Modes of resistance to anti-angiogenic therapy

Bergers, Gabriele; Hanahan, Douglas

doi:10.1038/nrc2442

Cited by 2,953Angiogenesis and VEGF in CancerCancer Cells and MetastasisLymphatic System and Diseases

Modes of resistance to anti-angiogenic therapy

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Bergers, Gabriele, Hanahan, Douglas·2008·Nature Reviews Cancer

DOI 10.1038/nrc2442PMC PMC2874834

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Abstract

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.

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Drug resistance in cancer can be cell-intrinsic or a combination of host and tumor mediated pathways.
“Drug resistance in cancer can be cell-intrinsic (Poulikakos and Rosen, 2011) or a combination of host and tumor mediated pathways (Bergers and Hanahan, 2008; Ebos et al., 2009).”
From A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis (2012) · cites this paper as Bergers and Hanahan, 2008
Several cellular and molecular mechanisms of escape from antiangiogenic therapies have been postulated and investigated, including activation of alternative angiogenic pathways, recruitment of proangiogenic myeloid cells, increased pericyte coverage of tumour blood vessels, increased tumour cell invasion and alternative modes of vessel recruitment.
“Several cellular and molecular mechanisms of escape from antiangiogenic therapies have been postulated and investigated, including activation of alternative angiogenic pathways, recruitment of proangiogenic myeloid cells, increased pericyte cell coverage of tumour blood vessels, increased tumour cell invasion, and alternative modes of vessel recruitment7,9,80”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [80]
Dual VEGF-ANG2 blockade can provide tumour control in some preclinical models, but the degree of benefit and mechanism appear context-dependent.
“This dual blockade approach can provide tumour control in some preclinical models, although the degree of benefit and the underlying mechanism of action seem to be context-dependent31,32,80,89.”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [80]

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Tan, C., de Noronha, R. G., Roecker, A. J., Pyrzyńska, B., Khwaja, F. W., Zhang, Z., Zhang, H., Teng, Q., Nicholson, A. C., Giannakakou, P., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.605.65.2 · Cited by 225 · see citing works
Tumor Stromal-Derived Factor-1 Recruits Vascular Progenitors to Mitotic Neovasculature, where Microenvironment Influences Their Differentiated Phenotypes
Aghi, M. K., Cohen, K. S., Klein, R. J., Scadden, D. T., & Chiocca, E. A. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3759 · Cited by 175 · cited 1× · see citing works
“In a study of neovascularization in glioblastoma multiforme (GBM), a tumour type characterized by extensive hypoxia and necrosis, HIF1α was found to promote angiogenesis and tumour growth by inducing recruitment of various pro-angiogenic bone marrow-derived CD45 + (also known as PTPRC + ) myeloid cells, including subp…”
Background
The HIF pathway in cancer
Maxwell, P. H. (2005) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2005.03.001 · Cited by 167 · cited 1× · see citing works
“The HIF regulatory network also holds promise as a target, given its global effects on angiogenesis, invasion and stress-adaptive cell physiolog”
Background
Differential diagnosis of pancreatic tumors using ultrasound contrast imaging
Sofuni, A., Iijima, H., Moriyasu, F., Nakayama, D., Shimizu, M., Nakamura, K., Itokawa, F., & Itoi, T. (2005) · Journal of Gastroenterology · doi:10.1007/s00535-005-1578-z · Cited by 166 · cited 1× · see citing works
“Pancreatic ductal adenocarcinoma (PDAC) may display another class of pre-existing resistance, manifest as a tumour type that is characteristically hypovascularized with a massive (largely avascular) desmoplastic stroma”
Background
Increased Plasma Vascular Endothelial Growth Factor (VEGF) as a Surrogate Marker for Optimal Therapeutic Dosing of VEGF Receptor-2 Monoclonal Antibodies
Bocci, G., Man, S., Green, S. K., Francia, G., Ebos, J. M. L., du Manoir, J. M., Weinerman, A. S., Emmenegger, U., Ma, L., Thorpe, P. E., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0401 · Cited by 162 · cited 1× · see citing works
“The fact that receptor tyrosine kinase inhibitors can transiently increase plasma levels of pro-angiogenic factors such as VEGF and placental growth factor (PlGF, also known as PGF ) has been previously recognized in the clinic, and even proposed as a predictive biomarker for tumour respons”
Background
Tumor Escape from Endogenous, Extracellular Matrix–Associated Angiogenesis Inhibitors by Up-Regulation of Multiple Proangiogenic Factors
Fernando, N. T., Koch, M., Rothrock, C., Gollogly, L. K., D'Amore, P. A., Ryeom, S. W., & Yoon, S. S. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4126 · Cited by 162 · cited 1× · see citing works
“, evasive resistance is largely indirect: alternative ways to sustain tumour growth are activated but the specific therapeutic target of the anti-angiogenic drug remains inhibite”
Background
Control of angiogenesis by the pericyte: Molecular mechanisms and significance
Hirschi, K. K., & D'Amore, P. A. (1997) · Proceedings of the Fourth International Symposium on Polarization Phenomena in Nuclear Reactions · doi:10.1007/978-3-0348-9006-9_18 · Cited by 161 · see citing works
The genetics of pancreatic cancer
Cowgill, S. M., & Muscarella, P. (2003) · The American Journal of Surgery · doi:10.1016/s0002-9610(03)00226-5 · Cited by 156 · cited 1× · see citing works
“For example, ∼75% of PDACs carry inactivating mutations in the TP53 tumour suppressor gen”
Background
Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations?
Sessa, C., Guibal, A., Conte, G. D., & Rüegg, C. (2008) · Nature Clinical Practice Oncology · doi:10.1038/ncponc1150 · Cited by 151 · see citing works
Genetic and hypoxic regulation of angiogenesis in gliomas
Kaur, B., Tan, C., Brat, D. J., & Meir, E. G. V. (2004) · Journal of Neuro-Oncology · doi:10.1007/s11060-004-2752-5 · Cited by 148 · cited 1× · see citing works
“These diffusely growing tumours do not form lesions with a prominent neovasculature containing proliferative endothelial cell”
Background
What brings pericytes to tumor vessels?
Jain, R. K., & Booth, M. F. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200320087 · Cited by 147 · see citing works
What brings pericytes to tumor vessels?
Jain, R. K., & Booth, M. F. (2003) · Journal of Clinical Investigation · doi:10.1172/jci20087 · Cited by 143 · see citing works
A Phase I Pharmacokinetic and Pharmacodynamic Study of TKI258, an Oral, Multitargeted Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
Sarker, D., Molife, R., Evans, T. R. J., Hardie, M., Marriott, C., Bützberger, P., Morrison, R., Fox, J. A., Heise, C. C., Louie, S. G., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1466 · Cited by 138 · see citing works
Heterogeneous Vascular Dependence of Tumor Cell Populations
Yu, J., Rak, J. W., Carmeliet, P., Nagy, A., Kerbel, R. S., & Coomber, B. L. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64083-7 · Cited by 134 · cited 1× · see citing works
“, loss of which in another tumour type has been shown to improve survival in hypoxic conditions, including ones induced by angiogenesis inhibitio”
Background
Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases
Lesslie, D. P., Summy, J. M., Parikh, N. U., Fan, F., Trevino, J., Sawyer, T. K., Metcalf, C. A., Shakespeare, W. C., Hicklin, D. J., Ellis, L. M., et al. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603143 · Cited by 126 · see citing works
Delta-like 4/Notch Signaling and Its Therapeutic Implications
Yan, M., & Plowman, G. D. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1393 · Cited by 122 · see citing works
Genetic alterations in pancreatic carcinoma.
Schneider, G., & Schmid, R. M. (2003) · Molecular Cancer · doi:10.1186/1476-4598-2-15 · Cited by 121 · cited 1× · see citing works
“For example, ∼75% of PDACs carry inactivating mutations in the TP53 tumour suppressor gen”
Background
Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion.
Wang, X., Le, P., Liang, C., Chan, J., Kiewlich, D., Miller, T. M., Harris, D., Sun, L., Rice, A. G., Vasile, S., et al. (2003) · PubMed · Cited by 114 · see citing works
Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia
Gorre, M. E., & Sawyers, C. L. (2002) · Current Opinion in Hematology · doi:10.1097/00062752-200207000-00007 · Cited by 114 · see citing works
Inhibiting angiogenesis and tumorigenesis by a synthetic molecule that blocks binding of both VEGF and PDGF to their receptors
Sun, J., Wang, D.-A., Jain, R. K., Carie, A., Paquette, S., Ennis, E., Blaskovich, M. A., Baldini, L., Coppola, D., Hamilton, A. D., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1208391 · Cited by 108 · see citing works
Emerging Roles of Targeted Small Molecule Protein-Tyrosine Kinase Inhibitors in Cancer Therapy
Smith, J. K., Mamoon, N. M., & Duhé, R. J. (2003) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.3727/000000003772462298 · Cited by 94 · see citing works
Vascular remodeling and clinical resistance to antiangiogenic cancer therapy
GLADEBENDER, J., COONEY, E., KANDEL, J., & Yamashiro, D. J. (2004) · Drug Resistance Updates · doi:10.1016/j.drup.2004.09.001 · Cited by 87 · see citing works
Molecular and cellular biomarkers for angiogenesis in clinical oncology
Bertolini, F., Mancuso, P., Shaked, Y., & Kerbel, R. S. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.08.011 · Cited by 83 · cited 1× · see citing works
“The fact that receptor tyrosine kinase inhibitors can transiently increase plasma levels of pro-angiogenic factors such as VEGF and placental growth factor (PlGF, also known as PGF ) has been previously recognized in the clinic, and even proposed as a predictive biomarker for tumour respons”
Background
Sustained VEGF Blockade Results in Microenvironmental Sequestration of VEGF by Tumors and Persistent VEGF Receptor-2 Activation
Kadenhe‐Chiweshe, A. V., Papa, J. C., McCrudden, K. W., Frischer, J. S., Bae, J.-O., Huang, J., Fisher, J. C., Lefkowitch, J. H., Feirt, N. M., Rudge, J. S., et al. (2008) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-07-0101 · Cited by 75 · cited 1× · see citing works
“, evasive resistance is largely indirect: alternative ways to sustain tumour growth are activated but the specific therapeutic target of the anti-angiogenic drug remains inhibite”
Background
Can tumor angiogenesis be inhibited without resistance?
Miller, K. D., Sweeney, C. J., & Sledge, G. W. (2005) · Birkhäuser Basel eBooks · doi:10.1007/3-7643-7311-3_7 · Cited by 69 · see citing works
Antiangiogenic Therapy for Cancer: An Update
Shojaei, F., & Ferrara, N. (2007) · The Cancer Journal · doi:10.1097/ppo.0b013e31815a7b69 · Cited by 68 · cited 1× · see citing works
“The clinical achievements with bevacizumab, sunitinib and sorafenib constitute a milestone event for the field of angiogenesis research, eliciting survival benefits in many aggressive tumours, but there is a sobering addendum: these VEGF pathway inhibitors are failing to produce enduring clinical responses in most pat…”
Background
Drug resistance in cancer – searching for mechanisms, markers and therapeutic agents
O'Connor, R. A., CLYNES, M. M., Dowling, P., O’Donovan, N., & O’Driscoll, L. (2007) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.3.6.805 · Cited by 62 · cited 1× · see citing works
“In contradistinction to traditional concepts of drug resistance being acquired by mutational alteration of the gene encoding a drug target or by alterations in drug uptake and efflu”
Background
The potential of anti-vascular endothelial growth factor therapy in metastatic breast cancer: Clinical experience with anti-angiogenic agents, focusing on bevacizumab
Marty, M. E., & Pivot, X. B. (2008) · European Journal of Cancer · doi:10.1016/j.ejca.2008.01.005 · Cited by 60 · see citing works
Therapeutic implications of intrinsic or induced angiogenic growth factor redundancy in tumors revealed
Kerbel, R. S. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.09.016 · Cited by 58 · see citing works
Pegaptanib sodium for the treatment of age-related macular degeneration
Apte, R. S. (2008) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.9.3.499 · Cited by 48 · cited 1× · see citing works
“Moreover, two VEGF pathway inhibitors (the RNA aptamer pegaptanib and a Fab derivative of bevacizumab) have been approved for treating the angiogenic (wet) form of macular degeneratio”
Monoclonal antibodies against components of the IGF system for cancer treatment.
Feng, Y., & Dimitrov, D. S. (2008) · PubMed · Cited by 27 · see citing works
A double blind phase II study of BIBF 1,120 in patients suffering from relapsed advanced non-small cell lung cancer (NSCLC)
von Pawel, J., Kaiser, R., Eschbach, C., Štefanič, M., Love, J., Gatzemeier, U., & Reck, M. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2007.25.18_suppl.7635 · Cited by 19 · see citing works
A phase I study of brivanib alaninate (BMS-582664), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full dose cetuximab (BC) in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy
Garrett, C. R., Siu, L. L., El-Khoueiry, A. B., Buter, J., Rocha‐Lima, C., Marshall, J. L., Kollia, G. D., Velasquez, L., Syed, S. S., & Feltquate, D. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.26.15_suppl.4111 · Cited by 17 · see citing works
A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full-dose cetuximab in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy
Garrett, C. R., Siu, L. L., Giaccone, G., El-Khoueiry, A. B., Marshall, J. L., LoRusso, P. M., Velasquez, L., Kollia, G. D., He, P., & Feltquate, D. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2007.25.18_suppl.14018 · Cited by 5 · see citing works

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Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
“…where potent angiogenesis inhibitors succeed in suppressing this hallmark capability, tumors adapt and shift from a dependence upon continuing angiogenesis to heightening the activity of another instead—invasiveness and metastasis (Azam et al., 2010: Ebos et al., 2009; Bergers and Hanahan, 2008).”
Self-citation
Molecular mechanisms and clinical applications of angiogenesis
Carmeliet, P., & Jain, R. K. (2011) · Nature · doi:10.1038/nature10144 · Cited by 5,467 · see citing works
“Aberrant FGF signalling promotes tumour angiogenesis and mediates the escape of tumour vascularization from VEGF- or epidermal growth factor receptor (EGFR)-inhibitor treatmen”
Background
Malignant Gliomas in Adults
Wen, P. Y., & Kesari, S. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0708126 · Cited by 4,200 · see citing works
Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group
Wen, P. Y., Macdonald, D. R., Reardon, D. A., Cloughesy, T. F., Sorensen, A. G., Galanis, E., DeGroot, J. F., Wick, W., Gilbert, M. R., Lassman, A. B., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.3541 · Cited by 3,814 · see citing works
“Increasing evidence suggests that anti-VEGF therapy may increase the tendency of tumor cells to co-opt existing blood vessels, resulting in an invasive nonenhancing phenotype.(52-54) Unlike the Macdonald Criteria, which do not take into account progressive nonenhancing disease, the new response assessment will conside…”
Background
Microenvironmental regulation of metastasis
Joyce, J. A., & Pollard, J. W. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2618 · Cited by 3,684 · see citing works
“The translational promise of this first targeted therapy against the tumour microenvironment, however, is somewhat tempered by emerging instances of resistance to anti-angiogenic therap”
Background
Basic and Therapeutic Aspects of Angiogenesis
Potente, M., Gerhardt, H., & Carmeliet, P. (2011) · Cell · doi:10.1016/j.cell.2011.08.039 · Cited by 2,771 · see citing works
“…adoption of a quiescent endothelial phalanx phenotype, basement membrane deposition, pericyte coverage, and branch regression. patients show benefit as tumors evolve mechanisms of resistance or are refractory towardVEGF (receptor) inhibitors (Bergers and Hanahan, 2008; Crawford and Ferrara, 2009a).”
Influential
VEGF in signaling and disease: beyond discovery and development
Apte, R. S., Chen, D. S., & Ferrara, N. (2019) · Cell · doi:10.1016/j.cell.2019.01.021 · Cited by 2,721 · see citing works
“Preclinical studies have implicated the release of hematopoietic growth factors from tumor or host cells and the resulting tumor infiltration of myeloid and other inflammatory cell types in the induction of VEGF-independent angiogenesis and escape (Bergers and Hanahan, 2008; De Palma et al., 2017; Shojaei et al., 2007…”
Background
Renal cell carcinoma
Hsieh, J. J.-D., Purdue, M. P., Signoretti, S., Swanton, C., Albiges, L. K., Schmidinger, M., Heng, D. Y. C., Larkin, J., & Ficarra, V. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.9 · Cited by 2,797 · see citing works
Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis
Pàez‐Ribes, M., Allen, E., Hudock, J., Takeda, T., Okuyama, H., Viñals, F., Inoue, M., Bergers, G., Hanahan, D., & Casanovas, O. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.01.027 · Cited by 2,344 · see citing works
“Notably, like most systemic therapies, these drugs have not produced enduring efficacy in terms of either tumor shrinkage or dormancy (stable disease) or long-term survival; rather, the common result is delayed time to progression following a period of clinical benefit, which is suggestive of an emergent resistance to…”
InfluentialSelf-citation
Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer
Schlumberger, M. J., Tahara, M., Wirth, L. J., Robinson, B. G., Brose, M. S., Elisei, R., Habra, M. A., Newbold, K. L., Shah, M. H., Hoff, A. O., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1406470 · Cited by 2,115 · see citing works
Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges
Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G., & Jain, R. K. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2018.29 · Cited by 2,027 · see citing works
Tumor angiogenesis: causes, consequences, challenges and opportunities
Lugano, R., Ramachandran, M., & Dimberg, A. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03351-7 · Cited by 2,040 · see citing works
Microenvironmental regulation of tumour angiogenesis
De Palma, M., Biziato, D., & Petrova, T. V. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.51 · Cited by 1,847 · see citing works
Pre-metastatic niches: organ-specific homes for metastases
Peinado, H., Zhang, H., Matei, I. R., Costa-Silva, B., Hoshino, A., Rodrigues, G., Psaila, B., Kaplan, R. N., Bromberg, J. F., Kang, Y., et al. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.6 · Cited by 1,889 · see citing works
Tumor angiogenesis: molecular pathways and therapeutic targets
Weis, S. M., & Cheresh, D. A. (2011) · Nature Medicine · doi:10.1038/nm.2537 · Cited by 1,739 · see citing works
Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis
Ebos, J. M. L., Lee, C. R., Cruz‐Muñoz, W., Bjarnason, G. A., Christensen, J. G., & Kerbel, R. S. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.01.021 · Cited by 1,710 · see citing works
Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases
Carmeliet, P., & Jain, R. K. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3455 · Cited by 1,678 · see citing works
“In addition, some preclinical studies show that blocking VEGF may promote metastasi”
Background
The role of myeloid cells in the promotion of tumour angiogenesis
Murdoch, C., Muthana, M., Coffelt, S. B., & Lewis, C. E. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2444 · Cited by 1,642 · see citing works
“The mechanisms underlying the effect of such cells on tumour resistance to other anti-angiogenic therapies are described in further detail by Bergers and Hanahan in this issu”
Background
Signal Transduction by Vascular Endothelial Growth Factor Receptors
Koch, S., Tugues, S., Li, X., Gualandi, L., & Claesson, L. (2011) · Biochemical Journal · doi:10.1042/bj20110301 · Cited by 1,628 · see citing works
“Finally, the recent challenges in the application of VEGF-targeted therapies with resistance, rescue (Bergers and Hanahan 2008), and, at least in mouse models, increased invasion and metastasis (Ebos et al. 2009; Paez-Ribes et al. 2009) have shown that we need to learn more about how blood vessels…”
Background
VEGF-targeted therapy: mechanisms of anti-tumour activity
Ellis, L. M., & Hicklin, D. J. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2403 · Cited by 1,673 · see citing works
Tumor angiogenesis and vascular normalization: alternative therapeutic targets
Viallard, C., & Larrivée, B. (2017) · Angiogenesis · doi:10.1007/s10456-017-9562-9 · Cited by 1,435 · see citing works
“Finally, the benefits of anti-VEGF are transitory and are followed by a resumption of tumor growth due to adaptive resistance or preexisting non-responsiveness [115].”
Background
Cabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor Growth
Yakes, F. M., Chen, J., Tan, J., Yamaguchi, T., Shi, Y., Yu, P., Qian, F., Chu, F., Bentzien, F., Cancilla, B., et al. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0264 · Cited by 1,350 · see citing works
Angiogenic signaling pathways and anti-angiogenic therapy for cancer
Liu, Z., Chen, H., Zheng, L., Sun, L., & Shi, L. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01460-1 · Cited by 1,387 · see citing works
Normalizing Tumor Microenvironment to Treat Cancer: Bench to Bedside to Biomarkers
Jain, R. K. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.46.3653 · Cited by 1,248 · see citing works
“Other evasive pathways emerging from preclinical and clinical studies include Ang2 and cMET.(16,89,90,97,171-173) These biomarkers and pathways need to be tested prospectively.”
Background
Regorafenib (BAY 73‐4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity
Wilhelm, S. M., Dumas, J., Adnane, L., Lynch, M., Carter, C. A., Schütz, G., Thierauch, K., & Zopf, D. (2011) · International Journal of Cancer · doi:10.1002/ijc.25864 · Cited by 1,355 · see citing works
“Indeed, adaptive responses by the tumor and its vasculature to anti-VEGF therapy have been hypothesized.(41) Such responses include hypoxia-mediated induction of other proangiogenic factors, such as Ang1 and FGFs,(42,43) or upregulation of PDGF-C expression in tumor-associated fibroblasts.”
Background
Hypoxia-Induced Angiogenesis: Good and Evil
Krock, B. L., Skuli, N., & Simon, M. C. (2011) · Genes & Cancer · doi:10.1177/1947601911423654 · Cited by 1,179 · see citing works
“Tumors often evade single-agent antiangiogenic therapies through the selective activation of alternate pro-angiogenic pathways.(95) Consequently, simultaneous blockade of multiple pro-angiogenic pathways is more effective than single-agent anti-angiogenics.”
Background
Continuation of Bevacizumab after First Progression in Metastatic Colorectal Cancer (ML18147): A Randomised Phase 3 Trial
Bennouna, J., Sastre, J., Arnold, D., Österlund, P., Greil, R., Van Cutsem, E., von Moos, R., Viéitez, J. M., Bouché, O., Borg, C., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70477-1 · Cited by 1,166 · see citing works
Hallmarks of cancer: Interactions with the tumor stroma
Pietras, K., & Östman, A. (2010) · Experimental Cell Research · doi:10.1016/j.yexcr.2010.02.045 · Cited by 1,137 · see citing works
“Given the proposed role for pericytes in the development of resistance to anti-angiogenic therapy [55], a better understanding of pericyte subpopulations may enable the prediction of response in patients to this new class of agents.”
Background
A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis
Acharyya, S., Oskarsson, T., Vanharanta, S., Malladi, S., Kim, J., Morris, P. G., Manova-Todorova, K., Leversha, M., Hogg, N., Seshan, V. E., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.042 · Cited by 1,085 · see citing works
“Drug resistance in cancer can be cell-intrinsic (Poulikakos and Rosen, 2011) or a combination of host and tumor mediated pathways (Bergers and Hanahan, 2008; Ebos et al., 2009).”
Macrophage Regulation of Tumor Responses to Anticancer Therapies
De Palma, M., & Lewis, C. E. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.013 · Cited by 1,079 · see citing works
“However, this seems increasingly unlikely, as it is now established that therapeutic interception of VEGF is counteracted by the compensatory induction of other proangiogenic factors, some of which are involved in monocyte/myeloid cell chemoattraction (Bergers and Hanahan, 2008; Ferrara, 2010).”
Background
Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response
McKeown, S. R. (2014) · The British Journal of Radiology · doi:10.1259/bjr.20130676 · Cited by 1,050 · see citing works
The seed and soil hypothesis revisited—The role of tumor‐stroma interactions in metastasis to different organs
Langley, R. R., & Fidler, I. J. (2011) · International Journal of Cancer · doi:10.1002/ijc.26031 · Cited by 958 · see citing works
Intrinsic therapeutic applications of noble metal nanoparticles: past, present and future
Arvizo, R. R., Bhattacharyya, S., Kudgus, R. A., Giri, K., Bhattacharya, R., & Mukherjee, P. (2012) · Chemical Society Reviews · doi:10.1039/c2cs15355f · Cited by 872 · see citing works
Antiangiogenic therapy in oncology: current status and future directions
Jayson, G. C., Kerbel, R. S., Ellis, L. M., & Harris, A. L. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01088-0 · Cited by 829 · see citing works
Combined antiangiogenic and anti–PD-L1 therapy stimulates tumor immunity through HEV formation
Allen, E., Jabouille, A., Rivera, L. B., Lodewijckx, I., Missiaen, R., Steri, V., Feyen, K., Tawney, J., Hanahan, D., Michael, I. P., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aak9679 · Cited by 820 · see citing works
Self-citation
Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization
Mazzone, M., Dettori, D., de Oliveira, R. L., Loges, S., Schmidt, T., Jonckx, B., Tian, Y.-M., Lanahan, A. A., Pollard, P. J., de Almodóvar, C. R., et al. (2009) · Cell · doi:10.1016/j.cell.2009.01.020 · Cited by 812 · see citing works
“Nonetheless, current antiangiogenic agents induce tumor hypoxia by pruning vessels or forming hypoperfused vessels, which can stimulate angiogenesis and limit their success (Bergers and Hanahan, 2008).”
Brivanib versus sorafenib as first‐line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK‐FL study
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Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice
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Authors: Bergers, G., & Hanahan, D.
Affiliations: University of California, San Francisco (US)
ORCID: Bergers, Gabriele
Hanahan, Douglas
Venue: Nature Reviews Cancer
Publisher: Springer Science and Business Media LLC
Published: 2008-08
Volume: 8
Issue: 8
Pages: 592-603
ISSN: 1474-175X (ISSN-L)
1474-1768
DOI: 10.1038/nrc2442
PMC: PMC2874834
OpenAlex: W2017322644
Cited by: 2,953
References: 101
Citations by year: 2026: 70 · 2025: 77 · 2024: 97 · 2023: 130 · 2022: 95 · 2021: 172 · 2020: 133 · 2019: 152 · 2018: 148 · 2017: 202 · 2016: 217 · 2015: 228 · 2014: 241 · 2013: 248 · 2012: 215
FWCI: 13.60
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Cancer (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (R01CA099948)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Keywords: anti-angiogenic therapy, drug resistance, vascular endothelial growth factor, VEGF signaling, tumor angiogenesis, intrinsic resistance, combination therapy
MeSH terms: Humans, Neoplasms, Neovascularization, Pathologic, Signal Transduction, Drug Resistance, Neoplasm, Angiogenesis Inhibitors, Vascular Endothelial Growth Factors

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Modes of resistance to anti-angiogenic therapy

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