Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis
Open accessAbstract
Significance: Cancer cells release from their cell surface membrane-lined microvesicles (MVs), which contain proteins, mRNAs, and microRNAs that can be taken up by other cells. We report that breast cancer cells exposed to decreased oxygen availability (hypoxia) increase their production of MVs, which stimulate invasion and metastasis by recipient breast cancer cells. Increased MV shedding by hypoxic cells requires expression of hypoxia-inducible factors (HIFs), which activate transcription of the RAB22A gene, and expression of the small GTPase RAB22A, which is a protein that localizes to budding MVs. Our results delineate a molecular mechanism by which hypoxia increases invasion and metastasis by stimulating MV shedding and provide further evidence that addition of HIF inhibitors to current treatment regimens may improve clinical outcome.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Hypoxic cells up-regulate RAB22A in a HIF-dependent manner to promote microvesicle shedding, invasion, and metastasis.
“Hypoxic cells up-regulate the small guanosine triphosphatase RAB22A in a HIF-dependent manner to promote microvesicle shedding, invasion, and metastasis (106).”
From Hypoxic control of metastasis (2016) · cites this paper as [106]
Cites
5 retracted
Lysyl oxidase is essential for hypoxia-induced metastasis
Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhöfer, N., Kong, C., Le, Q.-T., Chi, J.-T. A., Jeffrey, S. S., & Giaccia, A. J. (2006) · Nature · doi:10.1038/nature04695 · Cited by 1,309 · see citing works
RetractedZhang, H., Wong, C. C. L., Wei, H., Gilkes, D. M., Korangath, P., Chaturvedi, P., Schito, L., Chen, J., Krishnamachary, B., Winnard, P. T., et al. (2012) · Oncogene · doi:10.1038/onc.2011.365 · Cited by 326 · see citing works
Self-citationRetractedRETRACTED: Collagen Prolyl Hydroxylases Are Essential for Breast Cancer Metastasis
Gilkes, D. M., Chaturvedi, P., Bajpai, S., Wong, C. C., Wei, H., Pitcairn, S., Hubbi, M. E., Wirtz, D., & Semenza, G. L. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3963 · Cited by 296 · see citing works
Self-citationRetractedProcollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis
Gilkes, D. M., Bajpai, S., Wong, C. C., Chaturvedi, P., Hubbi, M. E., Wirtz, D., & Semenza, G. L. (2013) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-12-0629 · Cited by 252 · see citing works
Self-citationRetractedGilkes, D. M., Xiang, L., Lee, S. J., Chaturvedi, P., Hubbi, M. E., Wirtz, D., & Semenza, G. L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321510111 · Cited by 184 · see citing works
Self-citationRetractedComprehensive molecular portraits of human breast tumours
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11412 · Cited by 12,129 · see citing works
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · see citing works
Self-citationHypoxia — a key regulatory factor in tumour growth
Harris, A. L. (2002) · Nature Reviews Cancer · doi:10.1038/nrc704 · Cited by 5,177 · see citing works
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET
Peinado, H., Alečković, M., Lavotshkin, S., Matei, I., Costa-Silva, B., Moreno-Bueno, G., Hergueta-Redondo, M., Williams, C., García-Santos, G., Ghajar, C. M., et al. (2012) · Nature Medicine · doi:10.1038/nm.2753 · Cited by 3,715 · see citing works
Rab27a and Rab27b control different steps of the exosome secretion pathway
Ostrowski, M., Carmo, N., Krumeich, S., Fanget, I., Raposo, G., Savina, A., Moita, C. F., Schauer, K., Hume, A. N., Freitas, R. P., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb2000 · Cited by 2,761 · see citing works
Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy
Semenza, G. L. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.01.005 · Cited by 1,514 · see citing works
Self-citationHypoxic enhancement of exosome release by breast cancer cells
King, H. W., Michael, M. Z., & Gleadle, J. M. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-421 · Cited by 1,045 · see citing works
Heterogeneity in breast cancer
Polyák, K. (2011) · Journal of Clinical Investigation · doi:10.1172/jci60534 · Cited by 1,012 · see citing works
Microvesicles: mediators of extracellular communication during cancer progression
Muralidharan-Chari, V., Clancy, J. W., Sedgwick, A., & D’Souza‐Schorey, C. (2010) · Journal of Cell Science · doi:10.1242/jcs.064386 · Cited by 951 · see citing works
Kucharzewska, P., Christianson, H. C., Welch, J. E., Svensson, K. J., Fredlund, E., Ringnér, M., Mörgelin, M., Bourseau-Guilmain, E., Bengzon, J., & Belting, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220998110 · Cited by 939 · see citing works
Exosomes in Tumor Microenvironment Influence Cancer Progression and Metastasis
Kahlert, C., & Kalluri, R. (2013) · Journal of molecular medicine · doi:10.1007/s00109-013-1020-6 · Cited by 842 · see citing works
Brahimi-Horn, M. C., Chiche, J., & Pouysségur, J. (2007) · Journal of Molecular Medicine · doi:10.1007/s00109-007-0281-3 · Cited by 765 · see citing works
Bobrie, A., Krumeich, S., Reyal, F., Recchi, C., Moita, L. F., Seabra, M. C., Ostrowski, M., & Théry, C. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0925 · Cited by 647 · see citing works
Prabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641 · see citing works
Park, J. E., Tan, H. S., Datta, A., Lai, R. C., Zhang, H., Meng, W., Lim, S. K., & Sze, S. K. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m900381-mcp200 · Cited by 582 · see citing works
Timmerman, L. A., Holton, T., Yuneva, M., Louie, R. J., Padró, M., Daemen, A., Hu, M., Chan, D. A., Ethier, S. P., van ‘t Veer, L. J., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.08.020 · Cited by 573 · see citing works
D’Souza‐Schorey, C., & Clancy, J. W. (2012) · Genes & Development · doi:10.1101/gad.192351.112 · Cited by 528 · see citing works
Bos, R., van der Groep, P., Greijer, A. E., Shvarts, A., Meijer, S., Pinedo, H. M., Semenza, G. L., van Diest, P. J., & van der Wall, E. (2003) · Cancer · doi:10.1002/cncr.11246 · Cited by 500 · see citing works
Self-citationAntonyak, M. A., Li, B., Boroughs, L. K., Johnson, J. L., Druso, J. E., Bryant, K. L., Holowka, D. A., & Cerione, R. A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1017667108 · Cited by 497 · see citing works
Tumor hypoxia and malignant progression
Vaupel, P., Mayer, A., & Höckel, M. (2004) · Methods in Enzymology · doi:10.1016/s0076-6879(04)81023-1 · Cited by 496 · see citing works
Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation
Wong, C. C.-L., Gilkes, D. M., Zhang, H., Chen, J., Wei, H., Chaturvedi, P., Fraley, S. I., Wong, C.-M., Khoo, U.-S., Ng, I. O.-L., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113483108 · Cited by 437 · see citing works
GOBO: Gene Expression-Based Outcome for Breast Cancer Online
Ringnér, M., Fredlund, E., Häkkinen, J., Borg, Å., & Staaf, J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017911 · Cited by 421 · see citing works
(2002) · PubMed · Cited by 385 · see citing works
RhoA triggers a specific signaling pathway that generates transforming microvesicles in cancer cells
Li, B., Antonyak, M. A., Zhang, J., & Cerione, R. A. (2012) · Oncogene · doi:10.1038/onc.2011.636 · Cited by 378 · see citing works
Zhang, H., & Grizzle, W. E. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.09.027 · Cited by 352 · see citing works
Liao, D., Corle, C., Seagroves, T. N., & Johnson, R. S. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2701 · Cited by 339 · see citing works
Marino, N., Woditschka, S., Reed, L. T., Nakayama, J., Mayer, M., Wetzel, M., & Steeg, P. S. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.06.012 · Cited by 309 · see citing works
Svensson, K. J., Kucharzewska, P., Christianson, H. C., Sköld, S., Löfstedt, T., Johansson, M. C., Mörgelin, M., Bengzon, J., Ruf, W., & Belting, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1104261108 · Cited by 288 · see citing works
Role of hypoxia-inducible factors in breast cancer metastasis
Gilkes, D. M., & Semenza, G. L. (2013) · Future Oncology · doi:10.2217/fon.13.92 · Cited by 274 · see citing works
Self-citationDalès, J.-P., Garcia, S., Meunier-Carpentier, S., Andrac, L., Haddad, O., Lavaut, M., Allasia, C., Bonnier, P., & Charpin, C. (2005) · International Journal of Cancer · doi:10.1002/ijc.20984 · Cited by 263 · see citing works
Generali, D., Berruti, A., Brizzi, M. P., Campo, L., Bonardi, S., Wigfield, S., Bersiga, A., Allevi, G., Milani, M., Aguggini, S., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-2690 · Cited by 250 · see citing works
Chaturvedi, P., Gilkes, D. M., Wong, C. C., Gupta, K., Luo, W., Zhang, H., Wei, H., Takano, N., Schito, L., Levchenko, A., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci64993 · Cited by 241 · see citing works
Self-citationInsight into the heterogeneity of breast cancer through next-generation sequencing
Russnes, H. G., Navin, N. E., Hicks, J. B., & Børresen‐Dale, A. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57088 · Cited by 240 · see citing works
Luo, W., Chang, R., Zhong, J., Pandey, A., & Semenza, G. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217394109 · Cited by 228 · see citing works
Self-citationWong, C. C., Zhang, H., Gilkes, D. M., Chen, J., Wei, H., Chaturvedi, P., Hubbi, M. E., & Semenza, G. L. (2012) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0855-y · Cited by 224 · see citing works
Self-citationSchito, L., Rey, S., Tafani, M., Zhang, H., Wong, C. C.-L., Russo, A., Russo, M. A., & Semenza, G. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1214019109 · Cited by 224 · see citing works
Self-citationWysoczynski, M., & Ratajczak, M. Z. (2009) · International Journal of Cancer · doi:10.1002/ijc.24479 · Cited by 216 · see citing works
Hypoxia and adaptive landscapes in the evolution of carcinogenesis
Gillies, R. J., & Gatenby, R. A. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9065-z · Cited by 213 · see citing works
Dunn, L. K., Mohammad, K. S., Fournier, P. G. J., McKenna, C. R., Davis, H. W., Niewolna, M., Peng, X. H., Chirgwin, J. M., & Guise, T. A. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006896 · Cited by 212 · see citing works
Chaturvedi, P., Gilkes, D. M., Wong, C. C. L., Kshitiz, K., Luo, W., Zhang, H., Wei, H., Takano, N., Schito, L., Levchenko, A., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69244 · Cited by 181 · see citing works
Self-citationNegative Regulation of Hypoxic Responses via Induced Reptin Methylation
Lee, J. S., Kim, Y.-H., Kim, I. S., Kim, B., Choi, H. J., Lee, J. M., Shin, H. R., Kim, J. H., Kim, J.-Y., Seo, S., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.06.008 · Cited by 167 · see citing works
Self-citationElevated concentration of microvesicles isolated from peripheral blood in breast cancer patients
Galindo-Hernandez, O., Villegas-Comonfort, S., Candanedo, F., González-Vázquez, M.-C., Chavez-Ocaña, S., Jimenez-Villanueva, X., Sierra-Martinez, M., & Salazar, E. P. (2013) · Archives of Medical Research · doi:10.1016/j.arcmed.2013.03.002 · Cited by 152 · see citing works
Helczynska, K., Larsson, A.-M., Holmquist Mengelbier, L., Bridges, E., Fredlund, E., Borgquist, S., Landberg, G., Påhlman, S., & Jirström, K. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1135 · Cited by 136 · see citing works
Xiang, L., Gilkes, D. M., Chaturvedi, P., Luo, W., Hu, H., Takano, N., Liang, H., & Semenza, G. L. (2014) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1102-5 · Cited by 114 · see citing works
Self-citationDirect Targeting of Rab‐GTPase–Effector Interactions
Spiegel, J., Cromm, P. M., Itzen, A., Goody, R. S., Grossmann, T. N., & Waldmann, H. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201308568 · Cited by 86 · see citing works
c- erb B-2 Related Aggressiveness in Breast Cancer Is Hypoxia Inducible Factor-1α Dependent
Giatromanolaki, A. N., Koukourakis, M. I., Simopoulos, C., Polychronidis, A., Gatter, K. C., Harris, A. L., & Sivridis, E. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1068 · Cited by 81 · see citing works
Bendinelli, P., Maroni, P., Matteucci, E., Luzzati, A., Perrucchini, G. G., & Desiderio, M. A. (2013) · European Journal of Cancer · doi:10.1016/j.ejca.2013.03.002 · Cited by 66 · see citing works
Breast Tumor Kinase (Brk/PTK6) Is a Mediator of Hypoxia-Associated Breast Cancer Progression
Anderson, T. M. R., Peacock, D. L., Daniel, A. R., Hubbard, G. K., Lofgren, K. A., Girard, B. J., Schörg, A., Hoogewijs, D., Wenger, R. H., Seagroves, T. N., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-0523 · Cited by 58 · see citing works
Vesicle trafficking and RNA transfer add complexity and connectivity to cell-cell communication.
Roberts, C., & Kurre, P. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-0265 · Cited by 45 · see citing works
Melillo, G. (2013) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-1-4614-9167-5 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Shedding light on the cell biology of extracellular vesicles
van Niel, G., D'Angelo, G., & Raposo, G. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.125 · Cited by 8,369 · see citing works
Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles
Colombo, M., Raposo, G., & Théry, C. (2014) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-101512-122326 · Cited by 6,186 · 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
Rankin, E. B., & Giaccia, A. J. (2016) · Science · doi:10.1126/science.aaf4405 · Cited by 1,340 · see citing works
The hypoxic tumor microenvironment: A driving force for breast cancer progression
Semenza, G. L. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.05.036 · Cited by 535 · see citing works
Self-citationZhang, H., Lu, H., Xiang, L., Bullen, J. W., Zhang, C., Samanta, D., Gilkes, D. M., He, J., & Semenza, G. L. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520032112 · Cited by 420 · see citing works
Self-citationHIFs, angiogenesis, and metabolism: Elusive enemies in breast cancer
de Heer, E. C., Jalving, M., & Harris, A. L. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137552 · Cited by 372 · see citing works
Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence
Vissers, M. C. M., & Das, A. B. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00809 · Cited by 188 · see citing works
Song, J., Miermont, A., Lim, C. T., & Kamm, R. D. (2018) · Scientific Reports · doi:10.1038/s41598-018-36381-5 · Cited by 87 · see citing works
Zhang, H., Du, Z., Tu, C., Zhou, X., Menu, E., & Wang, J. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-0189 · Cited by 17 · see citing works
- Authors
- Wang, T., Gilkes, D. M., Takano, N., Xiang, L., Luo, W., Bishop, C. J., Chaturvedi, P., Green, J. J., & Semenza, G. L.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Vascular Program, Institute for Cell Engineering,
- Biomedical Engineering,
- Pediatrics and Genetics (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-06-17
- Volume
- 111
- Issue
- 31
- Pages
- E3234-42
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4128139
- OpenAlex
- W2098364791
- Cited by
- 493
- References
- 55
- Citations by year
- 2026: 8 · 2025: 25 · 2024: 42 · 2023: 39 · 2022: 54 · 2021: 63 · 2020: 63 · 2019: 54 · 2018: 48 · 2017: 29 · 2016: 30 · 2015: 31 · 2014: 7
- FWCI
- 13.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01eb016721-05)
- National Cancer Institute (U54CA143868, R00CA168746, K99CA168746, K99CA181352)
- National Institute of Biomedical Imaging and Bioengineering (R01-EB016721)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- hypoxia-inducible factor, RAB22A, microvesicles, breast cancer, tumor hypoxia, extracellular vesicles, exosomes, metastasis, tumor invasion, focal adhesions, small GTPases, tumor microenvironment, metastasis-free survival
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Breast Neoplasms, Extracellular Matrix, Female, Humans, Lung Neoplasms, Neoplasm Invasiveness, Neoplasm Metastasis, RNA, Messenger, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Survival Analysis, Mice, SCID, rab GTP-Binding Proteins, Protein Transport, Focal Adhesions, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Exosomes, Gene Knockdown Techniques
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
