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Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis
Open accessAbstract
Expression of HPV16 early region genes in basal keratinocytes of transgenic mice elicits a multistage pathway to squamous carcinoma. We report that infiltration by mast cells and activation of the matrix metalloproteinase MMP-9/gelatinase B coincides with the angiogenic switch in premalignant lesions. Mast cells infiltrate hyperplasias, dysplasias, and invasive fronts of carcinomas, but not the core of solid tumors, where they degranulate in close apposition to capillaries and epithelial basement membranes, releasing mast-cell-specific serine proteases MCP-4 (chymase) and MCP-6 (tryptase). MCP-6 is shown to be a mitogen for dermal fibroblasts that proliferate in the reactive stroma, whereas MCP-4 can activate progelatinase B and induce hyperplastic skin to become angiogenic in an in vitro bioassay. Notably, premalignant angiogenesis is abated in a mast-cell-deficient (KITW/KITWWv) HPV16 transgenic mouse. The data indicate that neoplastic progression in this model involves exploitation of an inflammatory response to tissue abnormality. Thus, regulation of angiogenesis during squamous carcinogenesis is biphasic: In hyperplasias, dysplasias, and invading cancer fronts, inflammatory mast cells are conscripted to reorganize stromal architecture and hyperactivate angiogenesis; within the cancer core, upregulation of angiogenesis factors in tumor cells apparently renders them self-sufficient at sustaining neovascularization.
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“Genetic and functional experiments indicate that neutrophils, mast cells, eosinophils and activated T lymphocytes also contribute to malignancies by releasing extracellular proteases, pro-angiogenic factors and chemokines11,23–26.”
From Inflammation and cancer (2002) · cites this paper as [24]
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Mast Cells, Angiogenesis and Cancer
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“Thus, γδ T cells protect against malignant conversion of chemically induced skin tumors (35), and infiltration of mast cells in premalignant lesions enhances angiogenesis and malignant conversion of HPV-16-induced cutaneous neoplasms ( 36 ).”
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“Third, certain tumors may also attract differentiated haematopoietic cells, including mast cells, monocytes, macrophages, and inflammatory cells (Coussens et al., 1999).”
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“Pre-adipocytes migrate to sites of neovascularization and adipose tissue is highly angiogenic (Coussens et al 1999).”
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“Further, mast cells have previously been shown to support SCC growth in tumour models driven by human papilloma virus (Coussens et al., 1999; Bergot et al., 2014) and indeed may contribute to the tumour promotion shown in our study.”
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“Proteinases of the plasminogen activator and MMPs degrade matrix molecules and thus liberate growth factors sequestered within the extracellular matrix (26).”
BackgroundChymase mediates mast cell-induced angiogenesis in hamster sponge granulomas
Muramatsu, M., Katada, J., Hattori, M., Hayashi, I., & Majima, M. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00350-2 · Cited by 64
TIMP-1 Alters Susceptibility to Carcinogenesis
Rhee, J.-S., Diaz, R. J., Korets, L. V., Hodgson, J., & Coussens, L. M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-2445 · Cited by 64
“Because TIMP-1 can regulate recruitment of inflammatory cells and activation of angiogenesis in some contexts (4, 32), and because we have previously reported inflammation and angiogenesis to be rate-limiting stage-specific characteristics of neoplastic progression in HPV16 transgenic mice (26, 27, 50), we also assess…”
BackgroundSelf-citationDöme, B., Tı́már, J., Ladányi, A., Paku, S., Renyi-Vamos, F., Klepetko, W., Láng, G., Döme, P., Bogos, K., & Tóvári, J. (2008) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2008.06.009 · Cited by 63
“Finally, reduction of tumor MC density/function as been shown to inhibit angiogenesis and, therefore, tumor rowth [97,98].”
BackgroundHuman Macrophages Promote the Motility and Invasiveness of Osteopontin-Knockdown Tumor Cells
Chéng, J., Huo, D.-H., Kuang, D., Yang, J., Zheng, L., & Zhuang, S. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4763 · Cited by 63
“For example, recent studies have shown that the outcome of primary oncogenic events in epithelial cells can be significantly modified by the nature of the surrounding nonmalignant cells (7, 8), indicating that these stromal cells can serve as novel intervention targets.”
ResultYu, Y., & Merlino, G. T. (2002) · PubMed · Cited by 64
Bennett, J. L., Blanchet, M., Zhao, L., Zbytnuik, L. D., Antignano, F., Gold, M., Kubes, P., & McNagny, K. M. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0801485 · Cited by 63
Jayshree, R. S. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.649815 · Cited by 67
“Infiltration of inflammatory cells into the tumors has also been observed in the K14HPV16 transgenic mouse model of CxCa (Coussens et al., 1999).”
BackgroundSugimoto, K., Kudo, M., Sundaram, A., Ren, X., Huang, K., Bernstein, X., Wang, Y., Raymond, W. W., Erle, D. J., Åbrink, M., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58815 · Cited by 63
Self-citationHost Myeloid Cells Are Necessary for Creating Bioengineered Human Vascular Networks In Vivo
Melero‐Martin, J. M., Obaldia, M. E. D., Allen, P., Dudley, A. C., Klagsbrun, M., & Bischoff, J. E. (2010) · Tissue Engineering Part A · doi:10.1089/ten.tea.2010.0024 · Cited by 62
Gokuladhas, K., Jayakumar, S., Subramani, P. C., Muralidharan, B., & Devaki, T. (2017) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2017.04.001 · Cited by 62
Pilkington, S. M., Barron, M. J., Watson, R. E. B., Griffiths, C. E. M., & Bulfone‐Paus, S. (2018) · British Journal of Dermatology · doi:10.1111/bjd.17268 · Cited by 64
Role of the tumor microenvironment in cancer hallmarks and targeted therapy (Review)
Naser, R., Fakhoury, I., El‑Fouani, A., Abi‑Habib, R., & El‑Sibai, M. (2022) · International Journal of Oncology · doi:10.3892/ijo.2022.5471 · Cited by 61
Mlącki, M., Darido, C., Jane, S. M., & Wilanowski, T. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089247 · Cited by 61
“These are known to support the development of SCC [26].”
BackgroundThe roles and role-players in thyroid cancer angiogenesis
Rajabi, S., Dehghan, M. H., Dastmalchi, R., Mashayekhi, F. J., Salami, S., & Hedayati, M. (2019) · Endocrine Journal · doi:10.1507/endocrj.ej18-0537 · Cited by 63
“Subsequently, the release of growth factors during proteolytic degradation and remodeling of the temporary matrix leads to proliferation and migration of endothelial cells [52].”
BackgroundERK5 Is a Critical Mediator of Inflammation-Driven Cancer
Finegan, K. G., Madrigal, D. P., Hitchin, J. R., Davies, C. C., Jordan, A. M., & Tournier, C. (2015) · Cancer Research · doi:10.1158/0008-5472.can-13-3043 · Cited by 63
“Together, our results are consistent with evidence that neutrophil recruitment is a prerequisite to the establishment of a chronic inflammatory microenvironment and thatmice deficient inmast cells are resistant to skin carcinogenesis (21).”
ResultPleiotrophin induces formation of functional neovasculature in vivo
Christman, K. L., Fang, Q., Kim, A. J., Sievers, R. E., Fok, H. H., Candia, A. F., Colley, K. J., Herradón, G., Ezquerra, L., Deuel, T. F., et al. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.04.174 · Cited by 60
van Dijk, R. A., Rijs, K., Wezel, A., Hamming, J. F., Kolodgie, F. D., Virmani, R., Schaapherder, A. F., & Lindeman, J. H. N. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.002860 · Cited by 59
Mast Cells in Liver Fibrogenesis
Weiskirchen, R., Meurer, S. K., Liedtke, C., & Huber, M. (2019) · Cells · doi:10.3390/cells8111429 · Cited by 60
“MCs are also known to modulate the growth/metastasis of certain solid tumors [27] and can contribute to the development of various fibrotic diseases [28].”
BackgroundDefinition of the Extended Substrate Specificity Determinants for β-Tryptases I and II
Harris, J. L., Niles, A. L., Burdick, K. W., Maffitt, M., Backes, B. J., Ellman, J. A., Kuntz, I. D., Haak‐Frendscho, M., & Craik, C. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102997200 · Cited by 59
Xu, W., Qian, J., Zeng, F., Li, S., Guo, W., Chen, L., Li, G., Zhang, Z., Wang, Q. J., & Deng, F. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1118-y · Cited by 58
Sammarco, G., Gallo, G., Vescio, G., Picciariello, A., Paola, G. D., Trompetto, M., Currò, G., & Ammendola, M. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9092852 · Cited by 58
“Thus, they are recruited in the initial step of tumorigenesis, promoting the angiogenic switch [37] through the release of anti- or pro-angiogenetic”
BackgroundChen, W., Li, F., Mead, L. E., White, H. A., Walker, J. J., Ingram, D. A., & Roman, A. (2007) · Virology · doi:10.1016/j.virol.2007.05.030 · Cited by 57
“The magnitude of an angiogenic response depends upon a complex set of interactions within the microenvironment (Coussens et al., 1999; Mueller and Fusenig, 2004; Zhu et al., 2002).”
BackgroundImmunohistochemical evaluation of mast cells and angiogenesis in oral squamous cell carcinoma
Sivapathasundharam, B., Sharma, B., Sriram, G., & Saraswathi, T. (2010) · Indian Journal of Dental Research · doi:10.4103/0970-9290.66655 · Cited by 57
Immuno-oncology-101: overview of major concepts and translational perspectives
Allard, B., Aspeslagh, S., Garaud, S., Dupont, F., Solinas, C., Kok, M., Routy, B., Sotiriou, C. P., Stagg, J., & Buisseret, L. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.02.005 · Cited by 60
Polyamines Are Present in Mast Cell Secretory Granules and Are Important for Granule Homeostasis
García‐Faroldi, G., Rodríguez, C. E., Urdiales, J. L., Pérez-Pomares, J. M., Dávila, J. C., Pejler, G., Sánchez‐Jiménez, F., & Fajardo, I. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015071 · Cited by 56
“However, mast cells are best known for their implication in a large number of physio-pathological settings, including allergy, asthma, atherosclerosis, inflammatory arthritis, multiple sclerosis and cancer [2–7].”
Hirshberg, A., Lib, M., Kozlovsky, A., & Kaplan, I. (2006) · Oral Oncology · doi:10.1016/j.oraloncology.2006.03.019 · Cited by 56
Ras regulation of vascular endothelial growth factor and angiogenesis
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Dermond, O., & Rüegg, C. (2001) · Drug Resistance Updates · doi:10.1054/drup.2001.0219 · Cited by 56
Kolesnikoff, N., Chen, C.-H., & Samuel, M. S. (2022) · Clinical Science · doi:10.1042/cs20210679 · Cited by 55
Wang, Y., Yuan, A.-J., Wu, Y., Wu, L., & Zhang, L. (2022) · Journal of Functional Foods · doi:10.1016/j.jff.2022.105384 · Cited by 54
Tumor diagnosis using carbon-based quantum dots: Detection based on the hallmarks of cancer
Wang, H., Yang, S., Chen, L., Li, Y., He, P., Wang, G., Dong, H., Ma, P., & Ding, G. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.10.004 · Cited by 55
“A second general group of substances involved in invasion and metastasis capacity are extracellular proteases: protease genes become up-regulated, protease inhibitor genes down-regulated, and the non-active zymogen forms of proteases converted to active enzymes [396,397].”
BackgroundTowards Understanding the Role of Cancer-Associated Inflammation in Chemoresistance
de Visser, K. E., & Jonkers, J. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209788453239 · Cited by 56
“Many groups are studying the complex mechanisms underlying the link between chronic inflammation and cancer [23-30].”
BackgroundKoudstaal, T., Boomars, K. A., & Kool, M. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9020561 · Cited by 54
Metadata
- Authors
- Coussens, L. M., Raymond, W. W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., Caughey, G. H., & Hanahan, D.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1999-06-01
- Volume
- 13
- Issue
- 11
- Pages
- 1382-1397
- ISSN
- 0890-9369 (ISSN-L)
- PMC
- PMC316772
- OpenAlex
- W2146440075
- Cited by
- 946
- References
- 87
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 11 · 2023: 13 · 2022: 27 · 2021: 18 · 2020: 29 · 2019: 31 · 2018: 27 · 2017: 29 · 2016: 39 · 2015: 32 · 2014: 52 · 2013: 32 · 2012: 49
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 24136, P01HL024136)
- National Cancer Institute (CA72006, P01CA072006)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- mast cells, angiogenesis, squamous cell carcinoma, HPV16, keratinocytes, MMP-9, chymase, tryptase, precancerous lesions, dermal fibroblasts, tumor stroma, inflammation, carcinogenesis, neovascularization
- MeSH terms
- Animals, Carcinoma, Squamous Cell, Extracellular Matrix, Humans, Mast Cells, Mice, Transgenic, Neovascularization, Pathologic, Serine Endopeptidases, Up-Regulation, Inflammation Mediators, Mice, Tryptases, Chymases
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