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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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“Yet other studies have not detected MMP-9 despite the presence of mast cells in normal skin (44).”
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“, 1995) and because mast cells have recently been demonstrated to have a key role in skin angiogenesis (Detmar et al., 1998; Coussens et al., 1999).”
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“Proteinases also liberate matrix-bound angiogenic growth factors, such as FGF-2, VEGF, insulin-like growth factor-1 (IGF-1), transforming growth factor-β (TGF-β) and tumour necrosis factor-α (TNF-α), and proteolytically activate angiogenic chemokines such as interleukin-1β (IL-1β; Coussens et al. 1999; Bergers et al.…”
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“For example, when inducing squamous epithelial carcinogenesis in these mice, neoplastic growth was attenuated in comparison to MCproficient littermates, mostly by a lower activation of the angiogenic vasculature and a failure of keratinocytes to reach hyperproliferative growth characteristics [32].”
BackgroundKhan, N., Syed, D. N., Pal, H. C., Mukhtar, H., & Afaq, F. (2012) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.2011.01063.x · Cited by 96
“expressing MMP-9 may trigger neoplastic transformation during squamous epithelial carcinogenesis (22).”
BackgroundTryptase-positive mast cells correlate with angiogenesis in early breast cancer patients
Ranieri, G. (2009) · International Journal of Oncology · doi:10.3892/ijo_00000319 · Cited by 95
“Tryptase is one of the most powerful angiogenic mediators released by human MCs and it may be angiogenic via several mechanisms (23-26).”
BackgroundMatrix Metalloproteinase-9 Functions as a Tumor Suppressor in Colitis-Associated Cancer
Garg, P., Sarma, D. S. R., Jeppsson, S., Patel, N. R., Gewirtz, A. T., Merlin, D., & Sitaraman, S. V. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3166 · Cited by 95
“stimulate cancer progression due to the release of MMPs from the inflammatory cells (29, 30).”
BackgroundRole and Significance of c-KIT Receptor Tyrosine Kinase in Cancer: A Review
Sheikh, E., Tran, T. T., Vranić, S., Levy, A., & Bonfil, R. D. (2022) · Bosnian Journal of Basic Medical Sciences · doi:10.17305/bjbms.2021.7399 · Cited by 105
Mast cell tryptase may modulate endothelial cell phenotype in healing myocardial infarcts
Somasundaram, P. E., Ren, G., Nagar, H., Kraemer, D., Mendoza, L. H., Michael, L. H., Caughey, G. H., Entman, M. L., & Frangogiannis, N. G. (2004) · The Journal of Pathology · doi:10.1002/path.1690 · Cited by 95
“Although mast cells are capable of modulating fibrosis and angiogenesis [30–33], both critical events in tissue repair, direct evidence supporting a crucial role for mast cells in healing wounds is lacking.”
BackgroundSelf-citationHan, Y., Yan, C., Zhou, L., Lan, Q., & Tsukamoto, H. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700554200 · Cited by 94
A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss
Lozano‐Ondoua, A. N., Wright, C., Vardanyan, A., King, T. E., Largent‐Milnes, T. M., Nelson, M. A., Jiménez‐Andrade, J. M., Mantyh, P. W., & Vanderah, T. W. (2010) · Life Sciences · doi:10.1016/j.lfs.2010.02.014 · Cited by 99
“…by producing pro-angiogenic factors such as cytokines, chemokines, VEGF and proteases (Condeelis and Pollard 2006; Theoharides and Conti 2004; Coussens et al. 1999; Lin and Pollard 2007; Ribatti et al. 2001; Ribatti et al. 2004; Benelli et al. 2003; Sinha et al. 2007; DePalma et al. 2005;…”
Cathepsin C is a tissue-specific regulator of squamous carcinogenesisPreprint
Ruffell, B., Affara, N. I., Cottone, L., Junankar, S. R., Johansson, M., DeNardo, D. G., Korets, L. V., Reinheckel, T., Sloane, B. F., Bogyo, M. S., et al. (2013) · Genes & Development · doi:10.1101/gad.224899.113 · Cited by 95
“Tissue specificity is a significant determinant of expression and activity for multiple classes of proteolytic enzymes, an issue that befuddled clinical trials of matrix metalloproteinase (MMP) inhibitors (Coussens et al. 2002).”
BackgroundSelf-citationLymphatic Vessels, Inflammation, and Immunity in Skin Cancer
Lund, A. W., Medler, T. R., Leachman, S. A., & Coussens, L. M. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0023 · Cited by 97
“Lymphatic capillaries are anchored directly to the ECM through anchoring filaments, such that under high levels of IFP, stretching of ECM results in distension of initial capillaries and enhanced fluid flows and cellular trafficking both by intercellular and transcellular mechanisms.”
BackgroundInfluentialSelf-citationThe Role of Mast Cells in Molding the Tumor Microenvironment
Rigoni, A., Colombo, M. P., & Pucillo, C. E. M. (2014) · Cancer Microenvironment · doi:10.1007/s12307-014-0152-8 · Cited by 93
“This process lasts until cancer cells become capable to autonomously produce pro-angiogenetic factors [75].”
Samoszuk, M. K., Kanakubo, E., & Chan, J. K. (2005) · BMC Cancer · doi:10.1186/1471-2407-5-121 · Cited by 93
“We acknowledge, however, that this possibility seems to be at odds with the accumulating evidence that mast cells promote rather than inhibit tumor growth [1,2].”
BackgroundMethodResultInfluentialThe roles of mast cells in anticancer immunity
Dalton, D. K., & Noelle, R. J. (2012) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-012-1246-0 · Cited by 97
“Thus, MCs promoted squamous cell carcinoma in this model by stimulating premalignant angiogenesis, tumor cell proliferation, and by MC proteases remodeling the stromal architecture at the invasive front of tumors [23].”
Zhang, M., Huang, X., Song, Y., Gao, P., Sun, J., & Wang, Z. (2017) · BioMed Research International · doi:10.1155/2017/9503025 · Cited by 97
Oncogenic Ras-Induced Expression of Cytokines: A New Target of Anti-Cancer Therapeutics
Ancrile, B. B., O’Hayer, K., & Counter, C. M. (2008) · Molecular Interventions · doi:10.1124/mi.8.1.6 · Cited by 91
Tumor and the Microenvironment: A Chance to Reframe the Paradigm of Carcinogenesis?
Bizzarri, M., & Cucina, A. (2014) · BioMed Research International · doi:10.1155/2014/934038 · Cited by 93
“In turn, tissue fibrosis and modification of physicochemical properties of ECM may likely influence tumor onset and progression by regulating soluble factors involved in inflammation [61] and angiogenesis [62].”
BackgroundMast cells and cancer: enemies or allies?
Dyduch, G., Kaczmarczyk, K., & Okoń, K. (2012) · PubMed · Cited by 91
The Role of Inflammation in Prostate Cancer
Sfanos, K. S., Hempel, H., & Marzo, A. M. D. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-3-0348-0837-8_7 · Cited by 92
Mast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancer
Chan, J. K., Magistris, A., Loizzi, V., Lin, F., Rutgers, J. K. L., Osann, K., DiSaia, P. J., & Samoszuk, M. K. (2005) · Gynecologic Oncology · doi:10.1016/j.ygyno.2005.05.042 · Cited by 93
Gius, D. R., Funk, M. C., Chuang, E. Y.-Y., Feng, S., Huettner, P. C., Nguyen, L., Bradbury, C. M., Mishra, M. V., Gao, S., Buttin, B. M., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0260 · Cited by 91
“This idea is consistent with several studies that have detected an increase in angiogenic growth factors and microvessel density in cervical cancer (21, 36).”
ResultTumor Angiogenesis as a Target for Dietary Cancer Prevention
Li, W. W., Li, V. W., Hutnik, M., & Chiou, A. S. (2011) · Journal of Oncology · doi:10.1155/2012/879623 · Cited by 89
“In hyperplasia, dysplasia, and at the invading cancer front, angiogenesis is associated with mast cell infiltration and degranulation [98].”
BackgroundMast cells and vasculature in atopic dermatitis – potential stimulus of neoangiogenesis
Groneberg, D. A., Bester, C., Grützkau, A., Serowka, F., Fischer, A., Henz, B. M., & Welker, P. (2004) · Allergy · doi:10.1111/j.1398-9995.2004.00628.x · Cited by 90
“As neovascular processes involve the action of angiogenic growth factors and require the localized proteolytic modification of the extracellular matrix (27), the presently identified mast cells which express both tryptase and chymase may be implicated as accessory cells for cutaneous angiogenesis in lesions of atopic…”
BackgroundFrank, B. T., Rossall, J. C., Caughey, G. H., & Fang, K. C. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.4.2783 · Cited by 89
“pendent of its MMP inhibitory functions (11, 54).”
BackgroundSelf-citationMangia, A., Malfettone, A., Rossi, R., Paradiso, A., Ranieri, G., Simone, G., & Resta, L. (2011) · Histopathology · doi:10.1111/j.1365-2559.2011.03842.x · Cited by 88
Kamaraj, S., Anandakumar, P., Sundaram, J., Ramakrishnan, G., & Devaki, T. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.09.017 · Cited by 89
Steroid hormones stimulate human prostate cancer progression and metastasis
Ricke, W. A., Ishii, K., Ricke, E. A., Simko, J. P., Wang, Y. Z., Hayward, S. W., & Cunha, G. R. (2005) · International Journal of Cancer · doi:10.1002/ijc.21614 · Cited by 88
“For several transgenic mouse models of tumorigenesis, the so-called ‘‘vascular switch’’ to high vessel density is a critical step in progression from benign to tumorigenic growth.(28,29) In the mUGM1BPH-1 model, vascular density changes quantitatively and qualitatively as one would expect during hormone-induced carcin…”
BackgroundSquamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation
Somerville, T. D. D., Biffi, G., Daßler‐Plenker, J., Hur, S. K., He, X., Vance, K. E., Miyabayashi, K., Xu, Y., Maia-Silva, D., Klingbeil, O., et al. (2020) · eLife · doi:10.7554/elife.53381 · Cited by 87
“…of TP63 confers a myriad of tumor cell-intrinsic phenotypes in PDA, such as enhanced motility, invasion, and resistance to cytotoxic chemotherapy (Danilov et al., 2011; Somerville et al., 2018), our work points to a powerful non cell-autonomous effect of TP63 in PDA in promoting inflammation.”
BackgroundMast Cells Protect Mice from Mycoplasma Pneumonia
Xu, X. M., Zhang, D., Lyubynska, N., Wolters, P. J., Killeen, N. P., Bałuk, P., McDonald, D. M., Hawgood, S. B., & Caughey, G. H. (2005) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200507-1034oc · Cited by 87
Self-citationO’Grady, A., Dunne, C., O’Kelly, P., MURPHY, G. M., Leader, M., & Kay, E. (2007) · Histopathology · doi:10.1111/j.1365-2559.2007.02885.x · Cited by 87
“Coussens et al.28 have shown that neutrophils, macrophages and mast cells are the predominant source of MMP-9 in a mouse model of multistage SCC, rather than the neoplastic cells themselves.”
BackgroundMast cells as therapeutic target in cancer
Ribatti, D. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.02.056 · Cited by 89
Nijsten, T. E. C., Colpaert, C., Vermeulen, P., Harris, A. L., Marck, E. V., & Lambert, J. (2004) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2004.06214.x · Cited by 87
Sevenich, L., Werner, F., Gajda, M., Schurigt, U., Sieber, C., Müller, S., Follo, M., Peters, C., & Reinheckel, T. (2011) · Oncogene · doi:10.1038/onc.2010.387 · Cited by 85
“…majority of tumor-promoting proteases is produced by cells of the tumor microenvironment, such as fibroblasts (Orimo et al., 2005), or tumor-associated immune cells, for example, macrophages and mast cells (Coussens et al., 1999; Allavena et al., 2008), rather than by the cancer cells themselves.”
InfluentialRole of Chemokines in Thyroid Cancer Microenvironment: Is CXCL8 the Main Player?
Rotondi, M., Coperchini, F., Latrofa, F., & Chiovato, L. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00314 · Cited by 77
Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment
van Kempen, L. C. L. T., Rhee, J.-S., Dehne, K., Lee, J., Coussens, L. M., Edwards, D. R., & Coussens, L. M. (2002) · Differentiation · doi:10.1046/j.1432-0436.2002.700914.x · Cited by 86
“In addition, mast cell-derived tryptase is a mitogen for both keratinocytes and dermal fibroblasts and induces expression of type I collagen mRNAs (Cairns and Walls, 1997; Coussens et al., 1999).”
BackgroundMethodInfluentialSelf-citation
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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