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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
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“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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“To some extent, the above studies throw light on the transitory clinical efficacies achieved by anti-VEGF-A therapy [14,15].”
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Heterogeneity of the tumor vasculature: the need for new tumor blood vessel type-specific targets
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Heralding a new paradigm in 3D tumor modeling
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“vival and contribute to resistance against anti-angiogenic VEGFdepletion therapies [54].”
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“These findings reflect challenging clinical outcomes derived from the single antiangiogenic therapy, suchasonlya short-termdelayof survival rate, adaptive resistance, intrinsic nonresponsiveness, and the rapid re-growth of tumor vessels after ceasing therapy (Bergers and Hanahan, 2008;Mancuso et al., 2006).”
Mechanical Forces in Tumor Angiogenesis
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Pathological neoangiogenesis depends on oxidative stress regulation by ATM
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Dual Antagonism of PDGF and VEGF in Neovascular Age-Related Macular Degeneration
Jaffe, G. J., Ciulla, T. A., Ciardella, A. P., Devin, F., Dugel, P. U., Eandi, C. M., Masonson, H., Monés, J., Pearlman, J. A., Maftouhi, M. Q.-E., et al. (2016) · Ophthalmology · doi:10.1016/j.ophtha.2016.10.010 · Cited by 153
“Pericyte stripping from a neovascular complex may leave the underlying endothelial cells in an unprotected and vulnerable state, thereby increasing their sensitivity to the effects of VEGF blockade.(18,19,21,24,28,31) Dual targeting of PDGF and VEGF in nAMD has been assessed in a phase I clinical trial of E10030 admin…”
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VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
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Therapeutic approaches for corneal neovascularization
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Non-angiogenic tumours and their influence on cancer biology
Dønnem, T., Reynolds, A. R., Kuczynski, E. A., Gatter, K. C., Vermeulen, P. B., Kerbel, R. S., Harris, A. L., & Pezzella, F. (2018) · Nature reviews. Cancer · doi:10.1038/nrc.2018.14 · Cited by 153
The endothelial tip-stalk cell selection and shuffling during angiogenesis
Chen, W., Xia, P., Wang, H., Tu, J., Liang, X., Zhang, X., & Li, L. (2019) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-019-00511-z · Cited by 157
Cancer stem cell targeted therapy: progress amid controversies
Wang, T., Shigdar, S. L., Gantier, M. P., Hou, Y., Wang, L., Li, Y., Shamaileh, H. A., Yin, W., Zhou, S., Zhao, X., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6176 · Cited by 150
Monoclonal Antibodies Targeting Vascular Endothelial Growth Factor
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“The mechanisms of VEGF pathway drug resistance are not clearly understood, but can be split into either adaptive or intrinsic resistance as detailed in the review by Bergers and Hanahan.”
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“However, the clinical translation of these therapies has faced challenges, with patients exhibiting resistance to these treatments [247, 248], possibly due to the emergence of VEGF-independent angiogenesis pathways or other redundant mechanisms in the tumors [249].”
BackgroundIntratumoral Myeloid Cells Regulate Responsiveness and Resistance to Antiangiogenic Therapy
Rivera, L. B., Meyronet, D., Hervieu, V., Frederick, M. J., Bergsland, E. K., & Bergers, G. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.055 · Cited by 148
“However, the beneficial effects observed across the multitude of cancers that respond are typically short-lived; therefore much effort has focused on uncovering the various mechanisms whereby tumors bypass the tumor-inhibitory effects of therapy (Bergers and Hanahan, 2008; Kerbel, 2008).”
Self-citationAntiangiogenic cancer treatment: The great discovery and greater complexity (Review)
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“It turned out that some types of cancer can be intrinsically refractory to antiangiogenic therapy or during the treatment acquire resistance to anti-VEGF agents (103,104).”
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Proangiogenic Contribution of Adiponectin toward Mammary Tumor Growth In vivo
Landskroner-Eiger, S., Qian, B., Muise, E. S., Nawrocki, A. R., Berger, J. P., Fine, E. J., Koba, W., Deng, Y., Pollard, J. W., & Scherer, P. E. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2649 · Cited by 145
“Antiangiogenic treatment can cause recruitment of various bone marrow–derived cells that have the capacity to fuel tumor growth (26, 28, 38).”
BackgroundInfluentialMural Cell Associated VEGF Is Required for Organotypic Vessel Formation
Evensen, L., Micklem, D., Blois, A. L., Berge, S. V., Aarsæther, N., Littlewood-Evans, A. J., Wood, J. M., & Lorens, J. B. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005798 · Cited by 146
“Mural cells exert a dominant effect on endothelial cell behavior that is necessary for vessel maturation and function, and that determines responses to anti-angiogenic therapeutics [2,3].”
BackgroundPerspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas
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Glioblastoma-derived Tumor Cells Induce Vasculogenic Mimicry through Flk-1 Protein Activation
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“For example, clinical trials using a neutralizing anti-VEGF antibody (Bevacizumab, also named Avastin) in recurrent GBMs revealedminimal benefit to patient survival (4, 6, 7).”
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“Upregulation of alternate proangiogenic signals, such as the FGF signaling pathway, may play a role in evasive resistance to VEGF-targeted antiangiogenic therapy (10).”
BackgroundTargeting Vascular NADPH Oxidase 1 Blocks Tumor Angiogenesis through a PPARα Mediated Mechanism
Garrido-Urbani, S., Jemelin, S., Deffert, C., Carnesecchi, S., Basset, O., Szyndralewiez, C., Heitz, F., Page, P., Montet, X., Michalik, L., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0014665 · Cited by 143
“Currently, the anti-VEGF antibody bevacizumab (Avastin), and several small molecular VEGFR tyrosine kinase inhibitors, are used as anti-angiogenic drugs to treat patients with advanced cancers [66,67].”
BackgroundLinking hypoxia, DNA damage and proliferation in multicellular tumor spheroids
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“While there have been some spectacular clinical successes with anti-angiogenics in cancer treatment, the overall and progression-free survival rates have been disappointing [26].”
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Interleukin-6: An angiogenic target in solid tumours
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“The mechanisms for the development of resistance to VEGF pathway inhibitors in tumors are far from fully elucidated (14, 16, 17), but various alternative angiogenic signaling pathways have been reported (39–41).”
BackgroundEco-evolutionary causes and consequences of temporal changes in intratumoural blood flow
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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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