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.
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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
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).
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).
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).
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).
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).
Senger, D. R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).
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).
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).
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).
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).
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).
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).
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).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Pezzella, F. et al. Angiogenesis in primary lung cancer and lung secondaries. Eur. J. Cancer 32A, 2494–2500 (1996).
Pezzella, F. et al. Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis. Am. J. Pathol. 151, 1417–1423 (1997).
Vasudev, N. S. & Reynolds, A. R. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 17, 471–494 (2014).
Ebos, J. M. & Kerbel, R. S. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat. Rev. Clin. Oncol. 8, 210–221 (2011).
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).
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).
Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).
Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).
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).
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).
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).
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).
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).
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).
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).
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).
Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Kerbel, R. S. Reappraising antiangiogenic therapy for breast cancer. Breast 20, S56–S60 (2011).
Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603 (2008).
Saharinen, P., Eklund, L. & Alitalo, K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat. Rev. Drug Discov. 16, 635–661 (2017).
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).
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).
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).
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).
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).
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).
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).
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).
Winkler, F. Hostile takeover: how tumours hijack pre-existing vascular environments to thrive. J. Pathol. 242, 267–272 (2017).
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).
Lenzi, P., Bocci, G. & Natale, G. John Hunter and the origin of the term “angiogenesis”. Angiogenesis 19, 255–256 (2016).
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).
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).
Greene, H. S. Heterologous transplantation of mammalian tumors: I. The transfer of rabbit tumors to alien species. J. Exp. Med. 73, 461–474 (1941).
Ribatti, D. Judah Folkman, a pioneer in the study of angiogenesis. Angiogenesis 11, 3–10 (2008).
Bugge, T. H. et al. Growth and dissemination of Lewis lung carcinoma in plasminogen-deficient mice. Blood 90, 4522–4531 (1997).
Fidler, I. J. Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res. 35, 218–224 (1975).
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).
Szabo, V. et al. Mechanism of tumour vascularization in experimental lung metastases. J. Pathol. 235, 384–396 (2015).
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).
Yamaguchi, R. Y. et al. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 28, 68–77 (1998).
Hu, J. et al. Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer. Oncogene 24, 1212–1219 (2005).
Offersen, B. V., Pfeiffer, P., Hamilton-Dutoit, S. & Overgaard, J. Patterns of angiogenesis in nonsmall-cell lung carcinoma. Cancer 91, 1500–1509 (2001).
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).
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).
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).
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).
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).
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).
Erichsen, J. Zwei falle von carcinosis acuta miliaris. Virchows Arch. 21, 465–479 (1861).
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).
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).
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).
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).
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).
Passalidou, E. et al. Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas. Br. J. Cancer 86, 244–249 (2002).
Yousem, S. A. Peripheral squamous cell carcinoma of lung: patterns of growth with particular focus on airspace filling. Hum. Pathol. 40, 861–867 (2009).
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).
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).
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).
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).
Warth, A. et al. Prognostic impact of intra-alveolar tumor spread in pulmonary adenocarcinoma. Am. J. Surg. Pathol. 39, 793–801 (2015).
Donnem, T. et al. Non-angiogenic tumours and their influence on cancer biology. Nat. Rev. Cancer 18, 323–336 (2018).
Adighibe, O. et al. Why some tumours trigger neovascularisation and others don’t: the story thus far. Chin. J. Cancer 35, 18 (2016).
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).
Rosenblatt, M. B., Lisa, J. R. & Collier, F. Primary and metastatic bronciolo-alveolar carcinoma. Dis. Chest 52, 147–152 (1967).
Breast Cancer Progression Working Party. Evidence for novel non-angiogenic pathway in breast-cancer metastasis. Lancet 355, 1787–1788 (2000).
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).
Breedis, C. & Young, G. The blood supply of neoplasms in the liver. Am. J. Pathol. 30, 969–977 (1954).
Kojiro, M. Pathology of Hepatocellular Carcinoma 63–75 (Blackwell Publishing, 2006).
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).
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).
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).
Nakashima, Y., Nakashima, O., Hsia, C. C., Kojiro, M. & Tabor, E. Vascularization of small hepatocellular carcinomas: correlation with differentiation. Liver 19, 12–18 (1999).
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).
Kita, K., Itoshima, T. & Tsuji, T. Observation of microvascular casts of human hepatocellular carcinoma by scanning electron microscopy. Gastroenterol. Japon. 26, 319–328 (1991).
Sugihara, S., Kojiro, M. & Nakashima, T. Ultrastructural study of hepatocellular carcinoma with replacing growth pattern. Acta Pathol. Japon. 35, 549–559 (1985).
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).
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).
Kin, M., Torimura, T., Ueno, T., Inuzuka, S. & Tanikawa, K. Sinusoidal capillarization in small hepatocellular carcinoma. Pathol. Int. 44, 771–778 (1994).
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).
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).
Kanai, T. et al. Pathology of small hepatocellular carcinoma. A proposal for a new gross classification. Cancer 60, 810–819 (1987).
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).
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).
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).
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).
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).
Gervaz, P. et al. Angiogenesis of liver metastases: role of sinusoidal endothelial cells. Dis. Colon Rectum 43, 980–986 (2000).
Paku, S. & Lapis, K. Morphological aspects of angiogenesis in experimental liver metastases. Am. J. Pathol. 143, 926–936 (1993).
van Dam, P. J. et al. Histopathological growth patterns as a candidate biomarker for immunomodulatory therapy. Semin. Cancer Biol. 52, 86–93 (2018).
Frentzas, S. et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat. Med. 22, 1294–1302 (2016).
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).
Dezso, K. et al. Structural analysis of oval-cell-mediated liver regeneration in rats. Hepatology 56, 1457–1467 (2012).
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).
Ding, B. S. et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97–102 (2014).
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).
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).
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).
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).
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).
Watson, A. J. Diffuse intra-sinusoidal metastatic carcinoma of the liver. J. Pathol. Bacteriol. 69, 207–217 (1955).
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).
Baumhoer, D., Tzankov, A., Dirnhofer, S., Tornillo, L. & Terracciano, L. M. Patterns of liver infiltration in lymphoproliferative disease. Histopathology 53, 81–90 (2008).
Shetty, S. et al. Recruitment mechanisms of primary and malignant B cells to the human liver. Hepatology 56, 1521–1531 (2012).
Willis, R. A. The Spread of Tumours in the Human Body (J&A Churchill, 1934).
Ewing, J. Neoplastic Diseases — A Treatise On Tumors 2nd edn (W.B. Saunders Company, 1922).
Winkler, F. et al. Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis. Glia 57, 1306–1315 (2009).
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).
Yao, H. et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature 560, 55–60 (2018).
Jain, R. K. et al. Angiogenesis in brain tumours. Nat. Rev. Neurosci. 8, 610–622 (2007).
Verhoeff, J. J. et al. Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme. BMC Cancer 9, 444 (2009).
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).
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).
Claes, A., Idema, A. J. & Wesseling, P. Diffuse glioma growth: a guerilla war. Acta Neuropathol. 114, 443–458 (2007).
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).
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).
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).
Lugassy, C. et al. Pericytic-like angiotropism of glioma and melanoma cells. Am. J. Dermatopathol. 24, 473–478 (2002).
Watkins, S. et al. Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat. Commun. 5, 4196 (2014).
Holash, J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998 (1999).
Cheng, L. et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153, 139–152 (2013).
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).
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).
Sakariassen, P. O. et al. Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc. Natl Acad. Sci. USA 103, 16466–16471 (2006).
Montana, V. & Sontheimer, H. Bradykinin promotes the chemotactic invasion of primary brain tumors. J. Neurosci. 31, 4858–4867 (2011).
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).
Griveau, A. et al. A glial signature and Wnt7 signaling regulate glioma-vascular interactions and tumor microenvironment. Cancer Cell 33, 874–889 (2018).
Berghoff, A. S. et al. Invasion patterns in brain metastases of solid cancers. Neuro Oncol. 15, 1664–1672 (2013).
Kienast, Y. et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 16, 116–122 (2010).
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).
Hung, T. et al. Angiotropism in primary cutaneous melanoma with brain metastasis: a study of 20 cases. Am. J. Dermatopathol. 35, 650–654 (2013).
Bugyik, E. et al. Lack of angiogenesis in experimental brain metastases. J. Neuropathol. Exp. Neurol. 70, 979–991 (2011).
Valiente, M. et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014).
Carbonell, W. S., Ansorge, O., Sibson, N. & Muschel, R. The vascular basement membrane as “soil” in brain metastasis. PLOS ONE 4, e5857 (2009).
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).
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).
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).
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).
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).
Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014).
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).
Wilmott, J. et al. Angiotropism is an independent predictor of microscopic satellites in primary cutaneous melanoma. Histopathology 61, 889–898 (2012).
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).
Naresh, K. N., Nerurkar, A. Y. & Borges, A. M. Angiogenesis is redundant for tumour growth in lymph node metastases. Histopathology 38, 466–470 (2001).
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).
Qian, C. N., Resau, J. H. & Teh, B. T. Prospects for vasculature reorganization in sentinel lymph nodes. Cell Cycle 6, 514–517 (2007).
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).
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).
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).
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).
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).
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).
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).
Qian, C. N. Hijacking the vasculature in ccRCC — co-option, remodelling and angiogenesis. Nat. Rev. Urol. 10, 300–304 (2013).
Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807 (2013).
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).
Raymaekers, K., Stegen, S., van Gastel, N. & Carmeliet, G. The vasculature: a vessel for bone metastasis. Bonekey Rep. 4, 742 (2015).
Duarte, D. et al. Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell 22, 64–77 (2018).
Liao, D. & Johnson, R. S. Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 26, 281–290 (2007).
Terayama, N., Terada, T. & Nakanuma, Y. Histologic growth patterns of metastatic carcinomas of the liver. Jpn. J. Clin. Oncol. 26, 24–29 (1996).
Kojiro, M. ‘Nodule-in-nodule’ appearance in hepatocellular carcinoma: its significance as a morphologic marker of dedifferentiation. Intervirology 47, 179–183 (2004).
Bugyik, E. et al. Mechanisms of vascularization in murine models of primary and metastatic tumor growth. Chin. J. Cancer 35, 19 (2016).
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).
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).
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).
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).
Rubenstein, J. L. et al. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2, 306–314 (2000).
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).
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).
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).
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).
Noguchi, M. et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 75, 2844–2852 (1995).
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).
Higashiyama, M. et al. Prognostic value of bronchiolo-alveolar carcinoma component of small lung adenocarcinoma. Ann. Thorac. Surg. 68, 2069–2073 (1999).
Reinmuth, N. et al. Prognostic significance of vessel architecture and vascular stability in non-small cell lung cancer. Lung Cancer 55, 53–60 (2007).
Pastorino, U. et al. Immunocytochemical markers in stage I lung cancer: relevance to prognosis. J. Clin. Oncol. 15, 2858–2865 (1997).
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).
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).
Eefsen, R. L. et al. Growth pattern of colorectal liver metastasis as a marker of recurrence risk. Clin. Exp. Metastasis 32, 369–381 (2015).
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).
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).
Brunner, S. M. et al. Prognosis according to histochemical analysis of liver metastases removed at liver resection. Br. J. Surg. 101, 1681–1691 (2014).
Gilbert, M. R. Antiangiogenic therapy for glioblastoma: complex biology and complicated results. J. Clin. Oncol. 34, 1567–1569 (2016).
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).
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).
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).
Lu, K. V. et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22, 21–35 (2012).
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).
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).
Norden, A. D. et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70, 779–787 (2008).
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).
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).
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).
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).
Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).
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).
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).
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).
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).
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).
Vlachogiannis, G. et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359, 920–926 (2018).
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).
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).
Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355–366 (2010).
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).
Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31, 2205–2218 (2013).
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).
Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).
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).
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).
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).
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).
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).
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).
Zhu, Q. et al. Arterial blood supply of hepatocellular carcinoma is associated with efficacy of sorafenib therapy. Ann. Transl Med. 3, 285 (2015).
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).
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).
Wan, J. C. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17, 223–238 (2017).
Perakis, S. & Speicher, M. R. Emerging concepts in liquid biopsies. BMC Med. 15, 75 (2017).
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).
Depner, C. et al. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. Nat. Commun. 7, 12329 (2016).
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).
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).
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).
Jahangiri, A., Aghi, M. K. & Carbonell, W. S. β1 integrin: critical path to antiangiogenic therapy resistance and beyond. Cancer Res. 74, 3–7 (2014).
Cortes-Santiago, N. et al. Soluble Tie2 overrides the heightened invasion induced by anti-angiogenesis therapies in gliomas. Oncotarget 7, 16146–16157 (2016).
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).
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).
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).
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).
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).
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).
St Croix, B. et al. Genes expressed in human tumor endothelium. Science 289, 1197–1202 (2000).
Carson-Walter, E. B. et al. Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res. 61, 6649–6655 (2001).
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).
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).
Ruoslahti, E. Vascular zip codes in angiogenesis and metastasis. Biochem. Soc. Trans. 32, 397–402 (2004).
Chaudhary, A. et al. TEM8/ANTXR1 blockade inhibits pathological angiogenesis and potentiates tumoricidal responses against multiple cancer types. Cancer Cell 21, 212–226 (2012).
Noy, P. J. et al. Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth. Oncogene 34, 5821–5831 (2015).
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).
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).
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).
Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60, 1878–1886 (2000).
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).
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).
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).
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).
Breitbach, C. J. et al. Targeting tumor vasculature with an oncolytic virus. Mol. Ther. 19, 886–894 (2011).
Kim, M. et al. Amplification of oncolytic vaccinia virus widespread tumor cell killing by sunitinib through multiple mechanisms. Cancer Res. 78, 922–937 (2017).
Allen, E. & Jabouille, A. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl Med. 9, eaak9679 (2017).
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).
Khan, K. A. & Kerbel, R. S. Improving immunotherapy outcomes with anti-angiogenic treatments and vicesversa. Nat. Rev. Clin. Oncol. 15, 310–324 (2018).
Lytton, D. G. & Resuhr, L. M. Galen on abnormal swellings. J. Hist. Med. Allied Sci. 33, 531–549 (1978).
Virchow, R. Die krankhaften Geschwulste (August Hirschwald, 1863).
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).
Thiersch, K. Der Epithelialkrebs, namenthlich der Haut mit Atlas (Wilhelm Engelmann, Leipzig, Germany, 1865).
Kolin, A. & Koutoulakis, T. Role of arterial occlusion in pulmonary scar cancers. Hum. Pathol. 19, 1161–1167 (1988).
Ritchie, A. C. in General Pathology (ed. Florey, H.) 551–597 (Lloyd-Luke Ltd., 1962).
Hamilton, D. J. A Text-Book of Pathology: Systematic & Practical (MacMillan and Co., 1894).
Ikeda, K. Alveolar cell carcinoma of the lung. Am. J. Clin. Pathol. 15, 50–63 (1945).
Malassez, L. Histological examination of a case of encephaloid cancer of the lung. Arch. Physiol. Norm. Path. 3, 353 (1876).
Hanot, V. & Gilbert, A. Etudes sur les Maladies du Foie: Cancer (Épithéliome), Sarcome Mélanomes Kystes Non Parasitaires, Angiomes (Asselin et Houzeau, 1888).
Helvestine, F. Primary carcinoma of the liver. J. Cancer Res. 7, 209–227 (1922).
Elias, H., S. J. C. & Bouldin, R. F. Reaction of the normal liver parenchyma to metastatic carcinoma. Acta Hepatosplenol. 9, 357–386 (1962).
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).
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).
Scherer, H. J. Structural development in gliomas. Am. J. Cancer 34, 333–351 (1938).
Lindgren, A. G. The vascular supply of tumours with special reference to the capillary angioarchitekture. Acta Pathol. Microbiol. Scand. 22, 493–522 (1945).
Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).
Hardee, M. E. & Zagzag, D. Mechanisms of glioma-associated neovascularization. Am. J. Pathol. 181, 1126–1141 (2012).
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).
Krusche, B. et al. EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells. eLife 5, e14845 (2016).
Butt, Y. M. & Allen, T. C. The demise of the term bronchioloalveolar carcinoma. Arch. Pathol. Lab. Med. 139, 981–983 (2015).
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).
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).
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).
Burger, R. A. et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N. Engl. J. Med. 365, 2473–2483 (2011).
Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014).
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).
Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 (2007).
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).
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).
Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014).
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).
Motzer, R. J. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007).
Perren, T. J. et al. A phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med. 365, 2484–2496 (2011).
Raymond, E. et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 501–513 (2011).
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).
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).
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).
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).
Sandler, A. et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542–2550 (2006).
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).
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).
Tewari, K. S. et al. Improved survival with bevacizumab in advanced cervical cancer. N. Engl. J. Med. 370, 734–743 (2014).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.