2020; 21: 5840.

[233] Kosgodage US, Mould R, Henley AB, et al. Cannabidiol (CBD) is a novel inhibitor for exosome and microvesicle (EMV) release in cancer. Front Pharmacol. 2018; 9: 889.

[234] Kosgodage US, Trindade RP, Thompson PR, Inal JM, Lange S. Chloramidine/bisindolylmaleimide-I-mediated inhibition of exosome and microvesicle release and enhanced efficacy of cancer chemotherapy. Int J Mol Sci. 2017; 18: 1007.

[235] Jia W-T, Xiang S, Zhang J-B, et al. Jiedu recipe, a compound Chinese herbal medicine, suppresses hepatocellular carcinoma metastasis by inhibiting the release of tumor-derived exosomes in a hypoxic microenvironment. J Integr Med. 2024; 22(6): 696-708.

[236] Jia W, Liang S, Jin M, et al. Oleanolic acid inhibits hypoxic tumor-derived exosomes-induced premetastatic niche formation in hepatocellular carcinoma by targeting ERK1/2-NFκB signaling. Phytomedicine. 2024; 126: 155208.

[237] Hindley JP, Jones E, Smart K, et al. T-cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T-cell depletion. Cancer Res. 2012; 72: 5473-5482.

[238] Offeddu GS, Hajal C, Foley CR, et al. The cancer glycocalyx mediates intravascular adhesion and extravasation during metastatic dissemination. Commun Biol. 2021; 4: 255.

[239] Zhang L, Xu J, Zhou S, et al. Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma. J Hepatol. 2024; 80: 82-98.

[240] Kuczynski EA, Reynolds AR. Vessel co-option and resistance to anti-angiogenic therapy. Angiogenesis. 2020; 23: 55-74.

[241] Wei X, Chen Y, Jiang X, et al. Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments. Mol Cancer. 2021; 20: 7.

[242] Frentzas S, Simoneau E, Bridgeman VL, et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med. 2016; 22: 1294-1302.

[243] Saravanan S, Vimalraj S, Pavani K, Nikarika R, Sumantran VN. Intussusceptive angiogenesis as a key therapeutic target for cancer therapy. Life Sci. 2020; 252: 117670.

[244] Teuwen L-A, De Rooij LPMH, Cuypers A, et al. Tumor vessel co-option probed by single-cell analysis. Cell Rep. 2021; 35: 109253.

[245] Cannell IG, Sawicka K, Pearsall I, et al. FOXC2 promotes vasculogenic mimicry and resistance to anti-angiogenic therapy. Cell Rep. 2023; 42: 112791.

[246] Michaelsen SR, Staberg M, Pedersen H, et al. VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. Neuro Oncol. 2018; 20: 1462-1474.

[247] Zhang M, Chu S, Zeng F, Xu H. Bevacizumab modulates the process of fibrosis in vitro. Clin Exp Ophthalmol. 2015; 43: 173-179.

[248] Vilà N, Coblentz J, Moreira-Neto C, Bravo-Filho V, Zoroquiain P, Burnier MN. Pretreatment of RPE cells with lutein can mitigate bevacizumab-induced increases in angiogenin and bFGF. Ophthalmic Res. 2017; 57: 48-53.

[249] Goede V, Coutelle O, Neuneier J, et al. Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br J Cancer. 2010; 103: 1407-1414.

[250] Carbone C, Moccia T, Zhu C, et al. Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype. Clin Cancer Res. 2011; 17: 5822-5832.

[251] Lopes-Coelho F, Martins F, Pereira SA, Serpa J. Anti-angiogenic therapy: current challenges and future perspectives. Int J Mol Sci. 2021; 22: 3765.

[252] Wang X, Abraham S, McKenzie JAG, et al. LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling. Nature. 2013; 499: 306-311.

[253] Jahangiri A, De Lay M, Miller LM, et al. Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance. Clin Cancer Res. 2013; 19: 1773-1783.

[254] Cheng J, Wei J, Tong T, et al. Prediction of histopathologic growth patterns of colorectal liver metastases with a noninvasive imaging method. Ann Surg Oncol. 2019; 26: 4587-4598.

[255] Thiel KW, Devor EJ, Filiaci VL, et al. TP53 sequencing and p53 immunohistochemistry predict outcomes when bevacizumab is added to frontline chemotherapy in endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. J Clin Oncol. 2022; 40: 3289-3300.

[256] Kozin SV, Kamoun WS, Huang Y, Dawson MR, Jain RK, Duda DG. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res. 2010; 70: 5679-5685.

[257] Dimova I, Karthik S, Makanya A, et al. SDF-1/CXCR4 signalling is involved in blood vessel growth and remodelling by intussusception. J Cell Mol Med. 2019; 23: 3916-3926.

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