The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
A Proangiogenic Signature Is Revealed in FGF-Mediated Bevacizumab-Resistant Head and Neck Squamous Cell Carcinoma
Open accessPublished version of a preprint
Abstract
Resistance to antiangiogenic therapies is a critical problem that has limited the utility of antiangiogenic agents in clinical settings. However, the molecular mechanisms underlying this resistance have yet to be fully elucidated. In this study, we established a novel xenograft model of acquired resistance to bevacizumab. To identify molecular changes initiated by the tumor cells, we performed human-specific microarray analysis on bevacizumab-sensitive and -resistant tumors. Efficiency analysis identified 150 genes upregulated and 31 genes downregulated in the resistant tumors. Among angiogenesis-related genes, we found upregulation of fibroblast growth factor-2 (FGF2) and fibroblast growth factor receptor-3 (FGFR3) in the resistant tumors. Inhibition of the FGFR in the resistant tumors led to the restoration of sensitivity to bevacizumab. Furthermore, increased FGF2 production in the resistant cells was found to be mediated by overexpression of upstream genes phospholipase C (PLCg2), frizzled receptor-4 (FZD4), chemokine [C-X3-C motif] (CX3CL1), and chemokine [C-C motif] ligand 5 (CCL5) via extracellular signal-regulated kinase (ERK). In summary, our work has identified an upregulation of a proangiogenic signature in bevacizumab-refractory HNSCC tumors that converges on ERK signaling to upregulate FGF2, which then mediates evasion of anti-VEGF therapy. These findings provide a new strategy on how to enhance the therapeutic efficacy of antiangiogenic therapy. Implications: Novel xenograft model leads to the discovery of FGF as a promising therapeutic target in overcoming the resistance of antiangiogenic therapy in HNSCC. Mol Cancer Res; 11(12); 1585–96. ©2013 AACR.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Using patient material and mouse/human xenograft models, PLCγ2 was revealed to be an overexpressed upstream mediator, among other factors resulting in ERK signaling, that induced increased FGF-mediated bevacizumab resistance in head and neck squamous cell carcinoma (154).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [154]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer
Sandler, A., Gray, R., Perry, M. C., Brahmer, J., Schiller, J. H., Dowlati, A., Lilenbaum, R., & Johnson, D. H. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa061884 · Cited by 5,761
Molecular mechanisms and clinical applications of angiogenesis
Carmeliet, P., & Jain, R. K. (2011) · Nature · doi:10.1038/nature10144 · Cited by 5,467
Modes of resistance to anti-angiogenic therapy
Bergers, G., & Hanahan, D. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2442 · Cited by 2,953
Fibroblast growth factor signalling: from development to cancer
Turner, N. C., & Grose, R. P. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2780 · Cited by 2,768
Yang, J. C., Haworth, L. R., Sherry, R. M., Hwu, P., Schwartzentruber, D. J., Topalian, S. L., Steinberg, S. M., Chen, H. X., & Rosenberg, S. A. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa021491 · Cited by 2,704
Giantonio, B. J., Catalano, P. J., Meropol, N. J., O'Dwyer, P. J., Mitchell, E. P., Alberts, S. R., Schwartz, M. A., & Benson, A. B. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.09.6305 · Cited by 2,279
Casanovas, O., Hicklin, D. J., Bergers, G., & Hanahan, D. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.09.005 · Cited by 1,621
A systems biology approach for pathway level analysisPreprint
Drăghici, S., Khatri, P., Tarca, A. L., Amin, K., Done, A., Voichiţa, C., Georgescu, C., & Romero, R. J. (2007) · Genome Research · doi:10.1101/gr.6202607 · Cited by 1,263
Pepper, M. S., Ferrara, N., Orci, L., & Montesano, R. (1992) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(92)92277-5 · Cited by 856
Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells
Shojaei, F., Wu, X., Malik, A. K., Zhong, C., Baldwin, M. E., Schanz, S., Fuh, G., Gerber, H.-P., & Ferrara, N. (2007) · Nature Biotechnology · doi:10.1038/nbt1323 · Cited by 849
Interleukin-8 Mediates Resistance to Antiangiogenic Agent Sunitinib in Renal Cell Carcinoma
Huang, D., Ding, Y., Zhou, M., Rini, B. I., Petillo, D., Qian, C.-N., Kahnoski, R. J., Futreal, P. A., Furge, K. A., & Teh, B. T. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3965 · Cited by 417
HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors
Shojaei, F., Lee, J. H., Simmons, B. H., Wong, A., Esparza, C. O., Plumlee, P. A., Feng, J., Stewart, A., Hu‐Lowe, D. D., & Christensen, J. G. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0489 · Cited by 320
Roles of Fibroblast Growth Factor Receptors in Carcinogenesis
Haugsten, E. M., Więdłocha, A., Olsnes, S., & Wesche, J. (2010) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-10-0168 · Cited by 320
Zhao, M., Sano, D., Pickering, C. R., Jasser, S. A., Henderson, Y. C., Clayman, G. L., Sturgis, E. M., Ow, T. J., Lotan, R., Carey, T. E., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0690 · Cited by 282
Self-citationCohen, E. E. W., Davis, D. W., Karrison, T. G., Seiwert, T. Y., Wong, S. J., Nattam, S. R., Kozloff, M. F., Clark, J. I., Yan, D., Liu, W., et al. (2009) · The Lancet Oncology · doi:10.1016/s1470-2045(09)70002-6 · Cited by 273
The role of fibroblast growth factors in vascular development
Javerzat, S., Auguste, P., & Bikfalvi, A. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)02394-8 · Cited by 266
Pathways Mediating Resistance to Vascular Endothelial Growth Factor–Targeted Therapy
Ellis, L. M., & Hicklin, D. J. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-5287 · Cited by 257
Fibroblast growth factors are required for efficient tumor angiogenesis.
Compagni, A., Wilgenbus, P., Impagnatiello, M.-A., Cotten, M. L., & Christofori, G. (2000) · PubMed · Cited by 227
Marek, L. A., Ware, K. E., Fritzsche, A., Hercule, P., Helton, W. R., Smith, J. E., McDermott, L. A., Coldren, C. D., Nemenoff, R. A., Merrick, D. T., et al. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.049544 · Cited by 225
HOXB7 Constitutively Activates Basic Fibroblast Growth Factor in Melanomas
Carè, A., Silvani, A., Meccia, E., Mattia, G., Stoppacciaro, A., Parmiani, G., Peschle, C., & Colombo, M. P. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4842 · Cited by 211
Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair.
Broadley, K. N., Aquino, A. M., Woodward, S. C., Buckley, A., Sato, Y., Rifkin, D. B., & Davidson, J. M. (1989) · PubMed · Cited by 198
Giavazzi, R., Sennino, B., Coltrini, D., Garofalo, A., Dossi, R., Ronca, R., Molinari-Tosatti, M. P., & Presta, M. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64325-8 · Cited by 185
Cascone, T., Herynk, M. H., Xu, L., Du, Z., Kadara, H. N., Nilsson, M. B., Oborn, C. J., Park, Y., Erez, B., Jacoby, J. J., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci42405 · Cited by 166
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
Allen, E., Walters, I. B., & Hanahan, D. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2847 · Cited by 148
Ware, K. E., Marshall, M. E., Heasley, L. R., Marek, L. A., Hinz, T. K., Hercule, P., Helfrich, B. A., Doebele, R. C., & Heasley, L. E. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014117 · Cited by 148
Tumor and stromal pathways mediating refractoriness/resistance to anti-angiogenic therapies
Crawford, Y., & Ferrara, N. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.09.004 · Cited by 144
Bello, E., Colella, G., Scarlato, V., Oliva, P., Berndt, A., Valbusa, G., Serra, S. C., D’Incalci, M., Cavalletti, E., Giavazzi, R., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-2700 · Cited by 143
Kim, S., Yazici, Y. D., Calzada, G., Wang, Z.-Y., Younes, M. N., Jasser, S. A., El‐Naggar, A. K., & Myers, J. N. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0595 · Cited by 138
Self-citationTille, J., Wood, J. M., Mandriota, S. J., Schnell, C., Ferrari, S. M., Mestan, J., Zhu, Z., Witte, L., & Pepper, M. S. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29231-4 · Cited by 127
Vascular Remodeling Marks Tumors That Recur During Chronic Suppression of Angiogenesis
Huang, J., Soffer, S. Z., Kim, E. S., McCrudden, K. W., Huang, J. T., New, T. N., Manley, C. A., Middlesworth, W., O’Toole, K., Yamashiro, D. J., et al. (2004) · Molecular Cancer Research · doi:10.1158/1541-7786.36.2.1 · Cited by 101
Carbone, C., Moccia, T., Zhu, C., Paradiso, G., Budillon, A., Chiao, P. J., Abbruzzese, J. L., & Melisi, D. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1185 · Cited by 92
Vokes, E. E., Cohen, E. E. W., Mauer, A. M., Karrison, T. G., Wong, S. J., Skoog-Sluman, L. J., Kozloff, M. F., Dancey, J. E., & Dekker, A. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.23.16_suppl.5504 · Cited by 91
Patel, S., & Lyons‐Weiler, J. (2004) · Applied Bioinformatics · doi:10.2165/00822942-200403010-00007 · Cited by 83
A pro‐inflammatory signature mediates FGF2‐induced angiogenesis
Andrés, G., Leali, D., Mitola, S. M. F., Coltrini, D., Camozzi, M., Corsini, M., Belleri, M., Hirsch, E., Schwendener, R. A., Christofori, G., et al. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00415.x · Cited by 77
d'AVIS, P. Y., Robertson, S., Meyer, A. L., Bardwell, W., Webster, M. K., & Donoghue, D. J. (1998) · PubMed · Cited by 72
Drug resistance associated with antiangiogenesis therapy
Eikesdal, H. P., & Kalluri, R. (2009) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2009.05.006 · Cited by 69
Gualandris, A., Urbinati, C., Rusnati, M., Ziche, M., & Presta, M. (1994) · Journal of Cellular Physiology · doi:10.1002/jcp.1041610118 · Cited by 62
Weekes, C. D., Hoff, D. D. V., Adjei, A. A., Leffingwell, D. P., Eckhardt, S., Gore, L., Lewis, K. D., Weiss, G. J., Ramanathan, R. K., Dy, G. K., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3529 · Cited by 59
Moffett, J., Kratz, E., Myers, J. M., Stachowiak, E. K., Florkiewicz, R. Z., & Stachowiak, M. K. (1998) · Molecular Biology of the Cell · doi:10.1091/mbc.9.8.2269 · Cited by 57
Self-citationSales, K. J., Boddy, S. C., Williams, A. R. W., Anderson, R. A., & Jabbour, H. N. (2007) · Endocrinology · doi:10.1210/en.2006-1517 · Cited by 38
Jordan, R. M., Patel, S., Hu, H., & Lyons‐Weiler, J. (2008) · Cancer Informatics · doi:10.4137/cin.s791 · Cited by 32
Gyanchandani, R., Sano, D., Alves, M. V. O., Klein, J. D., Knapick, B. A., Oh, S., Myers, J. N., & Kim, S. (2013) · Oral Oncology · doi:10.1016/j.oraloncology.2013.03.452 · Cited by 31
Self-citationKaramouzis, M. V., Friedland, D., Johnson, R., Rajasenan, K. K., Branstetter, B. F., & Argiris, A. E. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2007.25.18_suppl.6049 · Cited by 20
Cited by
Sorted by citations
Resistance Mechanisms to Anti-angiogenic Therapies in Cancer
Haibe, Y., Kreidieh, M., Hajj, H. E., Khalifeh, I. M., Mukherji, D., Temraz, S. N., & Shamseddine, A. I. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00221 · Cited by 430
Current Challenges of Cancer Anti-angiogenic Therapy and the Promise of Nanotherapeutics
Abdalla, A. M. E., Xiao, L., Ullah, M. W., Yu, M., Ouyang, C., & Yang, G. (2018) · Theranostics · doi:10.7150/thno.21674 · Cited by 240
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
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
Cancer combination therapies by angiogenesis inhibitors; a comprehensive review
Ansari, M. J., Bokov, D., Markov, A., Jalil, A. T., Shalaby, M. N., Suksatan, W., Chupradit, S., AL-Ghamdi, H. S., Shomali, N., Zamani, A., et al. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-022-00838-y · Cited by 197
Metadata
- Authors
- Gyanchandani, R., Ortega Alves, M. V., Myers, J. N., & Kim, S.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Authors' Affiliations: Departments of 1Pharmacology and Chemical Biology, and 2 Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and 3Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Corresponding author
- Kim, Seungwon
- Venue
- Molecular Cancer Research
- Published
- 2013-12-01
- Volume
- 11
- Issue
- 12
- Pages
- 1585-1596
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC3955724
- OpenAlex
- W2073944569
- Cited by
- 73
- References
- 44
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 8 · 2021: 8 · 2020: 15 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 5
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American College of Surgeons
- University of Pittsburgh
- Gladstone Ports Corporation
- National Cancer Institute (L30 CA136371)
- National Institute of Dental and Craniofacial Research (K08DE019201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Keywords
- bevacizumab resistance, head and neck squamous cell carcinoma, anti-angiogenic therapy, fibroblast growth factor 2, FGFR3, ERK signaling, PLCγ2, FZD4, fractalkine, RANTES, xenograft models, VEGF-independent angiogenesis, therapeutic target
- MeSH terms
- Bevacizumab, Squamous Cell Carcinoma of Head and Neck, Animals, Carcinoma, Squamous Cell, Drug Therapy, Combination, Female, Head and Neck Neoplasms, Humans, Mice, Nude, Neoplasms, Experimental, Neovascularization, Pathologic, Pyrimidines, Gene Expression Regulation, Neoplastic, Fibroblast Growth Factor 2, Drug Resistance, Neoplasm, Angiogenesis Inhibitors, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
