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Modes of resistance to anti-angiogenic therapy
Open accessAbstract
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 (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
In the citing paper
“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]
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“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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BackgroundDrug Resistance in Non-Small Cell Lung Cancer: A Potential for NOTCH Targeting?
Iglesias, V. S., Giuranno, L., Dubois, L. J., Theys, J., & Vooijs, M. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00267 · Cited by 233
“, FGF, PDGF, and TNF-α) and increase in local hypoxia (145, 146).”
BackgroundThe role IL-1 in tumor-mediated angiogenesis
Voronov, E., Carmi, Y., & Apte, R. N. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00114 · Cited by 234
“These include induced secretion of Bv8 by MDSCs and a subsequent VEGFindependent angiogenic response (Shojaei et al., 2007; Carmi et al., 2013) or expression of PDGF-C in cancer-associated fibroblasts (Bergers and Hanahan, 2008; Crawford et al., 2009).”
BackgroundPiao, Y., Liang, J., Holmes, L., Zurita, A. J., Henry, V., Heymach, J. V., & de Groot, J. (2012) · Neuro-Oncology · doi:10.1093/neuonc/nos158 · Cited by 235
“Although “tumor escape” from anti-VEGF therapy involves activation of other growth factors important for angiogenesis, laboratory data suggest that bone marrow–derived cells may play a critical role in tumor escape from antiangiogenic therapy.(5,6) In the early phases of antiangiogenic therapy, tumor oxygenation impro…”
BackgroundDLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo
Li, J., Sainson, R. C. A., Oon, C. E., Turley, H., Leek, R., Sheldon, H., Bridges, E., Shi, W., Snell, C. E., Bowden, E. T., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-1704 · Cited by 234
“Our findings may explain why so many patients in clinical trials do not respond to bevacizumab (13).”
BackgroundInfluentialCao, Z., Ding, B., Guo, P., Lee, S. B., Butler, J. M., Casey, S. C., Simons, M., Tam, W., Felsher, D. W., Shido, K., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.005 · Cited by 227
“…endothelial cells (ECs) are a specialized component of the tumor microenvironment that can orchestrate tumor growth and invasion (Beck et al., 2011; Bergers and Hanahan, 2008; Butler et al., 2010a; Calabrese et al., 2007; Carmeliet and Jain, 2011; Charles et al., 2010; Ghajar et al., 2013; Lu et…”
Tripathi, C., Tewari, B. N., Kanchan, R. K., Baghel, K. S., Nautiyal, N., Shrivastava, R., Kaur, H., Bhatt, M. L. B., & Bhadauria, S. (2014) · Oncotarget · doi:10.18632/oncotarget.2110 · Cited by 228
Xu, L., Stevens, J., Hilton, M. B., Seaman, S., Conrads, T. P., Veenstra, T. D., Logsdon, D. L., Morris, H., Swing, D. A., Patel, N. L., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008455 · Cited by 224
“Scie blast growth factor), BV8, IL-8 (interleukin-8), PDGF-C, and TEM8/ ANTXR1 (tumor endothelial marker 8/anthrax toxin receptor 1) (3, 4), but the therapeutic value of targeting these factors awaits clinical validation.”
Forty-Year Journey of Angiogenesis Translational Research
Cao, Y., Arbiser, J. L., D’Amato, R. J., D'Amore, P. A., Ingber, D. E., Kerbel, R. S., Klagsbrun, M., Lim, S., Moses, M. A., Zetter, B. R., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3003149 · Cited by 226
“Rather, resistance likely arises from compensation by other angiogenic factors (61, 116) and may be less common if more effective ADs are developed that inhibit EC responses to all angiogenic factors.”
BackgroundHarnessing the immune system in glioblastoma
Brown, N. F., Carter, T. J., Ottaviani, D., & Mulholland, P. J. (2018) · British Journal of Cancer · doi:10.1038/s41416-018-0258-8 · Cited by 227
Incio, J., Ligibel, J. A., McManus, D. T., Suboj, P., Jung, K., Kawaguchi, K., Pinter, M., Babykutty, S., Chin, S. M., Vardam, T. D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aag0945 · Cited by 222
López de Andrés, J., Griñán-Lisón, C., Jiménez, G., & Marchal, J. A. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00966-3 · Cited by 207
Allen, E., Miéville, P., Warren, C. M., Saghafinia, S., Li, L., Peng, M.-W., & Hanahan, D. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.029 · Cited by 221
“Remarkably, as summarized in the introduction, multiple modes of adaptive or evasive resistance to therapies targeting tumor angiogenesis have been reported (Casanovas et al., 2005; Shojaei and Ferrara, 2008; Bergers and Hanahan, 2008; Ebos et al., 2009; Pàez-Ribes et al., 2009; Sennino et al., 2012) in experimental t…”
miR-126 and miR-126*: New Players in Cancer
Meister, J., & Schmidt, M. H. H. (2010) · The Scientific World JOURNAL · doi:10.1100/tsw.2010.198 · Cited by 218
“Currently, inhibitors of the VEGF signaling pathway, like bevacizumab, sunitinib, and sorafenib, are clinically tested, but therapeutic benefits are often transient and followed by a rapid restoration of tumor growth and progression[62].”
BackgroundFinn, R. S., Kang, Y., Mulcahy, M. F., Polite, B. N., Lim, H. Y., Walters, I. B., Baudelet, C., Manekas, D., & Park, J. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1991 · Cited by 216
“Nevertheless, current VEGF-targeted agents fail to produce enduring clinical responses in most patients as a result of de novo or acquired resistance (7, 8).”
BackgroundInfluentialExtracellular Vesicles – Biomarkers and Effectors of the Cellular Interactome in Cancer
Rak, J. W. (2013) · Frontiers in Pharmacology · doi:10.3389/fphar.2013.00021 · Cited by 216
“These limitations could in each case be explained by several detailed biological mechanisms, many of which are intensively studied (Broxterman et al., 2003; Bergers and Hanahan, 2008).”
BackgroundBrandenburg, S., Müller, A., Turkowski, K., Radev, Y. T., Rot, S., Schmidt, C., Bungert, A. D., Acker, G., Schorr, A., Hippe, A., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1529-6 · Cited by 222
Bridgeman, V. L., Vermeulen, P. B., Foo, S., Bilecz, A., Daley, F., Kostaras, E., Nathan, M. R., Wan, E., Frentzas, S., Schweiger, T., et al. (2017) · The Journal of Pathology · doi:10.1002/path.4845 · Cited by 214
“Our interpretation of these data is that: [1] the vessels of angiogenic pushing growth pattern RENCA lung metastases are sensitive to sunitinib; and [2] sunitinib also induces a rapid shift in growth pattern to the alveolar/interstitial HGP, which permits the co-option of alveolar capillaries that are resistant to sun…”
BackgroundXue, Y., Lim, S., Yang, Y., Wang, Z., Jensen, L. D., Hedlund, E., Andersson, P., Sasahara, M., Larsson, O. S., Galter, D., et al. (2011) · Nature Medicine · doi:10.1038/nm.2575 · Cited by 218
Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis
Lee, S. H., Jeong, D., Han, Y., & Baek, M. J. (2015) · Annals of Surgical Treatment and Research · doi:10.4174/astr.2015.89.1.1 · Cited by 215
The Great Escape; the Hallmarks of Resistance to Antiangiogenic Therapy
B, J. R. V. B., Nowak-Sliwinska, P. M., Huijbers, E. J. M., Thijssen, V. L., & Griffioen, A. W. (2015) · Pharmacological Reviews · doi:10.1124/pr.114.010215 · Cited by 211
“…not limited to—angiopoietins (ANGs) (Fagiani and Christofori, 2013), fibroblast growth factors (FGFs) (Brooks et al., 2012), transforming growth factors (TGFs) (Pardali et al., 2010), and placental growth factor (PlGF) (Bergers and Hanahan, 2008; Carmeliet and Jain, 2011; Gacche and Meshram, 2014).”
BackgroundInfluentialAntibody-based proteomics: fast-tracking molecular diagnostics in oncology
Brennan, D. J., O’Connor, D. P., Rexhepaj, E., Pontén, F., & Gallagher, W. M. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2902 · Cited by 208
“Despite promising results in various tumour types, anti-angiogenic therapy is still limited by a lack of predictive biomarkers, particularly as innate and acquired resistance is an ever increasing clinical dilemm”
BackgroundThe dual role of thymidine phosphorylase in cancer development and chemotherapy
Bronckaers, A., Gago, F., Balzarini, J. M., & Liekens, S. (2009) · Medicinal Research Reviews · doi:10.1002/med.20159 · Cited by 204
“Although tumor resistance may be caused by various mechanisms such as poor pharmacokinetics, limited drug uptake, increased drug efflux, and mutation of the target proteins, tumor resistance may also be caused by circumvention of the angiogenic blockade by activation and/ or upregulation of alternative pro-angiogenic…”
BackgroundTugues, S., Koch, S., Gualandi, L., Li, X., & Claesson, L. (2011) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2011.04.004 · Cited by 209
The Met receptor tyrosine kinase: A key player in oncogenesis and drug resistance
Maroun, C. R., & Rowlands, T. M. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.12.014 · Cited by 206
“In glioblastoma, an initial response to the VEGF antibody bevacizumab is transient and often followed by radiographic progression attributed to resistance to this anti-angiogenic therapy (Bergers & Hanahan, 2008).”
BackgroundThe VEGF Pathway in Cancer and Disease: Responses, Resistance, and the Path ForwardPreprint
Kieran, M. W., Kalluri, R., & Cho, Y. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006593 · Cited by 212
“Others have defined resistance patterns in different ways that need to be discussed and evaluated (Ton and Jayson 2004; Bergers and Hanahan 2008; Azam et al. 2010).”
BackgroundJahangiri, A., Lay, M. D. D., Miller, L. M., Carbonell, W. S., Hu, Y., Lu, K. V., Tom, M. W., Paquette, J., Tokuyasu, T. A., Tsao, S. W., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1281 · Cited by 203
“Because transcriptional changes occur more readily than mutations (5), these changesmayoccur to some extent in all Authors' Affiliations: (1)Departments of Neurological Surgery, (2)Pathology, (3)Cellular and Molecular Pharmacology, and (4)Radiology; (5)Helen Diller Family Comprehensive Cancer Center; and (6)Computatio…”
BackgroundSelf-citationKienast, Y., Klein, C., Scheuer, W., Raemsch, R., Lorenzon, E., Bernicke, D., Herting, F., Yu, S., The, H. H., Martarello, L., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0081 · Cited by 201
Goveia, J., Stapor, P. C., & Carmeliet, P. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201404156 · Cited by 203
“…endothelial growth factor (VEGF) signaling) is the only clinically approved anti-angiogenic strategy, but the benefits are limited as tumors acquire resistance within months after treatment initiation (Bergers & Hanahan, 2008; Carme-liet & Jain, 2011; Ebos & Kerbel, 2011; Welti et al , 2013).”
Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated with a Mesenchymal Transition
Piao, Y., Liang, J., Holmes, L., Henry, V. K., Sulman, E. P., & de Groot, J. F. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1557 · Cited by 206
“Bevacizumab-resistant tumors are primed for enhanced angiogenesis One important mechanism of escape from anti-VEGF inhibitors is the development of VEGF-independent angiogenesis via secretion of a variety of proangiogenic factors (21, 23).”
BackgroundNew, J., Arnold, L., Ananth, M., Alvi, S. A., Thornton, M. M., Werner, L. R., Tawfik, O. W., Dai, H. D., Shnayder, Y., Kakarala, K., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-1077 · Cited by 202
“CAFs promote HNSCC progression by secreting growth factors, remodeling the extracellular matrix, and potentiating therapy resistance (5).”
Understanding tumour endothelial cell heterogeneity and function from single-cell omics
Zeng, Q., Mousa, M., Nadukkandy, A. S., Franssens, L., Alnaqbi, H., Alshamsi, F. Y., AlSafar, H. S., & Carmeliet, P. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00591-5 · Cited by 220
Resistance and Escape From Antiangiogenesis Therapy: Clinical Implications and Future Strategies
Bottsford-Miller, J. N., Coleman, R. L., & Sood, A. K. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.41.9242 · Cited by 201
“As an apparent corollary, three human studies reported patients with multifocal recurrence while receiving bevacizumab therapy.(37,86,87) These findings, in conjunction with data suggesting that fibroblasts can draw existing vessels toward and into a fresh wound, point toward cell populations that have the phenotypic…”
BackgroundTargeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy
Pisarsky, L., Bill, R., Fagiani, E., Dimeloe, S., Goosen, R., Hagmann, J., Hess, C., & Christofori, G. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.028 · Cited by 206
“, with bevacizumab, tumors escape by activating alternative pro-angiogenic signaling pathways, including signaling by fibroblast growth factors (FGFs), plateletderived growth factors (PDGFs), Bv8/prokineticin, and interleukin-17 (IL-17) (Bergers and Hanahan, 2008; Casanovas et al., 2005; Chung et al., 2013; Compagni e…”
BackgroundInfluential
Metadata
- Authors
- Bergers, G., & Hanahan, D.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Nature Reviews Cancer
- Published
- 2008-08
- Volume
- 8
- Issue
- 8
- Pages
- 592-603
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- 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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