Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Vessel co-option in cancer

Nature Reviews Clinical Oncology volume 16, pages 469–493 (2019)Cite this article

Subjects

Abstract

All solid tumours require a vascular supply in order to progress. Although the ability to induce angiogenesis (new blood vessel growth) has long been regarded as essential to this purpose, thus far, anti-angiogenic therapies have shown only modest efficacy in patients. Importantly, overshadowed by the literature on tumour angiogenesis is a long-standing, but continually emerging, body of research indicating that tumours can grow instead by hijacking pre-existing blood vessels of the surrounding nonmalignant tissue. This process, termed vessel co-option, is a frequently overlooked mechanism of tumour vascularization that can influence disease progression, metastasis and response to treatment. In this Review, we describe the evidence that tumours located at numerous anatomical sites can exploit vessel co-option. We also discuss the proposed molecular mechanisms involved and the multifaceted implications of vessel co-option for patient outcomes.

Key points

  • Vessel co-option is a non-angiogenic process through which tumour cells utilize pre-existing tissue blood vessels to support tumour growth, survival and metastasis.

  • Vessel co-option is identified histologically using the presence of specific morphological features but cannot be discriminated from angiogenesis by examining microvessel density alone.

  • Vessel co-option is adopted by a wide range of human tumours growing within numerous tissues including the brain, liver, lungs and lymph nodes.

  • Mechanisms driving vessel co-option are poorly understood, although tumour cell invasion and tumour cell adhesion pathways are known to be involved.

  • Vessel co-option is implicated in patient outcomes and resistance to cancer therapies and is a legitimate target of new therapeutic strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Summary of selected randomized phase III clinical trials evaluating the efficacy of anti-angiogenic agents.
Fig. 2: Historical timeline of selected key developments in vessel co-option and angiogenesis research.
Fig. 3: Tumour growth patterns associated with vessel co-option or angiogenesis in the lung.
Fig. 4: Tumour growth patterns associated with vessel co-option or angiogenesis in the liver.
Fig. 5: Tumour growth patterns associated with vessel co-option or angiogenesis in the brain.
Fig. 6: Potential strategies to inhibit vessel co-option in cancer.

Similar content being viewed by others

References

  1. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    CAS  PubMed  Google Scholar 

  2. Takahashi, Y., Kitadai, Y., Bucana, C. D., Cleary, K. R. & Ellis, L. M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 55, 3964–3968 (1995).

    CAS  PubMed  Google Scholar 

  3. Weidner, N., Semple, J. P., Welch, W. R. & Folkman, J. Tumor angiogenesis and metastasis — correlation in invasive breast carcinoma. N. Engl. J. Med. 324, 1–8 (1991).

    CAS  PubMed  Google Scholar 

  4. Graham, C. H., Rivers, J., Kerbel, R. S., Stankiewicz, K. S. & White, W. L. Extent of vascularization as a prognostic indicator in thin (<0.76 mm) malignant melanomas. Am. J. Pathol. 145, 510–514 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Weidner, N., Carroll, P. R., Flax, J., Blumenfeld, W. & Folkman, J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am. J. Pathol. 143, 401–409 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Macchiarini, P., Fontanini, G., Hardin, M. J., Squartini, F. & Angeletti, C. A. Relation of neovascularisation to metastasis of non-small-cell lung cancer. Lancet 340, 145–146 (1992).

    CAS  PubMed  Google Scholar 

  7. Senger, D. R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).

    CAS  PubMed  Google Scholar 

  8. Ferrara, N. & Henzel, W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161, 851–858 (1989).

    CAS  PubMed  Google Scholar 

  9. Chaudhry, I. H., O‘Donovan, D. G., Brenchley, P. E., Reid, H. & Roberts, I. S. Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas. Histopathology 39, 409–415 (2001).

    CAS  PubMed  Google Scholar 

  10. Mise, M. et al. Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology 23, 455–464 (1996).

    CAS  PubMed  Google Scholar 

  11. Obermair, A. et al. Correlation of vascular endothelial growth factor expression and microvessel density in cervical intraepithelial neoplasia. J. Natl Cancer Inst. 89, 1212–1217 (1997).

    CAS  PubMed  Google Scholar 

  12. Toi, M. et al. Vascular endothelial growth factor and platelet-derived endothelial cell growth factor are frequently coexpressed in highly vascularized human breast cancer. Clin. Cancer Res. 1, 961–964 (1995).

    CAS  PubMed  Google Scholar 

  13. O‘Reilly, M. S. et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79, 315–328 (1994).

    PubMed  Google Scholar 

  14. O‘Reilly, M. S., Holmgren, L., Chen, C. & Folkman, J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat. Med. 2, 689–692 (1996).

    PubMed  Google Scholar 

  15. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  16. Pezzella, F. et al. Angiogenesis in primary lung cancer and lung secondaries. Eur. J. Cancer 32A, 2494–2500 (1996).

    CAS  PubMed  Google Scholar 

  17. Pezzella, F. et al. Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis. Am. J. Pathol. 151, 1417–1423 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Vasudev, N. S. & Reynolds, A. R. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 17, 471–494 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ebos, J. M. & Kerbel, R. S. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat. Rev. Clin. Oncol. 8, 210–221 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Jayson, G. C., Kerbel, R., Ellis, L. M. & Harris, A. L. Antiangiogenic therapy in oncology: current status and future directions. Lancet 388, 518–529 (2016).

    CAS  PubMed  Google Scholar 

  21. Sanchez-Gastaldo, A., Kempf, E., Gonzalez Del Alba, A. & Duran, I. Systemic treatment of renal cell cancer: a comprehensive review. Cancer Treat. Rev. 60, 77–89 (2017).

    CAS  PubMed  Google Scholar 

  22. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    CAS  PubMed  Google Scholar 

  23. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    CAS  PubMed  Google Scholar 

  24. Tabernero, J. et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 16, 499–508 (2015).

    CAS  PubMed  Google Scholar 

  25. Bruix, J. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389, 56–66 (2017).

    CAS  PubMed  Google Scholar 

  26. Grothey, A. et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381, 303–312 (2013).

    CAS  PubMed  Google Scholar 

  27. Van Cutsem, E. et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J. Clin. Oncol. 30, 3499–3506 (2012).

    PubMed  Google Scholar 

  28. Kindler, H. L. et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J. Clin. Oncol. 28, 3617–3622 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kelly, W. K. et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J. Clin. Oncol. 30, 1534–1540 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Flaherty, K. T. et al. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J. Clin. Oncol. 31, 373–379 (2013).

    CAS  PubMed  Google Scholar 

  31. Miller, K. D. et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J. Clin. Oncol. 23, 792–799 (2005).

    CAS  PubMed  Google Scholar 

  32. Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007).

    CAS  PubMed  Google Scholar 

  33. Miles, D. W. et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2–negative metastatic breast cancer. J. Clin. Oncol. 28, 3239–3247 (2010).

    CAS  PubMed  Google Scholar 

  34. Robert, N. J. et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J. Clin. Oncol. 29, 1252–1260 (2011).

    CAS  PubMed  Google Scholar 

  35. Brufsky, A. M. et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol. 29, 4286–4293 (2011).

    CAS  PubMed  Google Scholar 

  36. Vrdoljak, E. et al. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann. Oncol. 27, 2046–2052 (2016).

    CAS  PubMed  Google Scholar 

  37. Gianni, L. et al. AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J. Clin. Oncol. 31, 1719–1725 (2013).

    CAS  PubMed  Google Scholar 

  38. Kurzrock, R. & Stewart, D. J. Exploring the benefit/risk associated with antiangiogenic agents for the treatment of non–small cell lung cancer patients. Clin. Cancer Res. 23, 1137–1148 (2017).

    CAS  PubMed  Google Scholar 

  39. Khasraw, M., Ameratunga, M. & Grommes, C. Bevacizumab for the treatment of high-grade glioma: an update after phase III trials. Expert Opin. Biol. Ther. 14, 729–740 (2014).

    CAS  PubMed  Google Scholar 

  40. Motzer, R. J. et al. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur. Urol. 73, 62–68 (2018).

    CAS  PubMed  Google Scholar 

  41. de Gramont, A. et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 13, 1225–1233 (2012).

    PubMed  Google Scholar 

  42. Allegra, C. J. et al. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J. Clin. Oncol. 31, 359–364 (2013).

    CAS  PubMed  Google Scholar 

  43. Haas, N. B. et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 387, 2008–2016 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Motzer, R. J. et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J. Clin. Oncol. 35, 3916–3923 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wakelee, H. A. et al. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet. Oncol. 18, 1610–1623 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 16, 1344–1354 (2015).

    CAS  PubMed  Google Scholar 

  47. Rana, P., Pritchard, K. I. & Kerbel, R. Plasma vascular endothelial growth factor as a predictive biomarker: door closed? Eur. J. Cancer 70, 143–145 (2017).

    PubMed  Google Scholar 

  48. Llovet, J. M. & Hernandez-Gea, V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin. Cancer Res. 20, 2072–2079 (2014).

    CAS  PubMed  Google Scholar 

  49. Kerbel, R. S. Reappraising antiangiogenic therapy for breast cancer. Breast 20, S56–S60 (2011).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Saharinen, P., Eklund, L. & Alitalo, K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat. Rev. Drug Discov. 16, 635–661 (2017).

    CAS  PubMed  Google Scholar 

  52. Reck, M. et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet. Oncol. 15, 143–155 (2014).

    CAS  PubMed  Google Scholar 

  53. Monk, B. J. et al. Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): long-term survival, impact of ascites, and progression-free survival-2. Gynecol. Oncol. 143, 27–34 (2016).

    CAS  PubMed  Google Scholar 

  54. Johnson, P. J. et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J. Clin. Oncol. 31, 3517–3524 (2013).

    CAS  PubMed  Google Scholar 

  55. Leenders, W. P., Küsters, B. & de Waal, R. M. Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis. Endothelium 9, 83–87 (2002).

    PubMed  Google Scholar 

  56. Dome, B., Hendrix, M. J. C., Paku, S., Tovari, J. & Timar, J. Alternative vascularization mechanisms in cancer — pathology and therapeutic implications. Am. J. Pathol. 170, 1–15 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Donnem, T. et al. Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? Cancer Med. 2, 427–436 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Maniotis, A. J. et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol. 155, 739–752 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Pezzella, F. & Gatter, K. C. Evidence showing that tumors can grow without angiogenesis and can switch between angiogenic and nonangiogenic phenotypes. J. Natl Cancer Inst. 108, djw032 (2016).

    PubMed  PubMed Central  Google Scholar 

  60. Winkler, F. Hostile takeover: how tumours hijack pre-existing vascular environments to thrive. J. Pathol. 242, 267–272 (2017).

    PubMed  Google Scholar 

  61. Lugassy, C. et al. Angiotropism, pericytic mimicry and extravascular migratory metastasis in melanoma: an alternative to intravascular cancer dissemination. Cancer Microenviron. 7, 139–152 (2014).

    PubMed  PubMed Central  Google Scholar 

  62. Lenzi, P., Bocci, G. & Natale, G. John Hunter and the origin of the term “angiogenesis”. Angiogenesis 19, 255–256 (2016).

    PubMed  Google Scholar 

  63. Greenblatt, M. & Shubi, P. Tumor angiogenesis: transfilter diffusion studies in the hamster by the transparent chamber technique. J. Natl Cancer Inst. 41, 111–124 (1968).

    CAS  PubMed  Google Scholar 

  64. Ide, A. G., Baker, N. H. & Warren, S. L. Vascularization of the Brown Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am. J. Roentgenol. 42, 891–899 (1939).

    Google Scholar 

  65. Greene, H. S. Heterologous transplantation of mammalian tumors: I. The transfer of rabbit tumors to alien species. J. Exp. Med. 73, 461–474 (1941).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Ribatti, D. Judah Folkman, a pioneer in the study of angiogenesis. Angiogenesis 11, 3–10 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Bugge, T. H. et al. Growth and dissemination of Lewis lung carcinoma in plasminogen-deficient mice. Blood 90, 4522–4531 (1997).

    CAS  PubMed  Google Scholar 

  68. Fidler, I. J. Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res. 35, 218–224 (1975).

    CAS  PubMed  Google Scholar 

  69. Gille, J. et al. Simultaneous blockade of VEGFR-1 and VEGFR-2 activation is necessary to efficiently inhibit experimental melanoma growth and metastasis formation. Int. J. Cancer 120, 1899–1908 (2007).

    CAS  PubMed  Google Scholar 

  70. Szabo, V. et al. Mechanism of tumour vascularization in experimental lung metastases. J. Pathol. 235, 384–396 (2015).

    CAS  PubMed  Google Scholar 

  71. Kuczynski, E. A. et al. Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma. J. Natl Cancer Inst. 108, djw030 (2016).

    PubMed Central  Google Scholar 

  72. Yamaguchi, R. Y. et al. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 28, 68–77 (1998).

    CAS  PubMed  Google Scholar 

  73. Hu, J. et al. Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer. Oncogene 24, 1212–1219 (2005).

    CAS  PubMed  Google Scholar 

  74. Offersen, B. V., Pfeiffer, P., Hamilton-Dutoit, S. & Overgaard, J. Patterns of angiogenesis in nonsmall-cell lung carcinoma. Cancer 91, 1500–1509 (2001).

    CAS  PubMed  Google Scholar 

  75. Jeong, H. S. et al. Investigation of the lack of angiogenesis in the formation of lymph node metastases. J. Natl Cancer Inst. 107, djv155 (2015).

    PubMed  PubMed Central  Google Scholar 

  76. Leenders, W. et al. Vascular endothelial growth factor-A determines detectability of experimental melanoma brain metastasis in GD-DTPA-enhanced MRI. Int. J. Cancer 105, 437–443 (2003).

    CAS  PubMed  Google Scholar 

  77. Kusters, B. et al. Vascular endothelial growth factor-A(165) induces progression of melanoma brain metastases without induction of sprouting angiogenesis. Cancer Res. 62, 341–345 (2002).

    CAS  PubMed  Google Scholar 

  78. Kim, E. S. et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc. Natl Acad. Sci. USA 99, 11399–11404 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Lazaris, A. et al. Vascularization of colorectal carcinoma liver metastasis: insight into stratification of patients for anti-angiogenic therapies. J. Pathol. Clin. Res. 4, 184–192 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Bridgeman, V. L. et al. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J. Pathol. 241, 362–374 (2017).

    CAS  PubMed  Google Scholar 

  81. Erichsen, J. Zwei falle von carcinosis acuta miliaris. Virchows Arch. 21, 465–479 (1861).

    Google Scholar 

  82. Moxon, W. Case of transplantation of epithelial cancer from the trachea to the pulmunary tissue, probably by desecent of cancer germs down the bronchial tubes. Trans. Pathol. Soc. 20, 28–29 (1869).

    Google Scholar 

  83. Sardari Nia, P. et al. Different growth patterns of non-small cell lung cancer represent distinct biologic subtypes. Ann. Thorac. Surg. 85, 395–405 (2008).

    PubMed  Google Scholar 

  84. Guedj, N. et al. Angiogenesis and extracellular matrix remodelling in bronchioloalveolar carcinomas: distinctive patterns in mucinous and non-mucinous tumours. Histopathology 44, 251–256 (2004).

    CAS  PubMed  Google Scholar 

  85. Travis, W. D. et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J. Thorac. Oncol. 10, 1243–1260 (2015).

    PubMed  Google Scholar 

  86. Sardari Nia, P., Hendriks, J., Friedel, G., Van Schil, P. & Van Marck, E. Distinct angiogenic and non-angiogenic growth patterns of lung metastases from renal cell carcinoma. Histopathology 51, 354–361 (2007).

    CAS  PubMed  Google Scholar 

  87. Passalidou, E. et al. Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas. Br. J. Cancer 86, 244–249 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Yousem, S. A. Peripheral squamous cell carcinoma of lung: patterns of growth with particular focus on airspace filling. Hum. Pathol. 40, 861–867 (2009).

    PubMed  Google Scholar 

  89. Adighibe, O. et al. Is nonangiogenesis a novel pathway for cancer progression? A study using 3-dimensional tumour reconstructions. Br. J. Cancer 94, 1176–1179 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Travis, W. D. et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J. Thorac. Oncol. 6, 244–285 (2011).

    PubMed  PubMed Central  Google Scholar 

  91. Lu, S. et al. Spread through air spaces (STAS) is an independent predictor of recurrence and lung cancer-specific death in squamous cell carcinoma. J. Thorac. Oncol. 12, 223–234 (2017).

    PubMed  Google Scholar 

  92. Kadota, K. et al. Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas. J. Thorac. Oncol. 10, 806–814 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Warth, A. et al. Prognostic impact of intra-alveolar tumor spread in pulmonary adenocarcinoma. Am. J. Surg. Pathol. 39, 793–801 (2015).

    PubMed  Google Scholar 

  94. Donnem, T. et al. Non-angiogenic tumours and their influence on cancer biology. Nat. Rev. Cancer 18, 323–336 (2018).

    CAS  PubMed  Google Scholar 

  95. Adighibe, O. et al. Why some tumours trigger neovascularisation and others don’t: the story thus far. Chin. J. Cancer 35, 18 (2016).

    PubMed  PubMed Central  Google Scholar 

  96. Paakko, P., Risteli, J., Risteli, L. & Autio-Harmainen, H. Immunohistochemical evidence that lung carcinomas grow on alveolar basement membranes. Am. J. Surg. Pathol. 14, 464–473 (1990).

    CAS  PubMed  Google Scholar 

  97. Rosenblatt, M. B., Lisa, J. R. & Collier, F. Primary and metastatic bronciolo-alveolar carcinoma. Dis. Chest 52, 147–152 (1967).

    CAS  PubMed  Google Scholar 

  98. Breast Cancer Progression Working Party. Evidence for novel non-angiogenic pathway in breast-cancer metastasis. Lancet 355, 1787–1788 (2000).

    Google Scholar 

  99. Mizuuchi, H. et al. Solitary pulmonary metastasis from malignant melanoma of the bulbar conjunctiva presenting as a pulmonary ground glass nodule: report of a case. Thorac. Cancer 6, 97–100 (2015).

    PubMed  PubMed Central  Google Scholar 

  100. Breedis, C. & Young, G. The blood supply of neoplasms in the liver. Am. J. Pathol. 30, 969–977 (1954).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Kojiro, M. Pathology of Hepatocellular Carcinoma 63–75 (Blackwell Publishing, 2006).

  102. Vermeulen, P. B. et al. Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J. Pathol. 195, 336–342 (2001).

    CAS  PubMed  Google Scholar 

  103. International Consensus Group for Hepatocellular Neoplasia. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49, 658–664 (2009).

    Google Scholar 

  104. Nakashima, O., Sugihara, S., Kage, M. & Kojiro, M. Pathomorphologic characteristics of small hepatocellular carcinoma: a special reference to small hepatocellular carcinoma with indistinct margins. Hepatology 22, 101–105 (1995).

    CAS  PubMed  Google Scholar 

  105. Nakashima, Y., Nakashima, O., Hsia, C. C., Kojiro, M. & Tabor, E. Vascularization of small hepatocellular carcinomas: correlation with differentiation. Liver 19, 12–18 (1999).

    CAS  PubMed  Google Scholar 

  106. Matsui, O. et al. Dynamic computed tomography during arterial portography: the most sensitive examination for small hepatocellular carcinomas. J. Comput. Assist. Tomogr. 9, 19–24 (1985).

    CAS  PubMed  Google Scholar 

  107. Kita, K., Itoshima, T. & Tsuji, T. Observation of microvascular casts of human hepatocellular carcinoma by scanning electron microscopy. Gastroenterol. Japon. 26, 319–328 (1991).

    CAS  Google Scholar 

  108. Sugihara, S., Kojiro, M. & Nakashima, T. Ultrastructural study of hepatocellular carcinoma with replacing growth pattern. Acta Pathol. Japon. 35, 549–559 (1985).

    CAS  Google Scholar 

  109. Park, H. J., Choi, B. I., Lee, E. S., Park, S. B. & Lee, J. B. How to differentiate borderline hepatic nodules in hepatocarcinogenesis: emphasis on imaging diagnosis. Liver Cancer 6, 189–203 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Kozaka, K. et al. A subgroup of intrahepatic cholangiocarcinoma with an infiltrating replacement growth pattern and a resemblance to reactive proliferating bile ductules: ‘bile ductular carcinoma’. Histopathology 51, 390–400 (2007).

    CAS  PubMed  Google Scholar 

  111. Kin, M., Torimura, T., Ueno, T., Inuzuka, S. & Tanikawa, K. Sinusoidal capillarization in small hepatocellular carcinoma. Pathol. Int. 44, 771–778 (1994).

    CAS  PubMed  Google Scholar 

  112. Géraud, C. et al. Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival. Liver Int. 33, 1428–1440 (2013).

    PubMed  Google Scholar 

  113. Nakashima, T. et al. Histologic growth pattern of hepatocellular carcinoma: relationship to orcein (hepatitis B surface antigen)-positive cells in cancer tissue. Hum. Pathol. 13, 563–568 (1982).

    CAS  PubMed  Google Scholar 

  114. Kanai, T. et al. Pathology of small hepatocellular carcinoma. A proposal for a new gross classification. Cancer 60, 810–819 (1987).

    CAS  PubMed  Google Scholar 

  115. Stessels, F. et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br. J. Cancer 90, 1429–1436 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Van den Eynden, G. G. et al. The histological growth pattern of colorectal cancer liver metastases has prognostic value. Clin. Exp. Metastasis 29, 541–549 (2012).

    PubMed  Google Scholar 

  117. van Dam, P. J. et al. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Br. J. Cancer 117, 1427–1441 (2017).

    PubMed  PubMed Central  Google Scholar 

  118. Mouta Carreira, C. et al. LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res. 61, 8079–8084 (2001).

    CAS  PubMed  Google Scholar 

  119. Terayama, N., Terada, T. & Nakanuma, Y. A morphometric and immunohistochemical study on angiogenesis of human metastatic carcinomas of the liver. Hepatology 24, 816–819 (1996).

    CAS  PubMed  Google Scholar 

  120. Gervaz, P. et al. Angiogenesis of liver metastases: role of sinusoidal endothelial cells. Dis. Colon Rectum 43, 980–986 (2000).

    CAS  PubMed  Google Scholar 

  121. Paku, S. & Lapis, K. Morphological aspects of angiogenesis in experimental liver metastases. Am. J. Pathol. 143, 926–936 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. van Dam, P. J. et al. Histopathological growth patterns as a candidate biomarker for immunomodulatory therapy. Semin. Cancer Biol. 52, 86–93 (2018).

    PubMed  Google Scholar 

  123. Frentzas, S. et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat. Med. 22, 1294–1302 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Fernandez Moro, C., Bozoky, B. & Gerling, M. Growth patterns of colorectal cancer liver metastases and their impact on prognosis: a systematic review. BMJ Open Gastroenterol. 5, e000217 (2018).

    PubMed  PubMed Central  Google Scholar 

  125. Dezso, K. et al. Structural analysis of oval-cell-mediated liver regeneration in rats. Hepatology 56, 1457–1467 (2012).

    CAS  PubMed  Google Scholar 

  126. Oertel, M., Menthena, A., Dabeva, M. D. & Shafritz, D. A. Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells. Gastroenterology 130, 507–520; quiz 590 (2006).

    PubMed  Google Scholar 

  127. Ding, B. S. et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97–102 (2014).

    PubMed  Google Scholar 

  128. Kruger, A. et al. Pattern and load of spontaneous liver metastasis dependent on host immune status studied with a lacZ transduced lymphoma. Blood 84, 3166–3174 (1994).

    CAS  PubMed  Google Scholar 

  129. Pogue-Geile, K. et al. Defective mismatch repair and benefit from bevacizumab for colon cancer: findings from NSABP C-08. J. Natl Cancer Inst. 105, 989–992 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Nielsen, K., Rolff, H. C., Eefsen, R. L. & Vainer, B. The morphological growth patterns of colorectal liver metastases are prognostic for overall survival. Mod. Pathol. 27, 1641–1648 (2014).

    CAS  PubMed  Google Scholar 

  131. Allison, K. H., Fligner, C. L. & Parks, W. T. Radiographically occult, diffuse intrasinusoidal hepatic metastases from primary breast carcinomas: a clinicopathologic study of 3 autopsy cases. Arch. Pathol. Lab. Med. 128, 1418–1423 (2004).

    PubMed  Google Scholar 

  132. Simone, C., Murphy, M., Shifrin, R., Zuluaga Toro, T. & Reisman, D. Rapid liver enlargement and hepatic failure secondary to radiographic occult tumor invasion: two case reports and review of the literature. J. Med. Case Rep. 6, 402 (2012).

    PubMed  PubMed Central  Google Scholar 

  133. Watson, A. J. Diffuse intra-sinusoidal metastatic carcinoma of the liver. J. Pathol. Bacteriol. 69, 207–217 (1955).

    CAS  PubMed  Google Scholar 

  134. Loddenkemper, C. et al. Frequency and diagnostic patterns of lymphomas in liver biopsies with respect to the WHO classification. Virchows Arch. 450, 493–502 (2007).

    PubMed  PubMed Central  Google Scholar 

  135. Baumhoer, D., Tzankov, A., Dirnhofer, S., Tornillo, L. & Terracciano, L. M. Patterns of liver infiltration in lymphoproliferative disease. Histopathology 53, 81–90 (2008).

    CAS  PubMed  Google Scholar 

  136. Shetty, S. et al. Recruitment mechanisms of primary and malignant B cells to the human liver. Hepatology 56, 1521–1531 (2012).

    CAS  PubMed  Google Scholar 

  137. Willis, R. A. The Spread of Tumours in the Human Body (J&A Churchill, 1934).

  138. Ewing, J. Neoplastic Diseases — A Treatise On Tumors 2nd edn (W.B. Saunders Company, 1922).

  139. Winkler, F. et al. Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis. Glia 57, 1306–1315 (2009).

    PubMed  Google Scholar 

  140. Bentolila, L. A. et al. Imaging of angiotropism/vascular co-option in a murine model of brain melanoma: implications for melanoma progression along extravascular pathways. Sci. Rep. 6, 23834 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Yao, H. et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature 560, 55–60 (2018).

    CAS  PubMed  Google Scholar 

  142. Jain, R. K. et al. Angiogenesis in brain tumours. Nat. Rev. Neurosci. 8, 610–622 (2007).

    CAS  PubMed  Google Scholar 

  143. Verhoeff, J. J. et al. Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme. BMC Cancer 9, 444 (2009).

    PubMed  PubMed Central  Google Scholar 

  144. Wesseling, P., van der Laak, J. A., de Leeuw, H., Ruiter, D. J. & Burger, P. C. Quantitative immunohistological analysis of the microvasculature in untreated human glioblastoma multiforme. Computer-assisted image analysis of whole-tumor sections. J. Neurosurg. 81, 902–909 (1994).

    CAS  PubMed  Google Scholar 

  145. Bernsen, H., Van der Laak, J., Kusters, B., Van der Ven, A. & Wesseling, P. Gliomatosis cerebri: quantitative proof of vessel recruitment by cooptation instead of angiogenesis. J. Neurosurg. 103, 702–706 (2005).

    PubMed  Google Scholar 

  146. Claes, A., Idema, A. J. & Wesseling, P. Diffuse glioma growth: a guerilla war. Acta Neuropathol. 114, 443–458 (2007).

    PubMed  PubMed Central  Google Scholar 

  147. Caspani, E. M., Crossley, P. H., Redondo-Garcia, C. & Martinez, S. Glioblastoma: a pathogenic crosstalk between tumor cells and pericytes. PLOS ONE 9, e101402 (2014).

    PubMed  PubMed Central  Google Scholar 

  148. Lyle, L. T. et al. Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer. Clin. Cancer Res. 22, 5287–5299 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Nagano, N., Sasaki, H., Aoyagi, M. & Hirakawa, K. Invasion of experimental rat brain tumor: early morphological changes following microinjection of C6 glioma cells. Acta Neuropathol. 86, 117–125 (1993).

    CAS  PubMed  Google Scholar 

  150. Lugassy, C. et al. Pericytic-like angiotropism of glioma and melanoma cells. Am. J. Dermatopathol. 24, 473–478 (2002).

    PubMed  Google Scholar 

  151. Watkins, S. et al. Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat. Commun. 5, 4196 (2014).

    CAS  PubMed  Google Scholar 

  152. Holash, J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998 (1999).

    CAS  PubMed  Google Scholar 

  153. Cheng, L. et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153, 139–152 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Gerstner, E. R. et al. VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer. Nat. Rev. Clin. Oncol. 6, 229–236 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Baker, G. J. et al. Mechanisms of glioma formation: iterative perivascular glioma growth and invasion leads to tumor progression, VEGF-independent vascularization, and resistance to antiangiogenic therapy. Neoplasia 16, 543–561 (2014).

    PubMed  PubMed Central  Google Scholar 

  156. Sakariassen, P. O. et al. Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc. Natl Acad. Sci. USA 103, 16466–16471 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Montana, V. & Sontheimer, H. Bradykinin promotes the chemotactic invasion of primary brain tumors. J. Neurosci. 31, 4858–4867 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Yadav, V. N. et al. CXCR4 increases in-vivo glioma perivascular invasion, and reduces radiation induced apoptosis: a genetic knockdown study. Oncotarget 7, 83701–83719 (2016).

    PubMed  PubMed Central  Google Scholar 

  159. Griveau, A. et al. A glial signature and Wnt7 signaling regulate glioma-vascular interactions and tumor microenvironment. Cancer Cell 33, 874–889 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Berghoff, A. S. et al. Invasion patterns in brain metastases of solid cancers. Neuro Oncol. 15, 1664–1672 (2013).

    PubMed  PubMed Central  Google Scholar 

  161. Kienast, Y. et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 16, 116–122 (2010).

    CAS  PubMed  Google Scholar 

  162. Siam, L. et al. The metastatic infiltration at the metastasis/brain parenchyma-interface is very heterogeneous and has a significant impact on survival in a prospective study. Oncotarget 6, 29254–29267 (2015).

    PubMed  PubMed Central  Google Scholar 

  163. Hung, T. et al. Angiotropism in primary cutaneous melanoma with brain metastasis: a study of 20 cases. Am. J. Dermatopathol. 35, 650–654 (2013).

    PubMed  Google Scholar 

  164. Bugyik, E. et al. Lack of angiogenesis in experimental brain metastases. J. Neuropathol. Exp. Neurol. 70, 979–991 (2011).

    PubMed  Google Scholar 

  165. Valiente, M. et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Carbonell, W. S., Ansorge, O., Sibson, N. & Muschel, R. The vascular basement membrane as “soil” in brain metastasis. PLOS ONE 4, e5857 (2009).

    PubMed  PubMed Central  Google Scholar 

  167. Dome, B., Timar, J. & Paku, S. A novel concept of glomeruloid body formation in experimental cerebral metastases. J. Neuropathol. Exp. Neurol. 62, 655–661 (2003).

    PubMed  Google Scholar 

  168. Spanberger, T. et al. Extent of peritumoral brain edema correlates with prognosis, tumoral growth pattern, HIF1a expression and angiogenic activity in patients with single brain metastases. Clin. Exp. Metastasis 30, 357–368 (2013).

    CAS  PubMed  Google Scholar 

  169. Dome, B., Paku, S., Somlai, B. & Timar, J. Vascularization of cutaneous melanoma involves vessel co-option and has clinical significance. J. Pathol. 197, 355–362 (2002).

    PubMed  Google Scholar 

  170. Lugassy, C. et al. Ultrastructural and immunohistochemical studies of the periendothelial matrix in human melanoma: evidence for an amorphous matrix containing laminin. J. Cutan. Pathol. 26, 78–83 (1999).

    CAS  PubMed  Google Scholar 

  171. Barnhill, R. L. & Lugassy, C. Angiotropic malignant melanoma and extravascular migratory metastasis: description of 36 cases with emphasis on a new mechanism of tumour spread. Pathology 36, 485–490 (2004).

    PubMed  Google Scholar 

  172. Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014).

    CAS  PubMed  Google Scholar 

  173. Van Es, S. L., Colman, M., Thompson, J. F., McCarthy, S. W. & Scolyer, R. A. Angiotropism is an independent predictor of local recurrence and in-transit metastasis in primary cutaneous melanoma. Am. J. Surg. Pathol. 32, 1396–1403 (2008).

    PubMed  Google Scholar 

  174. Wilmott, J. et al. Angiotropism is an independent predictor of microscopic satellites in primary cutaneous melanoma. Histopathology 61, 889–898 (2012).

    PubMed  Google Scholar 

  175. Colpaert, C. G. et al. Cutaneous breast cancer deposits show distinct growth patterns with different degrees of angiogenesis, hypoxia and fibrin deposition. Histopathology 42, 530–540 (2003).

    CAS  PubMed  Google Scholar 

  176. Naresh, K. N., Nerurkar, A. Y. & Borges, A. M. Angiogenesis is redundant for tumour growth in lymph node metastases. Histopathology 38, 466–470 (2001).

    CAS  PubMed  Google Scholar 

  177. Vermeulen, P. B., Sardari Nia, P., Colpaert, C., Dirix, L. Y. & Van Marck, E. Lack of angiogenesis in lymph node metastases of carcinomas is growth pattern-dependent. Histopathology 40, 105–107 (2002).

    CAS  PubMed  Google Scholar 

  178. Qian, C. N., Resau, J. H. & Teh, B. T. Prospects for vasculature reorganization in sentinel lymph nodes. Cell Cycle 6, 514–517 (2007).

    CAS  PubMed  Google Scholar 

  179. Lee, S. Y. et al. Changes in specialized blood vessels in lymph nodes and their role in cancer metastasis. J. Transl Med. 10, 206 (2012).

    PubMed  PubMed Central  Google Scholar 

  180. Mandelcorn, E. D., Palestine, A. G., Dubovy, S. & Davis, J. L. Vascular co-option in lung cancer metastatic to the eye after treatment with bevacizumab. J. Ophthalmic Inflamm. Infect. 1, 35–38 (2010).

    PubMed  PubMed Central  Google Scholar 

  181. Inoue, M., Hager, J. H., Ferrara, N., Gerber, H. P. & Hanahan, D. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 1, 193–202 (2002).

    CAS  PubMed  Google Scholar 

  182. Bugajski, A., Nowogrodzka-Zagorska, M., Lenko, J. & Miodonski, A. J. Angiomorphology of the human renal clear cell carcinoma. A light and scanning electron microscopic study. Virchows Arch. 415, 103–113 (1989).

    CAS  Google Scholar 

  183. Ronny, F. M. et al. Glomerular sparing pattern in primary kidney neoplasms: clinical, morphological and immunohistochemical study. Am. J. Clin. Exp. Urol. 2, 76–81 (2014).

    PubMed  PubMed Central  Google Scholar 

  184. Araki, H. et al. Relationship of pathologic factors to efficacy of sorafenib treatment in patients with metastatic clear cell renal cell carcinoma. Am. J. Clin. Pathol. 143, 492–499 (2015).

    CAS  PubMed  Google Scholar 

  185. Fukatsu, A. et al. Growth pattern, an important pathologic prognostic parameter for clear cell renal cell carcinoma. Am. J. Clin. Pathol. 140, 500–505 (2013).

    PubMed  Google Scholar 

  186. Qian, C. N. Hijacking the vasculature in ccRCC — co-option, remodelling and angiogenesis. Nat. Rev. Urol. 10, 300–304 (2013).

    CAS  PubMed  Google Scholar 

  187. Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Ishikawa, F. et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat. Biotechnol. 25, 1315–1321 (2007).

    CAS  PubMed  Google Scholar 

  189. Raymaekers, K., Stegen, S., van Gastel, N. & Carmeliet, G. The vasculature: a vessel for bone metastasis. Bonekey Rep. 4, 742 (2015).

    PubMed  PubMed Central  Google Scholar 

  190. Duarte, D. et al. Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell 22, 64–77 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Liao, D. & Johnson, R. S. Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 26, 281–290 (2007).

    CAS  PubMed  Google Scholar 

  192. Terayama, N., Terada, T. & Nakanuma, Y. Histologic growth patterns of metastatic carcinomas of the liver. Jpn. J. Clin. Oncol. 26, 24–29 (1996).

    CAS  PubMed  Google Scholar 

  193. Kojiro, M. ‘Nodule-in-nodule’ appearance in hepatocellular carcinoma: its significance as a morphologic marker of dedifferentiation. Intervirology 47, 179–183 (2004).

    PubMed  Google Scholar 

  194. Bugyik, E. et al. Mechanisms of vascularization in murine models of primary and metastatic tumor growth. Chin. J. Cancer 35, 19 (2016).

    PubMed  PubMed Central  Google Scholar 

  195. Milne, E. N., Margulis, A. R., Noonan, C. D. & Stoughton, J. T. Histologic type-specific vascular patterns in rat tumors. Cancer 20, 1635–1646 (1967).

    CAS  PubMed  Google Scholar 

  196. Guerin, E., Man, S., Xu, P. & Kerbel, R. S. A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs. Cancer Res. 73, 2743–2748 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Strand, T. E., Rostad, H., Strom, E. H. & Hasleton, P. The percentage of lepidic growth is an independent prognostic factor in invasive adenocarcinoma of the lung. Diagn. Pathol. 10, 94 (2015).

    PubMed  PubMed Central  Google Scholar 

  198. Simonsen, T. G., Gaustad, J. V. & Rofstad, E. K. Intertumor heterogeneity in vascularity and invasiveness of artificial melanoma brain metastases. J. Exp. Clin. Cancer Res. 34, 150 (2015).

    PubMed  PubMed Central  Google Scholar 

  199. Rubenstein, J. L. et al. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2, 306–314 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Leenders, W. P. et al. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin. Cancer Res. 10, 6222–6230 (2004).

    CAS  PubMed  Google Scholar 

  201. Keunen, O. et al. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc. Natl Acad. Sci. USA 108, 3749–3754 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. di Tomaso, E. et al. Glioblastoma recurrence after cediranib therapy in patients: lack of “rebound” revascularization as mode of escape. Cancer Res. 71, 19–28 (2011).

    PubMed  PubMed Central  Google Scholar 

  203. de Groot, J. F. et al. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol. 12, 233–242 (2010).

    PubMed  PubMed Central  Google Scholar 

  204. Noguchi, M. et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 75, 2844–2852 (1995).

    CAS  PubMed  Google Scholar 

  205. Carretta, A. et al. Evaluation of radiological and pathological prognostic factors in surgically-treated patients with bronchoalveolar carcinoma. Eur. J. Cardiothorac. Surg. 20, 367–371 (2001).

    CAS  PubMed  Google Scholar 

  206. Higashiyama, M. et al. Prognostic value of bronchiolo-alveolar carcinoma component of small lung adenocarcinoma. Ann. Thorac. Surg. 68, 2069–2073 (1999).

    CAS  PubMed  Google Scholar 

  207. Reinmuth, N. et al. Prognostic significance of vessel architecture and vascular stability in non-small cell lung cancer. Lung Cancer 55, 53–60 (2007).

    PubMed  Google Scholar 

  208. Pastorino, U. et al. Immunocytochemical markers in stage I lung cancer: relevance to prognosis. J. Clin. Oncol. 15, 2858–2865 (1997).

    CAS  PubMed  Google Scholar 

  209. Renyi-Vamos, F. et al. Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin. Cancer Res. 11, 7344–7353 (2005).

    CAS  PubMed  Google Scholar 

  210. Sardari Nia, P. et al. Prognostic value of nonangiogenic and angiogenic growth patterns in non-small-cell lung cancer. Br. J. Cancer 91, 1293–1300 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Eefsen, R. L. et al. Growth pattern of colorectal liver metastasis as a marker of recurrence risk. Clin. Exp. Metastasis 32, 369–381 (2015).

    CAS  PubMed  Google Scholar 

  212. Barnhill, R. et al. Replacement and desmoplastic histopathological growth patterns: a pilot study of prediction of outcome in patients with uveal melanoma liver metastases. J. Pathol. Clin. Res. 4, 227–240 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Barnhill, R., Dy, K. & Lugassy, C. Angiotropism in cutaneous melanoma: a prognostic factor strongly predicting risk for metastasis. J. Invest. Dermatol. 119, 705–706 (2002).

    CAS  PubMed  Google Scholar 

  214. Brunner, S. M. et al. Prognosis according to histochemical analysis of liver metastases removed at liver resection. Br. J. Surg. 101, 1681–1691 (2014).

    CAS  PubMed  Google Scholar 

  215. Gilbert, M. R. Antiangiogenic therapy for glioblastoma: complex biology and complicated results. J. Clin. Oncol. 34, 1567–1569 (2016).

    CAS  PubMed  Google Scholar 

  216. Kunkel, P. et al. Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res. 61, 6624–6628 (2001).

    CAS  PubMed  Google Scholar 

  217. Paez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Lucio-Eterovic, A. K., Piao, Y. & de Groot, J. F. Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin. Cancer Res. 15, 4589–4599 (2009).

    CAS  PubMed  Google Scholar 

  219. Lu, K. V. et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22, 21–35 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Navis, A. C. et al. Effects of dual targeting of tumor cells and stroma in human glioblastoma xenografts with a tyrosine kinase inhibitor against c-MET and VEGFR2. PLOS ONE 8, e58262 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Wick, W., Wick, A., Weiler, M. & Weller, M. Patterns of progression in malignant glioma following anti-VEGF therapy: perceptions and evidence. Curr. Neurol. Neurosci. Rep. 11, 305–312 (2011).

    CAS  PubMed  Google Scholar 

  222. Norden, A. D. et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70, 779–787 (2008).

    CAS  PubMed  Google Scholar 

  223. Kleinschmidt-DeMasters, B. K. & Damek, D. M. The imaging and neuropathological effects of bevacizumab (avastin) in patients with leptomeningeal carcinomatosis. J. Neurooncol. 96, 375–384 (2010).

    CAS  PubMed  Google Scholar 

  224. Abrams, T. J. et al. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with “standard of care” therapeutic agents for the treatment of breast cancer. Mol. Cancer Ther. 2, 1011–1021 (2003).

    CAS  PubMed  Google Scholar 

  225. Prewett, M. et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res. 59, 5209–5218 (1999).

    CAS  PubMed  Google Scholar 

  226. Bagri, A. et al. Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy. Clin. Cancer Res. 16, 3887–3900 (2010).

    CAS  PubMed  Google Scholar 

  227. Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Barrios, C. H. et al. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res. Treat. 121, 121–131 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Bergh, J. et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J. Clin. Oncol. 30, 921–929 (2012).

    CAS  PubMed  Google Scholar 

  230. Crown, J. P. et al. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J. Clin. Oncol. 31, 2870–2878 (2013).

    CAS  PubMed  Google Scholar 

  231. Robert, N. J. et al. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin. Breast Cancer 11, 82–92 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Giantonio, B. J. et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J. Clin. Oncol. 25, 1539–1544 (2007).

    CAS  PubMed  Google Scholar 

  233. Vlachogiannis, G. et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359, 920–926 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Simoneau, E. et al. The histological growth patterns of colorectal cancer liver metastasis are associated with disease progression post portal vein embolization. HPB 19, S59 (2017).

    Google Scholar 

  235. Lu, J. et al. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23, 171–185 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355–366 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Rockwell, S., Dobrucki, I. T., Kim, E. Y., Marrison, S. T. & Vu, V. T. Hypoxia and radiation therapy: past history, ongoing research, and future promise. Curr. Mol. Med. 9, 442–458 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31, 2205–2218 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl Med. 9, eaak9670 (2017).

    PubMed  Google Scholar 

  242. Bais, C. et al. Tumor microvessel density as a potential predictive marker for bevacizumab benefit: GOG-0218 biomarker analyses. J. Natl Cancer Inst. 109, djx066 (2017).

    PubMed Central  Google Scholar 

  243. Tolaney, S. M. et al. Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients. Proc. Natl Acad. Sci. 112, 14325–14330 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Miles, D. et al. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): a double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur. J. Cancer 70, 146–155 (2017).

    CAS  PubMed  Google Scholar 

  245. Boult, J. K. et al. Investigating intracranial tumour growth patterns with multiparametric MRI incorporating Gd-DTPA and USPIO-enhanced imaging. NMR Biomed. 29, 1608–1617 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Budde, M. D., Gold, E., Jordan, E. K., Smith-Brown, M. & Frank, J. A. Phase contrast MRI is an early marker of micrometastatic breast cancer development in the rat brain. NMR Biomed. 25, 726–736 (2012).

    PubMed  Google Scholar 

  247. Zhu, Q. et al. Arterial blood supply of hepatocellular carcinoma is associated with efficacy of sorafenib therapy. Ann. Transl Med. 3, 285 (2015).

    PubMed  PubMed Central  Google Scholar 

  248. Kudo, M., Hatanaka, K., Inoue, T. & Maekawa, K. Depiction of portal supply in early hepatocellular carcinoma and dysplastic nodule: value of pure arterial ultrasound imaging in hepatocellular carcinoma. Oncology 78 (Suppl. 1), 60–67 (2010).

    PubMed  Google Scholar 

  249. Semelka, R. C., Hussain, S. M., Marcos, H. B. & Woosley, J. T. Perilesional enhancement of hepatic metastases: correlation between MR imaging and histopathologic findings-initial observations. Radiology 215, 89–94 (2000).

    CAS  PubMed  Google Scholar 

  250. Wan, J. C. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17, 223–238 (2017).

    CAS  PubMed  Google Scholar 

  251. Perakis, S. & Speicher, M. R. Emerging concepts in liquid biopsies. BMC Med. 15, 75 (2017).

    PubMed  PubMed Central  Google Scholar 

  252. Sennino, B. et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2, 270–287 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Depner, C. et al. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. Nat. Commun. 7, 12329 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. Du, R. et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  255. Carbonell, W. S., DeLay, M., Jahangiri, A., Park, C. C. & Aghi, M. K. β1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma. Cancer Res. 73, 3145–3154 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Er, E. E. et al. Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization. Nat. Cell Biol. 20, 966–978 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Jahangiri, A., Aghi, M. K. & Carbonell, W. S. β1 integrin: critical path to antiangiogenic therapy resistance and beyond. Cancer Res. 74, 3–7 (2014).

    CAS  PubMed  Google Scholar 

  258. Cortes-Santiago, N. et al. Soluble Tie2 overrides the heightened invasion induced by anti-angiogenesis therapies in gliomas. Oncotarget 7, 16146–16157 (2016).

    PubMed  PubMed Central  Google Scholar 

  259. Scholz, A. et al. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol. Med. 8, 39–57 (2016).

    CAS  PubMed  Google Scholar 

  260. Peterson, T. E. et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl Acad. Sci. USA 113, 4470–4475 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Wu, F. T. et al. Efficacy of cotargeting angiopoietin-2 and the VEGF pathway in the adjuvant postsurgical setting for early breast, colorectal, and renal cancers. Cancer Res. 76, 6988–7000 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  262. Koh, Y. J. et al. Double antiangiogenic protein, DAAP, targeting VEGF-A and angiopoietins in tumor angiogenesis, metastasis, and vascular leakage. Cancer Cell 18, 171–184 (2010).

    CAS  PubMed  Google Scholar 

  263. Kienast, Y. et al. Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin. Cancer Res. 19, 6730–6740 (2013).

    CAS  PubMed  Google Scholar 

  264. Reardon, D. A. et al. Phase 2 and biomarker study of trebananib, an angiopoietin-blocking peptibody, with and without bevacizumab for patients with recurrent glioblastoma. Cancer 124, 1438–1448 (2017).

    PubMed  Google Scholar 

  265. St Croix, B. et al. Genes expressed in human tumor endothelium. Science 289, 1197–1202 (2000).

    Google Scholar 

  266. Carson-Walter, E. B. et al. Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res. 61, 6649–6655 (2001).

    CAS  PubMed  Google Scholar 

  267. Masiero, M. et al. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis. Cancer Cell 24, 229–241 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  268. Seaman, S. et al. Eradication of tumors through simultaneous ablation of CD276/B7-H3-positive tumor cells and tumor vasculature. Cancer Cell 31, 501–515 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Ruoslahti, E. Vascular zip codes in angiogenesis and metastasis. Biochem. Soc. Trans. 32, 397–402 (2004).

    CAS  PubMed  Google Scholar 

  270. Chaudhary, A. et al. TEM8/ANTXR1 blockade inhibits pathological angiogenesis and potentiates tumoricidal responses against multiple cancer types. Cancer Cell 21, 212–226 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  271. Noy, P. J. et al. Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth. Oncogene 34, 5821–5831 (2015).

    CAS  PubMed  Google Scholar 

  272. Khan, K. A. & Kerbel, R. S. A. CD276 antibody guided missile with one warhead and two targets: the tumor and its vasculature. Cancer Cell 31, 469–471 (2017).

    CAS  PubMed  Google Scholar 

  273. Paez-Ribes, M., Man, S., Xu, P. & Kerbel, R. S. Potential pro-invasive or metastatic effects of preclinical antiangiogenic therapy are prevented by concurrent chemotherapy. Clin. Cancer Res. 21, 5488–5498 (2015).

    CAS  PubMed  Google Scholar 

  274. Klement, G. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105, R15–24 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  275. Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60, 1878–1886 (2000).

    CAS  PubMed  Google Scholar 

  276. Hashimoto, K. et al. Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer. Mol. Cancer Ther. 9, 996–1006 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Jedeszko, C. et al. Postsurgical adjuvant or metastatic renal cell carcinoma therapy models reveal potent antitumor activity of metronomic oral topotecan with pazopanib. Sci. Transl Med. 7, 282ra50 (2015).

    PubMed  Google Scholar 

  278. Di Desidero, T., Xu, P., Man, S., Bocci, G. & Kerbel, R. S. Potent efficacy of metronomic topotecan and pazopanib combination therapy in preclinical models of primary or late stage metastatic triple-negative breast cancer. Oncotarget 6, 42396–42410 (2015).

    PubMed  PubMed Central  Google Scholar 

  279. Goertz, D. E. An overview of the influence of therapeutic ultrasound exposures on the vasculature: high intensity ultrasound and microbubble-mediated bioeffects. Int. J. Hyperthermia 31, 134–144 (2015).

    CAS  PubMed  Google Scholar 

  280. Breitbach, C. J. et al. Targeting tumor vasculature with an oncolytic virus. Mol. Ther. 19, 886–894 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  281. Kim, M. et al. Amplification of oncolytic vaccinia virus widespread tumor cell killing by sunitinib through multiple mechanisms. Cancer Res. 78, 922–937 (2017).

    PubMed  PubMed Central  Google Scholar 

  282. Allen, E. & Jabouille, A. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl Med. 9, eaak9679 (2017).

    PubMed  PubMed Central  Google Scholar 

  283. Boyerinas, B. et al. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol. Res. 3, 1148–1157 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  285. Lytton, D. G. & Resuhr, L. M. Galen on abnormal swellings. J. Hist. Med. Allied Sci. 33, 531–549 (1978).

  286. Virchow, R. Die krankhaften Geschwulste (August Hirschwald, 1863).

  287. Goldmann, E. The growth of malignant disease in man and the lower animals, with special reference to the vascular system. Proc. R. Soc. Med. 1, 1–13 (1908).

    CAS  PubMed  PubMed Central  Google Scholar 

  288. Thiersch, K. Der Epithelialkrebs, namenthlich der Haut mit Atlas (Wilhelm Engelmann, Leipzig, Germany, 1865).

  289. Kolin, A. & Koutoulakis, T. Role of arterial occlusion in pulmonary scar cancers. Hum. Pathol. 19, 1161–1167 (1988).

    CAS  PubMed  Google Scholar 

  290. Ritchie, A. C. in General Pathology (ed. Florey, H.) 551–597 (Lloyd-Luke Ltd., 1962).

  291. Hamilton, D. J. A Text-Book of Pathology: Systematic & Practical (MacMillan and Co., 1894).

  292. Ikeda, K. Alveolar cell carcinoma of the lung. Am. J. Clin. Pathol. 15, 50–63 (1945).

    Google Scholar 

  293. Malassez, L. Histological examination of a case of encephaloid cancer of the lung. Arch. Physiol. Norm. Path. 3, 353 (1876).

    Google Scholar 

  294. Hanot, V. & Gilbert, A. Etudes sur les Maladies du Foie: Cancer (Épithéliome), Sarcome Mélanomes Kystes Non Parasitaires, Angiomes (Asselin et Houzeau, 1888).

  295. Helvestine, F. Primary carcinoma of the liver. J. Cancer Res. 7, 209–227 (1922).

    Google Scholar 

  296. Elias, H., S. J. C. & Bouldin, R. F. Reaction of the normal liver parenchyma to metastatic carcinoma. Acta Hepatosplenol. 9, 357–386 (1962).

    CAS  Google Scholar 

  297. Elias, H., Bierring, F. & Grunnet, I. Cellular changes in the vicinity of metastatic carcinoma, observed by light and electron microscopy. Oncology 18, 210–224 (1964).

    CAS  Google Scholar 

  298. Masson, P. in Traité de Pathologie Médicale et de Thérapeutique Appliquée Vol. 27 Part II (eds Sergent, E., Ribadeau-Dumas, L. & Babonneix, L.) (A. Maloine & fils, 1923).

  299. Scherer, H. J. Structural development in gliomas. Am. J. Cancer 34, 333–351 (1938).

    Google Scholar 

  300. Lindgren, A. G. The vascular supply of tumours with special reference to the capillary angioarchitekture. Acta Pathol. Microbiol. Scand. 22, 493–522 (1945).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  302. Hardee, M. E. & Zagzag, D. Mechanisms of glioma-associated neovascularization. Am. J. Pathol. 181, 1126–1141 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  303. Zhao, C. et al. Distinct contributions of angiogenesis and vascular co-option during the initiation of primary microtumors and micrometastases. Carcinogenesis 32, 1143–1150 (2011).

    CAS  PubMed  Google Scholar 

  304. Krusche, B. et al. EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells. eLife 5, e14845 (2016).

    PubMed  PubMed Central  Google Scholar 

  305. Butt, Y. M. & Allen, T. C. The demise of the term bronchioloalveolar carcinoma. Arch. Pathol. Lab. Med. 139, 981–983 (2015).

    PubMed  Google Scholar 

  306. Fuchs, C. S. et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383, 31–39 (2014).

    CAS  PubMed  Google Scholar 

  307. Brose, M. et al. Final overall survival analysis of patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer (RAI-rDTC) treated with sorafenib in the phase 3 DECISION trial: an exploratory crossover adjustment analyses. Ann. Oncol. 27, 953PD (2016).

    Google Scholar 

  308. Brose, M. S. et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 384, 319–328 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  309. Burger, R. A. et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N. Engl. J. Med. 365, 2473–2483 (2011).

    CAS  PubMed  Google Scholar 

  310. Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014).

    CAS  PubMed  Google Scholar 

  311. Cunningham, D. et al. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2–3 trial. Lancet. Oncol. 18, 357–370 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  312. Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 (2007).

    CAS  PubMed  Google Scholar 

  313. Escudier, B. et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J. Clin. Oncol. 27, 3312–3318 (2009).

    CAS  PubMed  Google Scholar 

  314. Garon, E. B. et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 384, 665–673 (2014).

    CAS  PubMed  Google Scholar 

  315. Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  316. Motzer, R. J. et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 27, 3584–3590 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  317. Motzer, R. J. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007).

    CAS  PubMed  Google Scholar 

  318. Perren, T. J. et al. A phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med. 365, 2484–2496 (2011).

    CAS  PubMed  Google Scholar 

  319. Raymond, E. et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 501–513 (2011).

    CAS  PubMed  Google Scholar 

  320. Raymond, E. et al. Sunitinib (SU) in patients with advanced, progressive pancreatic neuroendocrine tumors (pNET): final overall survival (OS) results from a phase III randomized study including adjustment for crossover. J. Clin. Oncol. 34, 309–309 (2016).

    Google Scholar 

  321. Reck, M. et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J. Clin. Oncol. 27, 1227–1234 (2009).

    CAS  PubMed  Google Scholar 

  322. Reck, M. et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann. Oncol. 21, 1804–1809 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  323. Saltz, L. B. et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J. Clin. Oncol. 26, 2013–2019 (2008).

    CAS  PubMed  Google Scholar 

  324. Sandler, A. et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542–2550 (2006).

    CAS  PubMed  Google Scholar 

  325. Sternberg, C. N. et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J. Clin. Oncol. 28, 1061–1068 (2010).

    CAS  PubMed  Google Scholar 

  326. Sternberg, C. N. et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur. J. Cancer 49, 1287–1296 (2013).

    CAS  PubMed  Google Scholar 

  327. Tewari, K. S. et al. Improved survival with bevacizumab in advanced cervical cancer. N. Engl. J. Med. 370, 734–743 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  328. Wilke, H. et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet. Oncol. 15, 1224–1235 (2014).

    CAS  PubMed  Google Scholar 

  329. Zhu, A. X. et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet. Oncol. 16, 859–870 (2015).

    CAS  PubMed  Google Scholar 

  330. Tannock, I. F. et al. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet. Oncol. 14, 760–768 (2013).

    CAS  PubMed  Google Scholar 

  331. Rougier, P. et al. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur. J. Cancer 49, 2633–2642 (2013).

    CAS  PubMed  Google Scholar 

  332. Ramlau, R. et al. Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J. Clin. Oncol. 30, 3640–3647 (2012).

    CAS  PubMed  Google Scholar 

  333. Bear, H. D. et al. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet. Oncol. 16, 1037–1048 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  334. Miller, K. et al. Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: final results from Eastern Cooperative Oncology Group E5103. J. Clin. Oncol. 32, 500–500 (2014).

    Google Scholar 

  335. Slamon, D. et al. Abstract S1-03: Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab±bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. Cancer Res. 73, S1–03 (2013).

    Google Scholar 

  336. Bell, R. et al. Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer. Ann. Oncol. 28, 754–760 (2017).

    CAS  PubMed  Google Scholar 

  337. Allegra, C. J. et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J. Clin. Oncol. 29, 11–16 (2011).

    CAS  PubMed  Google Scholar 

  338. Kerr, R. S. et al. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet. Oncol. 17, 1543–1557 (2016).

    CAS  PubMed  Google Scholar 

  339. Corrie, P. G. et al. Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study. Lancet Oncol. 15, 620–630 (2014).

    CAS  PubMed  Google Scholar 

  340. Benson, A. B. et al. Intergroup randomized phase III study of postoperative oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) versus mFOLFOX6 and bevacizumab (Bev) for patients (pts) with stage II/ III rectal cancer receiving pre-operative chemoradiation. J. Clin. Oncol. 34, 3616–3616 (2016).

    Google Scholar 

Download references

Acknowledgements

The authors acknowledge financial support provided by Breast Cancer Now (A.R.R.) and Worldwide Cancer Research (R.S.K. and E.A.K.). The authors thank A. Berghoff and M. Preusser (Medical University of Vienna) for providing histopathological images of brain tumours and C. Cheng (University of Toronto) for her secretarial assistance. The authors also thank S. Barry (AstraZeneca) for providing critical comments on the manuscript.

Author information

Authors and Affiliations

  1. Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK

    Elizabeth A. Kuczynski

  2. Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada

    Elizabeth A. Kuczynski & Robert S. Kerbel

  3. HistoGeneX, Antwerp, Belgium

    Peter B. Vermeulen

  4. Translational Cancer Research Unit, GZA Hospitals St Augustinus, University of Antwerp, Wilrijk-Antwerp, Belgium

    Peter B. Vermeulen

  5. Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK

    Peter B. Vermeulen & Andrew R. Reynolds

  6. Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

    Francesco Pezzella

  7. Department of Medical Biophysics, University of Toronto, Toronto, Canada

    Robert S. Kerbel

  8. Oncology Translational Medicine Unit, IMED Biotech Unit, AstraZeneca, Cambridge, UK

    Andrew R. Reynolds

Authors
  1. Elizabeth A. Kuczynski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter B. Vermeulen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Pezzella
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert S. Kerbel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew R. Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for this article and made a substantial contribution to discussions of content, E.A.K. and A.R.R. wrote the manuscript, and all authors edited and/or reviewed the manuscript prior to submission.

Corresponding authors

Correspondence to Elizabeth A. Kuczynski or Andrew R. Reynolds.

Ethics declarations

Competing interests

E.A.K. and A.R.R. are full-time employees of AstraZeneca. R.S.K. has received honoraria from Apobiologix, Boehringer Ingelheim, Merck Pharmaceuticals and Merck Serono. F.P. and P.B.V. declare no competing interests.

Additional information

Publisher’s note

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kuczynski, E.A., Vermeulen, P.B., Pezzella, F. et al. Vessel co-option in cancer. Nat Rev Clin Oncol 16, 469–493 (2019). https://doi.org/10.1038/s41571-019-0181-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-019-0181-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer