Skip to main content

Advertisement

SpringerLink
Log in

Angiogenesis as a hallmark of solid tumors - clinical perspectives

  • Review
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Background

Angiogenesis is a key and early step in tumorigenesis, and is known as a hallmark of solid tumors and a key promoter of tumor recurrence. Unlike normal tissue vessels, the architecture of the tumor vasculature is abnormal, being leaky, tortuous, fragile and blind-ended. Perivascular cells are either detached or absent, causing reduction of vascular integrity, an increase in vessel immaturity, incoherent perfusion, defective functionality and enhanced tumor dissemination and metastasis. The abnormal tumor vasculature along with the defective tumor vessel functionality finally causes bouts of hypoxia and acidity in the tumor microenvironment (TME), further reinvigorating tumor aggression. Interstitial hypertension or high interstitial fluid pressure (IFP) is an outcome of tumor hyper-permeability. High IFP can be a barrier for either effective delivery of anti-cancer drugs toward the TME or accumulation of drugs within the tumor area, thus promoting tumor resistance to therapy. Some tumors do, however, not undergo angiogenesis but instead undergo vessel co-option or vascular mimicry, thereby adding another layer of complexity to cancer development and therapy.

Conclusions

Combination of anti-angiogenesis therapy with chemotherapy and particularly with immune checkpoint inhibitors (ICIs) is a promising strategy for a number of advanced cancers. Among the various approaches for targeting tumor angiogenesis, vascular normalization is considered as the most desired method, which allows effective penetration of chemotherapeutics into the tumor area, thus being an appropriate adjuvant to other cancer modalities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

EC:

endothelial cell

EPC:

endothelial progenitor cell

TME:

tumor microenvironment

IFP:

interstitial fluid pressure

SMC:

smooth muscle cell

ECM:

extracellular matrix

CSC:

cancer stem cell

BTB:

blood-tumor barrier

CXCL12:

C-X-C chemokine ligand 12

CXCR4:

C-X-C chemokine receptor type 4

TGF-β:

transforming growth factor-beta

VEGF:

vascular endothelial growth factor

M2:

macrophage type 2

CAF:

cancer-associated fibroblast

EGFR:

epidermal growth factor receptor

TKI:

tyrosine kinase inhibitor

PDGFR:

platelet-derived growth factor receptor

DC:

dendritic cell

CTLA-4:

cytotoxic T-lymphocyte-associated protein-4

PD-1:

programmed death-1 receptor

PD-L1:

programmed death ligand 1

dMMR/MSI:

deficient/microsatellite instability

pMMR/MMS:

mismatch repair proficient/microsatellite stable

TIL:

tumor-infiltrating lymphocyte

ICI:

immune checkpoint inhibitor

EMT:

epithelial-to-mesenchymal transition

MVD:

micro-vessel density

References

  1. Y. Fan, Vascular detransformation for cancer therapy. Trends Cancer 5, 460–463 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. N.K. Altorki, G.J. Markowitz, D. Gao, J.L. Port, A. Saxena, B. Stiles, T. McGraw, V. Mittal, The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer 19, 9–31 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. D.F. McDermott, M.A. Huseni, M.B. Atkins, R.J. Motzer, B.I. Rini, B. Escudier, L. Fong, R.W. Joseph, S.K. Pal, J.A. Reeves, M. Sznol, J. Hainsworth, W.K. Rathmell, W.M. Stadler, T. Hutson, M.E. Gore, A. Ravaud, S. Bracarda, C. Suárez, R. Danielli, V. Gruenwald, T.K. Choueiri, D. Nickles, S. Jhunjhunwala, E. Piault-Louis, A. Thobhani, J. Qiu, D.S. Chen, P.S. Hegde, C. Schiff, G.D. Fine, T. Powles, 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. G. Bergers, D. Hanahan, Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8, 592–603 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. A. Karsch-Bluman, A. Feiglin, E. Arbib, T. Stern, H. Shoval, O. Schwob, M. Berger, O. Benny, Tissue necrosis and its role in cancer progression. Oncogene 38, 1920–1935 (2019)

    Article  CAS  PubMed  Google Scholar 

  6. R. Kerbel, J. Folkman, Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2, 727–739 (2002)

    Article  CAS  PubMed  Google Scholar 

  7. R. Batlle, E. Andrés, L. Gonzalez, E. Llonch, A. Igea, N. Gutierrez-Prat, A. Berenguer-Llergo, A.R. Nebreda, Regulation of tumor angiogenesis and mesenchymal–endothelial transition by p38α through TGF-β and JNK signaling. Nat Commun 10, 1–18 (2019)

    Article  CAS  Google Scholar 

  8. C.J. Avraamides, B. Garmy-Susini, J.A. Varner, Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8, 604 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Y.C. Sung, P.-R. Jin, L.A. Chu, F.F. Hsu, M.R. Wang, C.C. Chang, S.J. Chiou, J.T. Qiu, D.Y. Gao, C.C. Lin, Y.S. Chen, Y.C. Hsu, J. Wang, F.-N. Wang, P.-L. Yu, A.-S. Chiang, A.Y.T. Wu, J.J.S. Ko, C.P.K. Lai, T.T. Lu, Y. Chen, Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies. Nat Nanotechnol. 14, 1160–1169 (2019)

    Article  CAS  PubMed  Google Scholar 

  10. M. De Palma, D. Biziato, T.V. Petrova, Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer 17, 457 (2017)

    Article  PubMed  CAS  Google Scholar 

  11. K. Mortezaee, Redox tolerance and metabolic reprogramming in solid tumors. Cell Biol Int. 45, 273–286 (2021)

    Article  CAS  PubMed  Google Scholar 

  12. H.E. Barker, J.T. Paget, A.A. Khan, K.J. Harrington, The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat rev Cancer 15, 409–425 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. A. Santi, F.G. Kugeratski, S. Zanivan, Cancer associated fibroblasts: the architects of stroma remodeling. Proteomics 18, e1700167 (2018)

  14. R.K. Jain, Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005)

    Article  CAS  PubMed  Google Scholar 

  15. P. Carmeliet, R.K. Jain, Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. T. Donnem, A.R. Reynolds, E.A. Kuczynski, K. Gatter, P.B. Vermeulen, R.S. Kerbel, A.L. Harris, F. Pezzella, Non-angiogenic tumours and their influence on cancer biology. Nat Rev Cancer 18, 323–336 (2018)

    Article  CAS  PubMed  Google Scholar 

  17. V.P. Chauhan, T. Stylianopoulos, Y. Boucher, R.K. Jain, Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annu Rev Chem Biomol Eng. 2, 281–298 (2011)

    Article  CAS  PubMed  Google Scholar 

  18. S. Sengupta, D. Eavarone, I. Capila, G. Zhao, N. Watson, T. Kiziltepe, R. Sasisekharan, Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nature 436, 568–572 (2005)

    Article  CAS  PubMed  Google Scholar 

  19. S. Nishide, S. Matsunaga, M. Shiota, T. Yamaguchi, S. Kitajima, Y. Maekawa, N. Takeda, M. Tomura, J. Uchida, K. Miura, T. Nakatani, S. Tomita, Controlling the phenotype of tumor-infiltrating macrophages via the PHD-HIF axis inhibits tumor growth in a mouse model. iScience 19, 940–954 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. D. Fukumura, J. Kloepper, Z. Amoozgar, D.G. Duda, R.K. Jain, Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 15, 325–340 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. L. Galluzzi, T.A. Chan, G. Kroemer, J.D. Wolchok, A. López-Soto, The hallmarks of successful anticancer immunotherapy. Sci. Transl. Med. 10, eaat7807 (2018)

  22. J. Hamzah, M. Jugold, F. Kiessling, P. Rigby, M. Manzur, H.H. Marti, T. Rabie, S. Kaden, H.-J. Gröne, G.J. Hämmerling, Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008)

    Article  CAS  PubMed  Google Scholar 

  23. P. Carmeliet, R.K. Jain, Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat rev Drug discov. 10, 417–427 (2011)

    Article  CAS  PubMed  Google Scholar 

  24. A.S. Chung, J. Lee, N. Ferrara, Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer 10, 505–514 (2010)

    Article  CAS  PubMed  Google Scholar 

  25. V.G. Cooke, V.S. LeBleu, D. Keskin, Z. Khan, J.T. O'Connell, Y. Teng, M.B. Duncan, L. Xie, G. Maeda, S. Vong, H. Sugimoto, R.M. Rocha, A. Damascena, R.R. Brentani, R. Kalluri, Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell. 21, 66–81 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. K. De Bock, M. Mazzone, P. Carmeliet, Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not? Nat Rev Clin oncol 8, 393–404 (2011)

    Article  PubMed  CAS  Google Scholar 

  27. O. Trédan, C.M. Galmarini, K. Patel, I.F. Tannock, Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99, 1441–1454 (2007)

    Article  PubMed  CAS  Google Scholar 

  28. M. Potente, H. Gerhardt, P. Carmeliet, Basic and therapeutic aspects of angiogenesis. Cell. 146, 873–887 (2011)

    Article  CAS  PubMed  Google Scholar 

  29. S. Goel, D.G. Duda, L. Xu, L.L. Munn, Y. Boucher, D. Fukumura, R.K. Jain, Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91, 1071–1121 (2011)

    Article  CAS  PubMed  Google Scholar 

  30. M.W. Dewhirst, T.W. Secomb, Transport of drugs from blood vessels to tumour tissue. Nat Rev Cancer 17, 738–750 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. L. Cheng, Z. Huang, W. Zhou, Q. Wu, S. Donnola, J.K. Liu, X. Fang, A.E. Sloan, Y. Mao, J.D. Lathia, W. Min, R.E. McLendon, J.N. Rich, S. Bao, Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153, 139–152 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. K.E. Emblem, K. Mouridsen, A. Bjornerud, C.T. Farrar, D. Jennings, R.J. Borra, P.Y. Wen, P. Ivy, T.T. Batchelor, B.R. Rosen, R.K. Jain, A.G. Sorensen, Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat med 19, 1178–1183 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. M. Chen, W.P. Wang, W.R. Jia, L. Tang, Y. Wang, W.W. Zhan, X.C. Fei, Three-dimensional contrast-enhanced sonography in the assessment of breast tumor angiogenesis: correlation with microvessel density and vascular endothelial growth factor expression. J Ultrasound Med. 33, 835–846 (2014)

    Article  PubMed  Google Scholar 

  34. J.F. de Groot, G. Fuller, A.J. Kumar, Y. Piao, K. Eterovic, Y. Ji, C.A. Conrad, Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol. 12, 233–242 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. D. Mihic-Probst, K. Ikenberg, M. Tinguely, P. Schraml, S. Behnke, B. Seifert, G. Civenni, L. Sommer, H. Moch, R. Dummer, Tumor cell plasticity and angiogenesis in human melanomas. PloS One 7, e33571 (2012)

  36. G. Follain, D. Herrmann, S. Harlepp, V. Hyenne, N. Osmani, S.C. Warren, P. Timpson, J.G. Goetz, Fluids and their mechanics in tumour transit: shaping metastasis. Nat Rev Cancer 20, 107–124 (2020)

    Article  CAS  PubMed  Google Scholar 

  37. T.D. Tailor, G. Hanna, P.S. Yarmolenko, M.R. Dreher, A.S. Betof, A.B. Nixon, I. Spasojevic, M.W. Dewhirst, Effect of pazopanib on tumor microenvironment and liposome delivery. Mol Cancer Ther 9, 1798–1808 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. E.S. Christenson, E. Jaffee, N.S. Azad, Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future. Lancet Oncol 21, e135–e145 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. A.N. Hosein, R.A. Brekken, A. Maitra, Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol. 17, 487–505 (2020)

    Article  PubMed  PubMed Central  Google Scholar 

  40. W.J. Ho, E.M. Jaffee, L. Zheng, The tumour microenvironment in pancreatic cancer—clinical challenges and opportunities. Nat Rev Clin Oncol, 1–14 (2020)

  41. K. Mortezaee, Hypoxia induces core-to-edge transition of progressive tumoral cells: a critical review on differential yet corroborative roles for HIF-1α and HIF-2α. Life Sci. 242, 117145 (2020)

  42. S. Liu, Y. Cong, D. Wang, Y. Sun, L. Deng, Y. Liu, R. Martin-Trevino, L. Shang, S.P. McDermott, M.D. Landis, S. Hong, A. Adams, R. D'Angelo, C. Ginestier, E. Charafe-Jauffret, S.G. Clouthier, D. Birnbaum, S.T. Wong, M. Zhan, J.C. Chang, M.S. Wicha, Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2, 78–91 (2014)

    Article  CAS  PubMed  Google Scholar 

  43. M. Najafi, B. Farhood, K. Mortezaee, E. Kharazinejad, J. Majidpoor, R. Ahadi, Hypoxia in solid tumors: a key promoter of cancer stem cell (CSC) resistance. J Cancer Res Clin Oncol 1, 19–31 (2020)

    Article  Google Scholar 

  44. D.L. Hess, M.R. Kelly-Goss, O.A. Cherepanova, A.T. Nguyen, R.A. Baylis, S. Tkachenko, B.H. Annex, S.M. Peirce, G.K. Owens, Perivascular cell-specific knockout of the stem cell pluripotency gene Oct4 inhibits angiogenesis. Nat Commun 10, 1–15 (2019)

    Article  CAS  Google Scholar 

  45. S.A. Sprowls, T.A. Arsiwala, J.R. Bumgarner, N. Shah, S.S. Lateef, B.N. Kielkowski, P.R. Lockman, Improving CNS delivery to brain metastases by blood–tumor barrier disruption. Trends Cancer 5, 495–505 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. M. Egeblad, E.S. Nakasone, Z. Werb, Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18, 884–901 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. D.A. Guerra, A.E. Paiva, I.F. Sena, P.O. Azevedo, W.N. Silva, A. Mintz, A. Birbrair, Targeting glioblastoma-derived pericytes improves chemotherapeutic outcome. Angiogenesis 21, 667–675 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. K. Hosaka, Y. Yang, T. Seki, C. Fischer, O. Dubey, E. Fredlund, J. Hartman, P. Religa, H. Morikawa, Y. Ishii, M. Sasahara, O. Larsson, G. Cossu, R. Cao, S. Lim, Y. Cao, Pericyte–fibroblast transition promotes tumor growth and metastasis. Proc Natl Acad Sci U S A. 113, E5618–E5627 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. N. Volz, S. Stintzing, W. Zhang, D. Yang, Y. Ning, T. Wakatsuki, R. El-Khoueiry, J. Li, A. Kardosh, F. Loupakis, C. Cremolini, A. Falcone, S.J. Scherer, H.J. Lenz, Genes involved in pericyte-driven tumor maturation predict treatment benefit of first-line FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer. Pharmacogenomics J 15, 69–76 (2015)

    Article  CAS  PubMed  Google Scholar 

  50. W. Zhou, C. Chen, Y. Shi, Q. Wu, R.C. Gimple, X. Fang, Z. Huang, K. Zhai, S.Q. Ke, Y.F. Ping, H. Feng, J.N. Rich, J.S. Yu, S. Bao, X.W. Bian, Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy. Cell Stem Cell. 21, 591–603 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. R. Soffietti, M. Ahluwalia, N. Lin, R. Rudà, Management of brain metastases according to molecular subtypes. Nat Rev Neurol 16, 557–574 (2020)

    Article  CAS  PubMed  Google Scholar 

  52. M. Najafi, K. Mortezaee, R. Ahadi, Cancer stem cell (a) symmetry & plasticity: tumorigenesis and therapy relevance. Life Sci. 231, 16520 (2019)

  53. K. Mortezaee, CXCL12/CXCR4 axis in the microenvironment of solid tumors: a critical mediator of metastasis. Life Sci. 249, 117534 (2020)

  54. K. Mortezaee, M. Najafi, Immune system in cancer radiotherapy: resistance mechanisms and therapy perspectives. Crit. Rev. Oncol. Hematol. 57, 103180 (2021)

  55. M. Najafi, K. Mortezaee, J. Majidpoor, Stromal reprogramming: a target for tumor therapy. Life Sci. 239, 117049 (2019)

  56. B. Sennino, D.M. McDonald, Controlling escape from angiogenesis inhibitors. Nat Rev Cancer 12, 699–709 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. R.J. Motzer, K. Penkov, J. Haanen, B. Rini, L. Albiges, M.T. Campbell, B. Venugopal, C. Kollmannsberger, S. Negrier, M. Uemura, J.L. Lee, A. Vasiliev, W.H. Miller Jr., H. Gurney, M. Schmidinger, J. Larkin, M.B. Atkins, J. Bedke, B. Alekseev, J. Wang, M. Mariani, P.B. Robbins, A. Chudnovsky, C. Fowst, S. Hariharan, B. Huang, A. di Pietro, T.K. Choueiri, Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 380, 1103–1115 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. T.T. Batchelor, A.G. Sorensen, E. di Tomaso, W.T. Zhang, D.G. Duda, K.S. Cohen, K.R. Kozak, D.P. Cahill, P.J. Chen, M. Zhu, M. Ancukiewicz, M.M. Mrugala, S. Plotkin, J. Drappatz, D.N. Louis, P. Ivy, D.T. Scadden, T. Benner, J.S. Loeffler, P.Y. Wen, R.K. Jain, AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 11, 83–95 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. S.M. Weis, D.A. Cheresh, Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437, 497–504 (2005)

    Article  CAS  PubMed  Google Scholar 

  60. M.G. Achen, B.K. McColl, S.A. Stacker, Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 7, 121–127 (2005)

    Article  CAS  PubMed  Google Scholar 

  61. A. Claes, P. Wesseling, J. Jeuken, C. Maass, A. Heerschap, W.P. Leenders, Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol Cancer Ther 7, 71–78 (2008)

    Article  CAS  PubMed  Google Scholar 

  62. R.R. Ramjiawan, A.W. Griffioen, D.G. Duda, Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis 20, 185–204 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  63. F. De Smet, I. Segura, K. De Bock, P.J. Hohensinner, P. Carmeliet, Mechanisms of vessel branching: filopodia on endothelial tip cells lead the way. Arterioscler Thromb Vasc Biol. 29, 639–649 (2009)

    Article  PubMed  CAS  Google Scholar 

  64. P. Saharinen, L. Eklund, K. Pulkki, P. Bono, K. Alitalo, VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med 17, 347–362 (2011)

    Article  CAS  PubMed  Google Scholar 

  65. J. Welti, S. Loges, S. Dimmeler, P. Carmeliet, Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Invest. 123, 3190–3200 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. N. Kozlova, J.E. Grossman, M.P. Iwanicki, T. Muranen, The interplay of the extracellular matrix and stromal cells as a drug target in stroma-rich cancers. Trends Pharmacol Sci 41, 183–198 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. K. Mortezaee, M. Najafi, B. Farhood, A. Ahmadi, D. Shabeeb, A.E. Musa, Resveratrol as an adjuvant for normal tissues protection and tumor sensitization. Curr Cancer Drug Targets. 20, 130–145 (2020)

    Article  CAS  PubMed  Google Scholar 

  68. K. Mortezaee, N.H. Goradel, P. Amini, D. Shabeeb, A.E. Musa, M. Najafi, B. Farhood, NADPH oxidase as a target for modulation of radiation response; implications to carcinogenesis and radiotherapy. Curr Mol Pharmacol 12, 50–60 (2019)

    Article  CAS  PubMed  Google Scholar 

  69. A. Albini, F. Tosetti, V.W. Li, D.M. Noonan, W.W. Li, Cancer prevention by targeting angiogenesis. Nat Rev Clin Oncol 9, 498–509 (2012)

    Article  CAS  PubMed  Google Scholar 

  70. J. Folkman, Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6, 273–286 (2007)

    Article  CAS  PubMed  Google Scholar 

  71. C. Porta, L. Cosmai, B.C. Leibovich, T. Powles, M. Gallieni, A. Bex, The adjuvant treatment of kidney cancer: a multidisciplinary outlook. Nat Rev Nephrol 15, 423–433 (2019)

    Article  PubMed  Google Scholar 

  72. L.R. Duska, G. Petroni, N. Varhegyi, J. Brown, D. Jelovac, K. Moore, W. McGuire, C. Darus, L. Barroilhet, A. Secord, A randomized phase II evaluation of weekly gemcitabine plus pazopanib versus weekly gemcitabine alone in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. Gynecol Oncol 157, 585–592 (2020)

    Article  CAS  PubMed  Google Scholar 

  73. B.I. Rini, E.R. Plimack, T. Takagi, P. Elson, L.S. Wood, R. Dreicer, T. Gilligan, J. Garcia, Z. Zhang, J. Kaouk, V. Krishnamurthi, A.J. Stephenson, A. Fergany, E.A. Klein, R.G. Uzzo, D.Y.T. Chen, S.C. Campbell, A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J Urol 194, 297–303 (2015)

    Article  CAS  PubMed  Google Scholar 

  74. J. Strosberg, J. Weber, J. Choi, T. Campos, T. Valone, G. Han, M. Schell, L. Kvols, A phase II clinical trial of sunitinib following hepatic transarterial embolization for metastatic neuroendocrine tumors. Ann Oncol. 23, 2335–2341 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. X. Sheng, J. Jin, Z. He, Y. Huang, A. Zhou, J. Wang, X. Ren, D. Ye, X. Zhang, S. Qin, F. Zhou, B. Wang, J. Guo, Pazopanib versus sunitinib in Chinese patients with locally advanced or metastatic renal cell carcinoma: pooled subgroup analysis from the randomized, COMPARZ studies. BMC Cancer 20, 219 (2020)

  76. M.D. Hellmann, J.E. Chaft, V. Rusch, M.S. Ginsberg, D.J. Finley, M.G. Kris, K.A. Price, C.G. Azzoli, M.G. Fury, G.J. Riely, L.M. Krug, R.J. Downey, M.S. Bains, C.S. Sima, N. Rizk, W.D. Travis, N.A. Rizvi, P.K. Paik, Risk of hemoptysis in patients with resected squamous cell and other high-risk lung cancers treated with adjuvant bevacizumab. Cancer Chemother Pharmacol 72, 453–461 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. J. Kalpathy-Cramer, V. Chandra, X. Da, Y. Ou, K.E. Emblem, A. Muzikansky, X. Cai, L. Douw, J.G. Evans, J. Dietrich, A.S. Chi, P.Y. Wen, S. Stufflebeam, B. Rosen, D.G. Duda, R.K. Jain, T.T. Batchelor, E.R. Gerstner, Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. J Neurooncol 131, 603–610 (2017)

    Article  CAS  PubMed  Google Scholar 

  78. J.A. Boockvar, A.J. Tsiouris, C.P. Hofstetter, I. Kovanlikaya, S. Fralin, K. Kesavabhotla, S.M. Seedial, S.C. Pannullo, T.H. Schwartz, P. Stieg, R.D. Zimmerman, J. Knopman, R.J. Scheff, P. Christos, S. Vallabhajosula, H.A. Riina, Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. J Neurosurg 114, 624–632 (2011)

    Article  CAS  PubMed  Google Scholar 

  79. M. Suenaga, N. Mizunuma, K. Kobayashi, E. Shinozaki, S. Matsusaka, K. Chin, Y. Kuboki, T. Ichimura, M. Ozaka, M. Ogura, Y. Fujiwara, K. Matsueda, F. Konishi, K. Hatake, Management of venous thromboembolism in colorectal cancer patients treated with bevacizumab. Med Oncol 27, 807–814 (2010)

    Article  CAS  PubMed  Google Scholar 

  80. S. Pignata, D. Lorusso, F. Joly, C. Gallo, N. Colombo, C. Sessa, A. Bamias, V. Salutari, F. Selle, S. Frezzini, U. De Giorgi, P. Pautier, A. Bologna, M. Orditura, C. Dubot, A. Gadducci, S. Mammoliti, I. Ray-Coquard, E. Zafarana, E. Breda, L. Favier, A. Ardizzoia, S. Cinieri, R. Largillier, D. Sambataro, E. Guardiola, R. Lauria, C. Pisano, F. Raspagliesi, G. Scambia, G. Daniele, F. Perrone, MITO16b/MANGO–OV2/ENGOT–ov17 Investigators, Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial. Lancet Oncol 22, 267–276 (2021)

    Article  CAS  PubMed  Google Scholar 

  81. K. Shinozaki, T. Yamada, J. Nasu, T. Matsumoto, Y. Yuasa, T. Shiraishi, H. Nagano, I. Moriyama, T. Fujiwara, M. Miguchi, R. Yoshida, K. Nozaka, H. Tanioka, T. Nagasaka, Y. Kurisu, M. Kobayashi, K. Tsuchihashi, M. Inukai, T. Kikuchi, T. Nishina, A phase II study of FOLFOXIRI plus bevacizumab as initial chemotherapy for patients with untreated metastatic colorectal cancer: TRICC1414 (BeTRI). Int J Clin Oncol 26, 399–408 (2021)

    Article  CAS  PubMed  Google Scholar 

  82. M. Miyo, T. Kato, T. Yoshino, T. Yamanaka, H. Bando, H. Satake, K. Yamazaki, H. Taniguchi, E. Oki, M. Kotaka, K. Oba, Y. Miyata, K. Muro, Y. Komatsu, H. Baba, A. Tsuji, Protocol of the QUATTRO-II study: a multicenter randomized phase II study comparing CAPOXIRI plus bevacizumab with FOLFOXIRI plus bevacizumab as a first-line treatment in patients with metastatic colorectal cancer. BMC Cancer 20, 687 (2020)

  83. B. Chibaudel, J. Henriques, M. Rakez, B. Brenner, T.W. Kim, M. Martinez-Villacampa, J. Gallego-Plazas, A. Cervantes, K. Shim, D. Jonker, V. Guerin-Meyer, L. Mineur, C. Banzi, A. Dewdney, T. Dejthevaporn, H.J. Bloemendal, A. Roth, M. Moehler, E. Aranda, E. Van Cutsem, J. Tabernero, H.-J. Schmoll, P.M. Hoff, T. André, A. de Gramont, Association of bevacizumab plus oxaliplatin-based chemotherapy with disease-free survival and overall survival in patients with stage II colon cancer: a secondary analysis of the AVANT trial. JAMA Netw. Open 3, e2020425 (2020)

  84. T. André, D. Vernerey, S. Im, G. Bodoky, R. Buzzoni, S. Reingold, F. Rivera, J. McKendrick, W. Scheithauer, G. Ravit, G. Fountzilas, W.P. Yong, R. Isaacs, P. Österlund, J.T. Liang, G.J. Creemers, M. Rakez, E. Van Cutsem, D. Cunningham, J. Tabernero, A. de Gramont, Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group. Ann Oncol 31, 246–256 (2020)

    Article  PubMed  Google Scholar 

  85. S. Liu, C. Jiang, L. Yang, J. Huang, R. Peng, X. Wang, W. He, L. Bai, Y. Zhou, B. Zhang, L. Xia, First-line cetuximab improves the efficacy of subsequent bevacizumab for RAS wild-type left-sided metastatic colorectal cancer: an observational retrospective study. Sci. Rep. 10, 12336 (2020)

  86. E. Van Cutsem, C. Paccard, M. Chiron, J. Tabernero, Impact of prior bevacizumab treatment on VEGF-A and PlGF levels and outcome following second-line aflibercept treatment: Biomarker post hoc analysis of the VELOUR trial. Clin Cancer Res 26, 717–725 (2020)

    Article  PubMed  Google Scholar 

  87. S.E. Taylor, T. Chu, J.A. Elvin, R.P. Edwards, K.K. Zorn, Phase II study of everolimus and bevacizumab in recurrent ovarian, peritoneal, and fallopian tube cancer. Gynecol Oncol 156, 32–37 (2020)

    Article  CAS  PubMed  Google Scholar 

  88. J. Pfisterer, C.M. Shannon, K. Baumann, J. Rau, P. Harter, F. Joly, J. Sehouli, U. Canzler, B. Schmalfeldt, A.P. Dean, A. Hein, A.G. Zeimet, L.C. Hanker, T. Petit, F. Marmé, A. El-Balat, R. Glasspool, N. de Gregorio, S. Mahner, T.M. Meniawy, T.-W. Park-Simon, M.-A. Mouret-Reynier, C. Costan, W. Meier, A. Reinthaller, J.C. Goh, T. L'Haridon, S.B. Hay, S. Kommoss, A. du Bois, J.-E. Kurtz, AGO-OVAR 2.21/ENGOT-ov 18 Investigators. Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial. Lancet Oncol 21, 699–709 (2020)

    Article  CAS  PubMed  Google Scholar 

  89. I. Ray-Coquard, P. Pautier, S. Pignata, D. Pérol, A. González-Martín, R. Berger, K. Fujiwara, I. Vergote, N. Colombo, J. Mäenpää, F. Selle, J. Sehouli, D. Lorusso, E.M.G. Alía, A. Reinthaller, S. Nagao, C. Lefeuvre-Plesse, U. Canzler, G. Scambia, A. Lortholary, F. Marmé, P. Combe, N. de Gregorio, M. Rodrigues, P. Buderath, C. Dubot, A. Burges, B. You, E. Pujade-Lauraine, P. Harter, PAOLA-1 Investigators, Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 381, 2416–2428 (2019)

    Article  CAS  PubMed  Google Scholar 

  90. K.A. Khan, R.S. Kerbel, Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 15, 310–324 (2018)

    Article  CAS  PubMed  Google Scholar 

  91. Y.L. Li, H. Zhao, X.B. Ren, Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward? Cancer Biol Med 13, 206–214 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. F.S. Hodi, D. Lawrence, C. Lezcano, X. Wu, J. Zhou, T. Sasada, W. Zeng, A. Giobbie-Hurder, M.B. Atkins, N. Ibrahim, P. Friedlander, K.T. Flaherty, G.F. Murphy, S. Rodig, E.F. Velazquez, M.C. Mihm Jr., S. Russell, P.J. DiPiro, J.T. Yap, N. Ramaiya, A.D. Van den Abbeele, M. Gargano, D. McDermott, Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res 2, 632–642 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. A.C. Ziogas, N.G. Gavalas, M. Tsiatas, O. Tsitsilonis, E. Politi, E. Terpos, A. Rodolakis, G. Vlahos, N. Thomakos, D. Haidopoulos, A. Antsaklis, M.A. Dimopoulos, A. Bamias, VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor type 2. Int J Cancer 130, 857–864 (2012)

    Article  CAS  PubMed  Google Scholar 

  94. N.G. Gavalas, M. Tsiatas, O. Tsitsilonis, E. Politi, K. Ioannou, A.C. Ziogas, A. Rodolakis, G. Vlahos, N. Thomakos, D. Haidopoulos, E. Terpos, A. Antsaklis, M.A. Dimopoulos, A. Bamias, 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. K. Mortezaee, Immune escape: a critical hallmark in solid tumors. Life Sci. 258, 118110 (2020)

  96. Q. Li, Y. Wang, W. Jia, H. Deng, G. Li, W. Deng, J. Chen, B.Y. Kim, W. Jiang, Q. Liu, J. Liu, Low-dose anti-angiogenic therapy sensitizes breast cancer to PD-1 blockade. Clin Cancer Res 26, 1712–1724 (2020)

    Article  CAS  PubMed  Google Scholar 

  97. M.S. Lee, B.Y. Ryoo, C.H. Hsu, K. Numata, S. Stein, W. Verret, S.P. Hack, J. Spahn, B. Liu, H. Abdullah, Y. Wang, A.R. He, K.H. Lee, GO30140 investigators, Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lancet Oncol 21, 808–820 (2020)

    Article  CAS  PubMed  Google Scholar 

  98. S.P. Hack, J. Spahn, M. Chen, A.-L. Cheng, A. Kaseb, M. Kudo, H.C. Lee, A. Yopp, P. Chow, S. Qin, 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)

    Article  CAS  PubMed  Google Scholar 

  99. R.S. Finn, S. Qin, M. Ikeda, P.R. Galle, M. Ducreux, T.Y. Kim, M. Kudo, V. Breder, P. Merle, A.O. Kaseb, D. Li, W. Verret, D.Z. Xu, S. Hernandez, J. Liu, C. Huang, S. Mulla, Y. Wang, H.Y. Lim, A.X. Zhu, A.L. Cheng, IMbrave150 investigators, atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med 382, 1894–1905 (2020)

    Article  CAS  PubMed  Google Scholar 

  100. C. Antoniotti, B. Borelli, D. Rossini, F. Pietrantonio, F. Morano, L. Salvatore, S. Lonardi, F. Marmorino, S. Tamberi, S. Corallo, G. Tortora, F. Bergamo, D. Brunella, A. Boccaccino, E. Grassi, P. Racca, E. Tamburini, G. Aprile, R. Moretto, L. Boni, A. Falcone, C. Cremolini, AtezoTRIBE: a randomised phase II study of FOLFOXIRI plus bevacizumab alone or in combination with atezolizumab as initial therapy for patients with unresectable metastatic colorectal cancer. BMC Cancer 20, 683 (2020)

  101. B.A. McGregor, R.R. McKay, D.A. Braun, L. Werner, K. Gray, A. Flaifel, S. Signoretti, M.S. Hirsch, J.A. Steinharter, Z. Bakouny, R. Flippot, X.X. Wei, A. Choudhury, K. Kilbridge, G.J. Freeman, E.M. Van Allen, L.C. Harshman, D.F. McDermott, U. Vaishampayan, T.K. Choueiri, Results of a multicenter phase II study of atezolizumab and bevacizumab for patients with metastatic renal cell carcinoma with variant histology and/or sarcomatoid features. J. Clin. Oncol. 38, 63–70 (2020)

    Article  CAS  PubMed  Google Scholar 

  102. A.Z. Dudek, L.C. Liu, S. Gupta, T.F. Logan, E.A. Singer, M. Joshi, Y.N. Zakharia, J.M. Lang, J.K. Schwarz, A. Al-Janadi, A.S. Alva, Phase Ib/II clinical trial of pembrolizumab with bevacizumab for metastatic renal cell carcinoma: BTCRC-GU14-003. J. Clin. Oncol. 38, 1138–1145 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. T.K. Choueiri, R.J. Motzer, B.I. Rini, J. Haanen, M. Campbell, B. Venugopal, C. Kollmannsberger, G. Gravis-Mescam, M. Uemura, J. Lee, M.O. Grimm, H. Gurney, M. Schmidinger, J. Larkin, M.B. Atkins, S.K. Pal, J. Wang, M. Mariani, S. Krishnaswami, P. Cislo, A. Chudnovsky, C. Fowst, B. Huang, A. di Pietro, L. Albiges, Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann. Oncol. 31, 1030–1039 (2020)

    Article  CAS  PubMed  Google Scholar 

  104. R.J. Motzer, P.B. Robbins, T. Powles, L. Albiges, J.B. Haanen, J. Larkin, X.J. Mu, K.A. Ching, M. Uemura, S.K. Pal, B. Alekseev, G. Gravis, M.T. Campbell, K. Penkov, J.L. Lee, S. Hariharan, X. Wang, W. Zhang, J. Wang, A. Chudnovsky, A. di Pietro, A.C. Donahue, T.K. Choueiri, Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: Biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nat. Med. 26, 1733–1741 (2020)

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  105. G. Procopio, F. Nichetti, E. Verzoni, Pembrolizumab plus axitinib: another step ahead in advanced renal cell carcinoma. Lancet Oncol. 21, 1538–1539 (2020)

    Article  CAS  PubMed  Google Scholar 

  106. R.J. Motzer, B.I. Rini, D.F. McDermott, O.A. Frontera, H.J. Hammers, M.A. Carducci, P. Salman, B. Escudier, B. Beuselinck, A. Amin, C. Porta, S. George, V. Neiman, S. Bracarda, S.S. Tykodi, P. Barthélémy, R. Leibowitz-Amit, E.R. Plimack, S.F. Oosting, B. Redman, B. Melichar, T. Powles, P. Nathan, S. Oudard, D. Pook, T.K. Choueiri, F. Donskov, M.-O. Grimm, H. Gurney, D.Y.C. Heng, C.K. Kollmannsberger, M.R. Harrison, Y. Tomita, I. Duran, V. Grünwald, M.B. McHenry, S. Mekan, N.M. Tannir, CheckMate 214 investigators, Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 20, 1370–1385 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. E.A. Kuczynski, P.B. Vermeulen, F. Pezzella, R.S. Kerbel, A.R. Reynolds, Vessel co-option in cancer. Nat. Rev. Clin. Oncol. 16, 469–493 (2019)

    Article  CAS  PubMed  Google Scholar 

  108. W. Xu, M.B. Atkins, D.F. McDermott, Checkpoint inhibitor immunotherapy in kidney cancer. Nat. Rev. Urol. 17, 137–150 (2020)

    Article  CAS  PubMed  Google Scholar 

  109. F. Pezzella, A.L. Harris, When cancer co-opts the vasculature. N. Engl. J. Med. 370, 2146–2147 (2014)

    Article  CAS  PubMed  Google Scholar 

  110. E.R. Gerstner, X. Ye, D.G. Duda, M.A. Levine, T. Mikkelsen, T.J. Kaley, J.J. Olson, B.L. Nabors, M.S. Ahluwalia, P.Y. Wen, R.K. Jain, T.T. Batchelor, S. Grossman, A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma. Neuro. Oncol. 17, 1386–1392 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. B. Farhood, M. Najafi, K. Mortezaee, Cancer-associated fibroblasts: Secretions, interactions, and therapy. J. Cell Biochem. 120, 2791–2800 (2019)

    Article  CAS  PubMed  Google Scholar 

  112. B. Zhao, M. Wu, Z. Hu, Y. Ma, W. Qi, Y. Zhang, Y. Li, M. Yu, H. Wang, W. Mo, Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation. Signal Transduct. Target Ther. 5, 1–12 (2020)

    PubMed  PubMed Central  Google Scholar 

  113. J. Yang, Y. Lu, Y.Y. Lin, Z.Y. Zheng, J.H. Fang, S. He, S.M. Zhuang, Vascular mimicry formation is promoted by paracrine TGF-β and SDF1 of cancer-associated fibroblasts and inhibited by miR-101 in hepatocellular carcinoma. Cancer Lett 383, 18–27 (2016)

    Article  CAS  PubMed  Google Scholar 

  114. K. Mortezaee, Organ tropism in solid tumor metastasis: an updated review. Future Oncol. (2021). https://doi.org/10.2217/fon-2020-1103

  115. R. Xu, A. Rai, M. Chen, W. Suwakulsiri, D.W. Greening, R.J. Simpson, Extracellular vesicles in cancer—implications for future improvements in cancer care. Nat. Rev. Clin. Oncol. 15, 617–638 (2018)

    Article  CAS  PubMed  Google Scholar 

  116. W. Lu, H. Zhang, Y. Niu, Y. Wu, W. Sun, H. Li, J. Kong, K. Ding, H.-M. Shen, H. Wu, Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150-5p. Mol. Cancer 16, 118 (2017)

  117. H.H. Popper, Progression and metastasis of lung cancer. Cancer Metastasis Rev. 35, 75–91 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. I.E. Demir, K. Kujundzic, P.L. Pfitzinger, Ö.C. Saricaoglu, S. Teller, T. Kehl, C.M. Reyes, L.S. Ertl, Z. Miao, T.J. Schall, E. Tieftrunk, B. Haller, K.N. Diakopoulos, M.U. Kurkowski, M. Lesina, A. Krüger, H. Algül, H. Friess, G.O. Ceyhan, Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells. Proc. Natl. Acad Sci. U S A. 114, E85–E94 (2017)

    Article  CAS  PubMed  Google Scholar 

  119. I. Catalano, E. Grassi, A. Bertotti, L. Trusolino, Immunogenomics of colorectal tumors: facts and hypotheses on an evolving saga. Trends Cancer 5, 779–788 (2019)

    Article  CAS  PubMed  Google Scholar 

  120. S.J. Conley, E. Gheordunescu, P. Kakarala, B. Newman, H. Korkaya, A.N. Heath, S.G. Clouthier, M.S. Wicha, Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc. Natl. Acad Sci. U S A. 109, 2784–2789 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. O. Keunen, M. Johansson, A. Oudin, M. Sanzey, S.A.A. Rahim, F. Fack, F. Thorsen, T. Taxt, M. Bartos, R. Jirik, , H. Miletic, J. Wang, D. Stieber, L. Stuhr, I. Moen, C.B. Rygh, R. Bjerkvig, S.P. Niclou. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc. Natl. Acad Sci. U S A. 108, 3749-3754 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. J. Majidpoor, K. Mortezaee, Steps in metastasis: an updated review. Med. Oncol. 38, 1–17 (2021)

    Article  Google Scholar 

  123. A. Brodziak, P. Sobczuk, E. Bartnik, M. Fiedorowicz, C. Porta, C. Szczylik, A.M. Czarnecka, Drug resistance in papillary RCC: from putative mechanisms to clinical practicalities. Nat. Rev. Urol. 16, 655–673 (2019)

    Article  PubMed  Google Scholar 

  124. D. Mennerich, K. Kubaichuk, T. Kietzmann, DUBs, hypoxia, and cancer. Trends Cancer 5, 632–653 (2019)

    Article  CAS  PubMed  Google Scholar 

  125. K. Mortezaee, Enriched cancer stem cells, dense stroma, and cold immunity: interrelated events in pancreatic cancer. J. Biochem. Mol. Toxicol. 24, e22708 (2021)

  126. M. Taylor, F. Billiot, V. Marty, V. Rouffiac, P. Cohen, E. Tournay, P. Opolon, F. Louache, G. Vassal, C. Laplace-Builhé, P. Vielh, J.C. Soria, F. Farace, Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells. Cancer Discover. 2, 434–449 (2012)

    Article  CAS  Google Scholar 

  127. K.D. Falkenberg, K. Rohlenova, Y. Luo, P. Carmeliet, The metabolic engine of endothelial cells. Nat. Metab. 1, 937–946 (2019)

    Article  PubMed  Google Scholar 

  128. K. Hida, N. Maishi, D.A. Annan, Y. Hida, Contribution of tumor endothelial cells in cancer progression. Int. J. Mol. Sci. 19, 1272 (2018)

    Article  PubMed Central  CAS  Google Scholar 

  129. R. Xu, F. Shimizu, K. Hovinga, K. Beal, S. Karimi, L. Droms, K.K. Peck, P. Gutin, J.B. Iorgulescu, T. Kaley, L. DeAngelis, E. Pentsova, C. Nolan, C. Grommes , T. Chan, D. Bobrow, A. Hormigo, J.R Cross, N. Wu, N. Takebe, K. Panageas, P. Ivy, J.G Supko, V. Tabar, A. Omuro, Molecular and clinical effects of Notch inhibition in glioma patients: a phase 0/I trial. Clin. Cancer Res. 22, 4786–94796 (2016)

  130. H. Yousefi, M. Vatanmakanian, M. Mahdiannasser, L. Mashouri, N.V. Alahari, M.R. Monjezi, S. Ilbeigi, S.K. Alahari, Understanding the role of integrins in breast cancer invasion, metastasis, angiogenesis, and drug resistance. Oncogene. 40, 1–21 (2021)

    Article  CAS  Google Scholar 

  131. C. Rolny, M. Mazzone, S. Tugues, D. Laoui, I. Johansson, C. Coulon, M.L. Squadrito, I. Segura, X. Li, E. Knevels, S. Costa, S. Vinckier, T. Dresselaer, P. Åkerud, M.D. Mol, H. Salomäki, M. Phillipson, S. Wyns, E. Larsson, I. Buysschaert, J. Botling, U. Himmelreich, J.A. Ginderachter, M.D. Palma, M. Dewerchin, L. Claesson-Welsh, P. Carmeliet, HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell. 19, 31–44 (2011)

    Article  CAS  PubMed  Google Scholar 

  132. X. Song, L. Feng, C. Liang, K. Yang, Z. Liu, Ultrasound triggered tumor oxygenation with oxygen-shuttle nanoperfluorocarbon to overcome hypoxia-associated resistance in cancer therapies. Nano Lett 16, 6145–6153 (2016)

    Article  CAS  PubMed  Google Scholar 

  133. C.V. Pecot, R. Rupaimoole, D. Yang, R. Akbani, C. Ivan, C. Lu, S. Wu, H.-D. Han, M.Y. Shah, C. Rodriguez-Aguayo, J. Bottsford-Miller, Y. Liu, S.B. Kim, A. Unruh, V. Gonzalez-Villasana, L. Huang, B. Zand, M. Moreno-Smith, L.S. Mangala, M. Taylor, H.J. Dalton, V. Sehgal, Y. Wen, Y. Kang, K.A. Baggerly, J.S. Lee, P.T. Ram, M.K. Ravoori, V. Kundra, X. Zhang, R. Ali-Fehmi, A.M. Gonzalez-Angulo, P.P. Massion, G.A. Calin, G. Lopez-Berestein, W. Zhang, A.K. Sood, Tumour angiogenesis regulation by the miR-200 family. Nat. Commun. 4, 2427 (2013)

    Article  PubMed  CAS  Google Scholar 

  134. A. Matejuk, G. Collet, M. Nadim, C. Grillon, C. Kieda, MicroRNAs and tumor vasculature normalization: impact on anti-tumor immune response. Arch. Immunol. Ther. Exp. (Warsz) 61, 285–299 (2013)

    Article  CAS  Google Scholar 

  135. L. Tian, A. Goldstein, H. Wang, H.C. Lo, I.S. Kim, T. Welte, K. Sheng, L.E. Dobrolecki, X. Zhang, N. Putluri, T.L. Phung, S.A. Mani, F. Stossi, A. Sreekumar, M.A. Mancini, W.K. Decker, C. Zong, M.T. Lewis, X.H.F. Zhang, Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature. 544, 250–254 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. T.N. Schumacher, R.D. Schreiber, Neoantigens in cancer immunotherapy. Science. 348, 69–74 (2015)

    Article  CAS  PubMed  Google Scholar 

  137. D.F. Quail, A.J. Dannenberg, The obese adipose tissue microenvironment in cancer development and progression. Nat. Rev. Endocrinol. 15, 139–154 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  138. Y.-L. Hu, M. DeLay, A. Jahangiri, A.M. Molinaro, S.D. Rose, W.S. Carbonell, M.K. Aghi, Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res. 72, 1773–1783 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. T. Stylianopoulos, R.K. Jain, Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc. Natl. Acad. Sci. U S A. 110, 18632–18637 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. F.G. Herrera, M. Irving, L.E. Kandalaft, G. Coukos, Rational combinations of immunotherapy with radiotherapy in ovarian cancer. Lancet Oncol. 20, e417–e433 (2019)

  141. G. Collet, K. Skrzypek, C. Grillon, A. Matejuk, B. El Hafni-Rahbi, N. Lamerant-Fayel, C. Kieda, Hypoxia control to normalize pathologic angiogenesis: potential role for endothelial precursor cells and miRNAs regulation. Vascul. Pharmacol. 56, 252–261 (2012)

    Article  CAS  PubMed  Google Scholar 

  142. H. Maes, A. Kuchnio, A. Peric, S. Moens, K. Nys, K. De Bock, A. Quaegebeur, S. Schoors, M. Georgiadou, J. Wouters, S. Vinckier, H. Vankelecom, M. Garmyn, A.C. Vion, F. Radtke, C. Boulanger, H. Gerhardt, E. Dejana, M. Dewerchin, B. Ghesquière, W. Annaert, P. Agostinis, P. Carmeliet, Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell. 26, 190–206 (2014)

    Article  CAS  PubMed  Google Scholar 

  143. M.E. Rodriguez-Ruiz, I. Vitale, K.J. Harrington, I. Melero, L. Galluzzi, Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat. Immunol. 21, 1–15 (2019)

    Google Scholar 

  144. F. Klug, H. Prakash, P.E. Huber, T. Seibel, N. Bender, N. Halama, C. Pfirschke, R.H. Voss, C. Timke, L. Umansky, K. Klapproth, K. Schäkel, N. Garbi, D. Jäger, J. Weitz, H. Schmitz-Winnenthal, G.J. Hämmerling, P. Beckhove, Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 24, 589–602 (2013)

    Article  CAS  PubMed  Google Scholar 

  145. C.V. Pecot, R. Rupaimoole, D. Yang, R. Akbani, C. Ivan, C. Lu, S. Wu, H.-D. Han, M.Y. Shah, C. Rodriguez-Aguayo, J. Bottsford-Miller, Y. Liu, S.B. Kim, A. Unruh, V. Gonzalez-Villasana, L. Huang, B. Zand, M. Moreno-Smith, L.S. Mangala, M. Taylor, H.J. Dalton, V. Sehgal, Y. Wen, Y. Kang, K.A. Baggerly, J.S. Lee, P.T. Ram, M.K. Ravoori, V. Kundra, X. Zhang, R. Ali-Fehmi, A.M. Gonzalez-Angulo, P.P. Massion, G.A. Calin, G. Lopez-Berestein, W. Zhang, A.K. Sood, Tumour angiogenesis regulation by the miR-200 family. Nat. Commun. 4, 1–14 (2013)

    Article  CAS  Google Scholar 

  146. Y. Hsu, J. Hung, W. Chang, Y. Lin, Y. Pan, P. Tsai, C. Wu, P. Kuo, Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 36, 4929–4942 (2017)

    Article  CAS  PubMed  Google Scholar 

  147. S.K. Calderwood, J. Gong, Heat shock proteins promote cancer: it's a protection racket. Trends Biochem. Sci. 41, 311–323 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. S. Lheureux, M. Braunstein, A.M. Oza, Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J. Clin. 69, 280–304 (2019)

    PubMed  Google Scholar 

  149. T. André, M. Saunders, A. Kanehisa, E. Gandossi, R. Fougeray, N.C. Amellal, A. Falcone, First-line trifluridine/tipiracil plus bevacizumab for unresectable metastatic colorectal cancer: SOLSTICE study design. Future Oncol. 16, 21–29 (2020)

    Article  PubMed  CAS  Google Scholar 

  150. M. Yanagisawa, K. Yorozu, M. Kurasawa, K. Nakano, K. Furugaki, Y. Yamashita, K. Mori, K. Fujimoto-Ouchi, Bevacizumab improves the delivery and efficacy of paclitaxel. Anti-Cancer Drugs 21, 687–694 (2010)

    Article  CAS  PubMed  Google Scholar 

  151. T.F. Hansen, B.S. Nielsen, F.B. Sørensen, A. Johnsson, A. Jakobsen, Epidermal growth factor–like domain 7 predicts response to first-line chemotherapy and bevacizumab in patients with metastatic colorectal cancer. Mol .Cancer Ther. 13, 2238–2245 (2014)

  152. C. Bais, B. Mueller, M.F. Brady, R.S. Mannel, R.A. Burger, W. Wei, K.M. Marien, M.M. Kockx, A. Husain, M.J. Birrer, Tumor microvessel density as a potential predictive marker for bevacizumab benefit: GOG-0218 biomarker analyses. J. Natl. Cancer Inst. 109, djx066 (2017)

  153. Q. Jia, J. Xu, W. Jiang, M. Zheng, M. Wei, J. Chen, L. Wang, Y. Huan, Dynamic contrast-enhanced mr imaging in a phase II study on neoadjuvant chemotherapy combining Rh-endostatin with docetaxel and epirubicin for locally advanced breast cancer. Int. J. Med. Sci. 10, 110 (2013)

    Article  PubMed  Google Scholar 

  154. E.S. Han, R.A. Burger, K.M. Darcy, M.W. Sill, L.M. Randall, D. Chase, B. Parmakhtiar, B.J. Monk, B.E. Greer, P. Connelly, K. Degeest, J.P. Fruehauf, Predictive and prognostic angiogenic markers in a gynecologic oncology group phase II trial of bevacizumab in recurrent and persistent ovarian or peritoneal cancer. Gynecol. Oncol. 119, 484–490 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. M.S. Gordon, F. Robert, D. Matei, D.S. Mendelson, J.W. Goldman, E.G. Chiorean, R.M. Strother, B.K. Seon, W.D. Figg, C.J. Peer, D. Alvarez, B.J. Adams, C.P. Theuer, Lee S Rosen, An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer. Clin. Cancer Res. 20, 5918–5926 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. D.M. Chase, M.W. Sill, B.J. Monk, M.D. Chambers, K.M. Darcy, E.S. Han, B.J. Buening, J.I. Sorosky, J.P. Fruehauf, R.A. Burger, Changes in tumor blood flow as measured by Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) may predict activity of single agent bevacizumab in recurrent epithelial ovarian (EOC) and Primary Peritoneal Cancer (PPC) patients: an exploratory analysis of a Gynecologic Oncology Group Phase II study. Gynecol. Oncol. 126, 375–380 (2012)

    Article  PubMed  Google Scholar 

  157. T. Yau, P.-J. Chen, P. Chan, C.M. Curtis, P.S. Murphy, A.B. Suttle, J. Gauvin, J.P. Hodge, M.M. Dar, R.T. Poon, Phase I dose-finding study of pazopanib in hepatocellular carcinoma: evaluation of early efficacy, pharmacokinetics, and pharmacodynamics. Clin. Cancer Res. 17, 6914–6923 (2011)

    Article  CAS  PubMed  Google Scholar 

  158. T.Q. Chu, H. Ding, D.H. Garfield, A.Q. Gu, J. Pei, W.D. Du, B.H. Han, Can determination of circulating endothelial cells and serum caspase-cleaved CK18 predict for response and survival in patients with advanced non–small-cell lung cancer receiving endostatin and paclitaxel–carboplatin chemotherapy? A Retrospective Study. J. Thorac. Oncol. 7, 1781–1789 (2012)

    Article  CAS  PubMed  Google Scholar 

  159. A.M. Groves, M. Shastry, M. Rodriguez-Justo, A. Malhotra, R. Endozo, T. Davidson, T. Kelleher, K.A. Miles, P.J. Ell, M.R. Keshtgar, 18 F-FDG PET and biomarkers for tumour angiogenesis in early breast cancer. Keshtgar, Eur. J. Nucl. Med. Mol. Imaging 38, 46–52 (2011)

    Article  CAS  PubMed  Google Scholar 

  160. M. Pölcher, C. Rudlowski, N. Friedrichs, M. Mielich, T. Höller, M. Wolfgarten, K. Kübler, R. Büttner, W. Kuhn, M. Braun, In vivo intratumor angiogenic treatment effects during taxane-based neoadjuvant chemotherapy of ovarian cancer. BMC Cancer. 10, 1–8 (2010)

    Article  CAS  Google Scholar 

  161. S. Ueda, T. Saeki, H. Takeuchi, T. Shigekawa, T. Yamane, I. Kuji, A. Osaki, In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br. J. cancer 114, 1212–1218 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. R. Coriat, H. Gouya, O. Mir, S. Ropert, O. Vignaux, S. Chaussade, P. Sogni, S. Pol, B. Blanchet, P. Legmann, F. Goldwasser, Reversible decrease of portal venous flow in cirrhotic patients: a positive side effect of sorafenib. PLoS One 6, e16978 (2011)

  163. G. Curigliano, V. Bagnardi, F. Bertolini, M. Alcalay, M.A. Locatelli, L. Fumagalli, C. Rabascio, A. Calleri, L. Adamoli, C. Criscitiello, G. Viale, A. Goldhirsch, Antiangiogenic therapy in recurrent breast cancer with lymphangitic spread to the chest wall: A randomized phase II trial of bevacizumab with sequential or concurrent oral vinorelbine and capecitabine. Breast 24, 263–271 (2015)

    Article  PubMed  Google Scholar 

  164. T.T. Batchelor, E.R. Gerstner, K.E. Emblem, D.G. Duda, J. Kalpathy-Cramer, M. Snuderl, M. Ancukiewicz, P. Polaskova, M.C. Pinho, D. Jennings, S.R. Plotkin, A.S. Chi, A.F. Eichler, J. Dietrich, F.H. Hochberg, C. Lu-Emerson, A.J. Iafrate, S.P. Ivy, B.R. Rosen, J.S. Loeffler, P.Y. Wen, A.G. Sorensen, R.K. Jain, Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc. Natl. Acad. Sci. U S A. 110, 19059–19064 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. G. Gasparini, F. Torino, T. Ueno, S. Cascinu, T. Troiani, A. Ballestrero, R. Berardi, J. Shishido, A. Yoshizawa, Y. Mori, S. Nagayama, P. Morosini, M. Toi, A phase II study of neoadjuvant bevacizumab plus capecitabine and concomitant radiotherapy in patients with locally advanced rectal cancer. Angiogenesis. 15, 141–150 (2012)

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anatomy, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran

    Jamal Majidpoor

  2. Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Keywan Mortezaee

  3. Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Keywan Mortezaee

Authors
  1. Jamal Majidpoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keywan Mortezaee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.M and K.M wrote the initial manuscript. Final revisions were made by K.M. K.M also selected the articles for interpretation. Both authors approved the final draft.

Corresponding author

Correspondence to Keywan Mortezaee.

Ethics declarations

Conflicts of interest/competing interests

The authors declare to conflict of interest.

Compliance with research ethics

The manuscript received the ethical code IR.MUK.REC.1399.108 from Kurdistan University of Medical Sciences.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Highlights

• Structural (architectural) and functional abnormalities in tumor vasculature favor immune evasion, drug impedance and metastasis.

• Aberrant angiogenesis and abnormal tumor vasculature account for increased hypoxia and acidity in the TME, as well as causing high IFP.

• Exploiting vascular mimicry and vessel co-option by cancer type indicates that anti-angiogenic therapy is not effective for all cancers.

• A suggestive strategy is to use combinations of anti-angiogenic therapy with other treatment modalities, including chemotherapy and particularly ICIs.

• Selection of appropriate adjuvants and considering the time and dose of administration are useful modalities for improving the efficacy of therapy and reducing the chance of tumor relapse and resistance.

• Vascular normalization is an effective strategy for potentiating the delivery of chemotherapeutic drugs and enhancing their efficacy, as well as reducing the chance of tumor recurrence and metastasis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Majidpoor, J., Mortezaee, K. Angiogenesis as a hallmark of solid tumors - clinical perspectives. Cell Oncol. 44, 715–737 (2021). https://doi.org/10.1007/s13402-021-00602-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-021-00602-3

Keywords

Search

Navigation