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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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The Complexity of Translating Anti-angiogenesis Therapy from Basic Science to the Clinic
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Targeting cancer cell metabolism in pancreatic adenocarcinoma
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Targeted therapy in metastatic colorectal cancer – An example of personalised medicine in action
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“Some tumours show intrinsic resistance to bevacizumab and, when they do occur, responses are often transitory with patients showing restoration of tumour growth due to evasive resistance.(43)”
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Angiogenesis as a Therapeutic Target in Malignant Gliomas
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“Several distinct mechanisms of treatment resistance have been hypothesized [123].”
BackgroundTranslating the ‘Sugar Code’ into Immune and Vascular Signaling Programs
Cerliani, J. P., Blidner, A. G., Toscano, M. A., Croci, D. O., & Rabinovich, G. A. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.11.003 · Cited by 119
Shojaei, F., & Ferrara, N. (2008) · Drug Resistance Updates · doi:10.1016/j.drup.2008.09.001 · Cited by 119
Pathogenesis of herpes stromal keratitis – A focus on corneal neovascularization
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“Apparently inhibiting miR132 also acts to restrain retinal angiogenesis and this effect does not result in the compensatory angiogenic mechanisms that usually substitute for VEGF signaling when VEGF is inhibited (Bergers and Hanahan, 2008).”
BackgroundVascular Normalization: A New Window Opened for Cancer Therapies
Yang, T., Xiao, H., Liu, X., Wang, Z., Zhang, Q., Wei, N., & Guo, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.719836 · Cited by 126
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“Several different mechanisms of resistance to antiangiogenic therapies have been described (Bergers and Hanahan, 2008).”
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“…cells (De Palma et al., 2003) as well as Tie2+ monocytes (De Palma et al., 2005; Welford et al., 2011) to create a pro-angiogenic environment with high levels of VEGF and other pro-angiogenic factors, which trigger the angiogenic switch (Bergers and Hanahan, 2008; Saharinen et al., 2011).”
BackgroundYalçın, M., Dyskin, E., Lansing, L., Bharali, D. J., Mousa, S. S., Bridoux, A., Hercbergs, A. H., Lin, H., Davis, F. B., Glinsky, G. V., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1926 · Cited by 117
“than as primary anticancer modalities (34).”
Current and future systemic treatments for renal cell carcinoma
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“…factors in anti-angiogenic-therapy naïve tumors might cause tumors to be refractory to VEGF inhibition or that up-regulation of these factors during the course of therapy could lead to acquired resistance to VEGF pathway inhibition (Casanovas et al. 2005; Kerbel 2005; Bergers and Hanahan 2008).”
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“It has been suggested that increased pericyte fortification can render vessels insensitive to anti-VEGF therapy [31].”
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Tumor Stroma, Tumor Blood Vessels, and Antiangiogenesis Therapy
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“Copyright © 2015 Wolters Kluwer is, MV, and FA, and DV precursors,(69,79,80) but is much less effective against tumors with an established vasculature rich in “late” blood vessels.(81) Human cancers, of course, have grown for many months or years before detection and are therefore presumably supplied by many late bloo…”
BackgroundTumor Angiogenesis: Insights and Innovations
Nussenbaum, F., & Herman, I. M. (2010) · Journal of Oncology · doi:10.1155/2010/132641 · Cited by 122
A preclinical and clinical review of aflibercept for the management of cancer
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“Many patients with advanced disease who are treated with these agents show disease progression shortly after their initial response, which is thought to be related to the development of resistance.(37,38) Additionally, adverse events such as hypertension and proteinuria are a direct consequence of VEGF signaling pathw…”
Quantification and cell-to-cell variation of vascular endothelial growth factor receptors
Imoukhuede, P. I., & Popel, A. S. (2010) · Experimental Cell Research · doi:10.1016/j.yexcr.2010.12.014 · Cited by 112
“metastatic breast cancer, metastatic colorectal cancer, and glioblastoma multiforme—the most common and most aggressive form of brain cancer [5]; however, this anti-angiogenic therapy has only had moderate effects on patient survival, ultimately leading to anti-angiogenic resistance and non-responsiveness [6].”
Progression types after antiangiogenic therapy are related to outcome in recurrent glioblastoma
Nowosielski, M., Wiestler, B., Goebel, G., Hutterer, M., Schlemmer, H. P., Stockhammer, G., Wick, W., Bendszus, M., & Radbruch, A. (2014) · Neurology · doi:10.1212/wnl.0000000000000402 · Cited by 114
Hypoxia inducible factor-1α: Its role in colorectal carcinogenesis and metastasis
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“Clinical trials have demonstrated the activity of antiangiogenic agents in CRC [6,7], highlighting the importance of angiogenesis and its underlying molecular pathways in the biology of CRC.”
BackgroundCurrent Understanding of the Molecular Biology of Pancreatic Neuroendocrine Tumors
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The role of tumor-associated macrophages in tumor vascularization
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“Tumor hypoxia induced by anti-angiogenic treatment may promote the recruitment of BM-derived myeloid cells, including TEMs, to the tumors through chemotactic factors [131-133].”
Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy
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“Evidence suggests that coating by pericytes helps the tumor endothelium to survive and function even in the absence of VEGF, and thereby enables tumors to grow during the course of an anti-angiogenic therapeutic regimen (Bergers and Hanahan, 2008).”
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The paradoxical effect of bevacizumab in the therapy of malignant gliomas
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Molecular Regulation of Tumor Angiogenesis and Perfusion via Redox Signaling
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Methods to study the tumor microenvironment under controlled oxygen conditions
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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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