Cited by 946Angiogenesis and VEGF in CancerMast cells and histamineProtease and Inhibitor Mechanisms

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Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis

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Coussens, L. M., Raymond, W. W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., Caughey, G. H., Hanahan, D.·1999·Genes & Development

DOI 10.1101/gad.13.11.1382PMC PMC316772

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Abstract

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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Effect of aerobic exercise on immunoglobulins and anemia after chemotherapy in breast cancer patients
Ashem, H. N., Hamada, H. A., & Abbas, R. L. (2020) · Journal of Bodywork and Movement Therapies · doi:10.1016/j.jbmt.2020.01.001 · Cited by 9
Effect of radiotherapy on expression of hyaluronan and EGFR and presence of mast cells in squamous cell carcinoma of the head and neck
Jonsson, E. L., Nylander, K., HALLÉN, L., & Laurell, G. F. E. (2012) · Oncology Letters · doi:10.3892/ol.2012.907 · Cited by 9
“There is an established correlation between chronic inflammation and cancer (35) and mast cells are known to contribute to pre-malignant progression (36-39).”
Metaloproteinases: aspectos fisiopatológicos sistêmicos e sua importância na cicatrização
Araújo, R. V. D. S., Silva, F. O., de Melo-Júnior, M. R., & Porto, A. L. F. (2011) · Revista de Ciências Médicas e Biológicas · doi:10.9771/cmbio.v10i1.5470 · Cited by 9
Increased Mast Cell Counts in Benign and Malignant Salivary Gland Tumors
Jaafari‐Ashkavandi, Z., & Ashraf, M. J. (2014) · PubMed Central · doi:10.5681/joddd.2014.003 · Cited by 9
Mast Cells in Allergy and Tumor Disease
Wasiuk, A., de Vries, V. C., Nowak, E. C., & Noelle, R. J. (2009) · Humana Press eBooks · doi:10.1007/978-1-60761-451-7_6 · Cited by 9
“matrix metalloproteinase (MMP)-9 coincided with the angiogenic switch in early tumor lesions [92].”
Background
Squamous cell carcinoma and dental implants: A systematic review of case reports
Jeelani, S. A., Rajkumar, E., Mary, G., Khan, P., Gopal, H., Roy, S., Maheswaran, T., & Anand, B. (2015) · Journal of Pharmacy And Bioallied Sciences · doi:10.4103/0975-7406.163457 · Cited by 9
“[13] 14-20]”
Bone Marrow Angiogenesis in Systemic Mast Cell Disease
Baek, J.-Y., Li, C., Pardanani, A. D., Butterfield, J. H., & Tefferi, A. (2002) · Stem Cells and Development · doi:10.1089/152581602753448603 · Cited by 9
“Furthermore, both experimental and clinical data suggest that increased mast cell infiltration of tumor tissue may facilitate disease progression and may be associated with shortened patient survival (17,23,27,28).”
Human Mast Cell and Basophil/Eosinophil Progenitors
Gauvreau, G. M., & Denburg, J. A. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-1568-2_4 · Cited by 9
Argininosuccinate synthase as a novel biomarker for inflammatory conditions
Cao, M., George, T. J., Prima, V., Nelson, D. R., & Svetlov, S. I. (2013) · Biomarkers · doi:10.3109/1354750x.2013.773080 · Cited by 8
“However, during later tumor growth, it appears proinflammatory factors, such as MMPs, come under direct control by the tumors themselves (Coussens et al., 1999).”
BackgroundInfluential
Adipocytes, mast cells and angiogenesis
Ribatti, D., Annese, T., & Tamma, R. (2021) · Romanian Journal of Morphology and Embryology · doi:10.47162/rjme.61.4.07 · Cited by 9
“Mast cells infiltrate and MMP-9 activation coincided with the angiogenic switch in premalignant lesions, and premalignant angiogenesis was abrogated in a mast cell-deficient HPV16 transgenic mouse [68, 69].”
Background
The tumor microenvironment as a target for anticancer treatment
Bizzarri, M., Cucina, A., & Proietti, S. (2014) · Oncobiology and Targets · doi:10.4103/2395-4469.145341 · Cited by 8
“[29] In turn, tissue fibrosis and modification of physical‐chemical properties of ECM may likely influence tumor onset and progression by regulating soluble factors involved in inflammation[30] and angiogenesis.[31]”
Background
Purification of Immune Cell Populations from Freshly Isolated Murine Tumors and Organs by Consecutive Magnetic Cell Sorting and Multi-parameter Flow Cytometry-Based Sorting
Salvagno, C., & de Visser, K. E. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3801-8_10 · Cited by 8
Insights into Early-Pregnancy Mechanisms: Mast Cells and Chymase CMA1 Shape the Phenotype and Modulate the Functionality of Human Trophoblast Cells, Vascular Smooth-Muscle Cells and Endothelial Cells
Zhang, N., Schumacher, A., Fink, B., Bauer, M., Zenclussen, A. C., & Meyer, N. (2022) · Cells · doi:10.3390/cells11071158 · Cited by 8
“Another study indicated that chymase may induce angiogenesis by activating MMP9 to regulate ECM remodeling [86].”
Background
Mast Cells and Tumor Microenvironment
Theoharides, T. C., Alysandratos, K., Angelidou, A., & Zhang, B. (2010) · Springer eBooks · doi:10.1007/978-1-4419-6615-5_17 · Cited by 8
“…of mast cells has been shown repeatedly with the use of W/W v mast cell deficient mice, which developed fewer lung metastases to subcutaneous B16-BL6 tumors (Starkey et al. 1988), and in which mice premalignant angiogenesis of squamous epithelial carcinogenesis was blocked (Coussens et al. 1999).”
Background
Regulation of colon gene expression by vitamin B 6 supplementation
Toya, K., Hirata, A., Ohata, T., Sanada, Y., Katô, N., & Yanaka, N. (2012) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201100707 · Cited by 8
Impact of immunodeficiency on lingual carcinogenesis and lymph node metastasis in mice
Wang, S., Li, F., Dongxia, Q., Hu, Z., Meng, Y., Shi, L., Zhao, E., & Niu, Y. (2019) · Journal of Oral Pathology and Medicine · doi:10.1111/jop.12916 · Cited by 8
Proteolysis in Carcinogenesis
Bugge, T. H. (2003) · Elsevier eBooks · doi:10.1016/b978-012239990-9/50011-4 · Cited by 8
Reduction with dithiothreitol causes serglycin-specific defects in secretory granule integrity of bone marrow derived mast cells
Braga, T., Ringvall, M., Tveit, H., Åbrink, M., & Pejler, G. (2008) · Molecular Immunology · doi:10.1016/j.molimm.2008.10.019 · Cited by 8
Activated Akt-1 in specific cell populations during multi-stage skin carcinogenesis.
Affara, N. I., Schanbacher, B. L., Mihm, M. J., Cook, A. C., Pei, P., Mallery, S. R., Trempus, C. S., Bauer, J. A., & Robertson, F. M. (2004) · PubMed · Cited by 8
Mast cells and ocular surface: An update review
Barone, V., Scirocco, L., Surico, P. L., Micera, A., Cutrupi, F., Coassin, M., & Zazzo, A. D. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.109982 · Cited by 8
Simultaneous demonstration of mast cells and blood vessels by the combined method CD34--alcian blue-safranin in lip tumors.
Gaje, P. N., Bocan, E. V., Cîmpean, A. M., Izvernariu, D. A., Streian, F., & Raica, M. (2007) · PubMed · Cited by 7
Association of expression of inflammatory response genes and DNA repair genes in colorectal carcinoma
Germini, D. E., Franco, M. I. F., Fonseca, F. L. A., Gehrke, F. D. S., Alves, B. D. C. A., Cardili, L., Oshima, C. T. F., Theodoro, T. R., & Waisberg, J. (2019) · Tumor Biology · doi:10.1177/1010428319843042 · Cited by 7
Characterizing the Inflammatory Microenvironment in K14-HPV16 Transgenic Mice: Mast Cell Infiltration and MicroRNA Expression
Costa, A. C., Santos, J., Medeiros‐Fonseca, B., Oliveira, P. A., Bastos, M. M. S. M., Brito, H. O., da Costa, R. M. G., & Medeiros, R. (2022) · Cancers · doi:10.3390/cancers14092216 · Cited by 7
“In K14-HPV16 mice, it was shown that cutaneous mast cells release proteases and reorganize stromal architecture and hyperactivate angiogenesis [43].”
Background
Specific intraepithelial localization of mast cells in differentiated vulvar intraepithelial neoplasia and its possible contribution to vulvar squamous cell carcinoma development
van de Nieuwenhof, H. P., Hebeda, K. M., Bulten, J., Otte‐Höller, I., Massuger, L. F. A. G., de Hullu, J. A., & van Kempen, L. C. L. T. (2010) · Histopathology · doi:10.1111/j.1365-2559.2010.03635.x · Cited by 7
“fibroblast activation, extracellular matrix remodelling and activation of angiogenesis.(16,17) In order to find similarities and differences in the composition of the inflammatory response in vulvar premalignancy (LS and dVIN) and vulvar SCC that can support our hypothesis, we have quantified a subset of inflammatory…”
Result
Three‐Dimensional Visualization of Blood and Lymphatic Vasculature in Tissue Whole Mounts Using Confocal Microscopy
Eichten, A., Shen, H., & Coussens, L. M. (2005) · Current Protocols in Cytometry · doi:10.1002/0471142956.cy1205s32 · Cited by 7
Self-citation
Relationship between Numerous Mast Cells and Early Follicular Development in Neonatal MRL/MpJ Mouse Ovaries
Nakamura, T., Otsuka, S., Ichii, O., Sakata, Y., Nagasaki, K., Hashimoto, Y., & Kon, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077246 · Cited by 7
Fibrosis and Mast Cells in Colorectal Lesions: Significance in Adenoma-Colorectal Cancer Sequence and Association with Diet
Alves, I. S. S., Coser, P. H. P., Loureiro, G. J. Z., da Gama, L. P. N., Ribeiro, F. D. S. S., Bautz, W. G., Coburn, K. L. A., Pacheco, M. D. S., & da Gama-de-Souza, L. N. (2016) · Journal of Gastrointestinal Cancer · doi:10.1007/s12029-016-9829-1 · Cited by 7
“, chymase and tryptase secretion by cells is an important aspect in tissue remodeling [25].”
Background
The Development of Blood Vessels: Cellular and Molecular Mechanisms
Carmeliet, P. (2002) · Birkhäuser Boston eBooks · doi:10.1007/978-1-4612-0109-0_1 · Cited by 7
Involvement of mast cells in the regulation of matrix metalloproteinase-9 and tissue inhibitor of metalloproteases-1 in 12-O-tetradecanoylphorbolacetate-induced inflammation in mice
Iba, Y., Shirai, M., Dei, C., Hirata, T., Harada, C., & Masukawa, T. (2007) · International Immunopharmacology · doi:10.1016/j.intimp.2006.12.012 · Cited by 7
Quiescent Hypervascularity Mediated by Gain of HIF-1 FunctionPreprint
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The role of innate immune cells in modulating vascular dynamics in skin malignancies
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Innate Immunity and Platelets: Unveiling Their Role in Chronic Pancreatitis and Pancreatic Cancer
Blümke, J., Schameitat, M., Verma, A., Limbecker, C., Arlt, E., Kessler, S. M., Kielstein, H., Krug, S., Bazwinsky‐Wutschke, I., & Hämmerle, M. (2025) · Cancers · doi:10.3390/cancers17101689 · Cited by 7
“Therefore, they contributed significantly to the angiogenic switch during tumor progression [150,151].”
TRIP13: A promising cancer immunotherapy target
Jing, S., Zhao, L., Zhao, L., Gao, Y., & He, T. (2024) · Cancer Innovation · doi:10.1002/cai2.147 · Cited by 6
“Mast cells, myeloid ‐ derived suppressor cells, and monocytes have been associated with an inflammatory microenvironment that promotes tumor growth [57, 74, 75].”
Session 2: Inflammation and Cancer
(2004) · Toxicologic Pathology · doi:10.1080/01926230490882402 · Cited by 6

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)
ORCID: Coussens, L. M.
Bergers, G.
Werb, Z.
Caughey, G. H.
Hanahan, D.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 1999-06-01
Volume: 13
Issue: 11
Pages: 1382-1397
ISSN: 0890-9369 (ISSN-L)
DOI: 10.1101/gad.13.11.1382
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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Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis

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