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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Background
Chronic allergic contact dermatitis promotes skin cancer
Demehri, S., Cunningham, T. J., Hurst, E. A., Schaffer, A., Sheinbein, D. M., & Yokoyama, W. M. (2014) · Journal of Clinical Investigation · doi:10.1172/jci77843 · Cited by 21
Sustained Endothelial Expression of HoxA5 In Vivo Impairs Pathological Angiogenesis And Tumor Progression
Cuevas, I., Layman, H., Coussens, L. M., & Boudreau, N. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0121720 · Cited by 21
“development of angiogenic vasculature [18].”
BackgroundResultInfluentialSelf-citation
Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture
Alim, A., Ackermann, P. W., Eliasson, P., Blomgran, P., Kristiansson, P., Pejler, G., & Peterson, M. (2017) · Cell and Tissue Research · doi:10.1007/s00441-017-2684-y · Cited by 21
Although Abundant in Tumor Tissue, Mast Cells Have No Effect on Immunological Micro-milieu or Growth of HPV-Induced or Transplanted Tumors
Ghouse, S. M., Polikarpova, A., Muhandes, L., Dudeck, J., Tantcheva‐Poór, I., Hartmann, K., Lesche, M., Dahl, A., Eming, S. A., Müller, W., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.010 · Cited by 21
Mast cells induce epithelial-to-mesenchymal transition and migration in non-small cell lung cancer through IL-8/Wnt/β-catenin pathway
Qu, J., Cheng, T., Liu, L., Heng, J., Liu, X., Sun, Z., Wang, W., Li, K., & Yang, N. (2019) · Journal of Cancer · doi:10.7150/jca.29953 · Cited by 21
Retracted
Stromal issues in cervical cancer: a review of the role and function of basement membrane, stroma, immune response and angiogenesis in cervical cancer development
Sahebali, S., den Eynden, G. V., Murta, E. F. C., Michelin, M. A., Cusumano, P. G., Petignat, P., & Bogers, J. (2010) · European Journal of Cancer Prevention · doi:10.1097/cej.0b013e32833720de · Cited by 21
“In a transgenic mouse model expressing HPV16 genes in basal keratinocytes, carcinogenesis was accompanied by infiltration of mast cells (Coussens et al., 1999; Huang et al., 2002).”
Background
Stromal responses in human primary melanoma of the skin
van Kempen, L. C. L. T. (2005) · Frontiers in bioscience · doi:10.2741/1748 · Cited by 21
“The observations that (i) MMP-9 is variably expressed in (micro-invasive) radial growth phase melanoma (63), (ii) melanoma in situ evidences increased density of lesional mast cells compared to nevi (64), and that (iii) peritumoural accumulation of mast cells correlates with microvessel density and poor prognosis in m…”
BackgroundInfluential
Chemopreventive effect of celecoxib and expression of cyclooxygenase‐1 and cyclooxygenase‐2 on chemically‐induced rat mammary tumours
Jang, T. J., Jung, H. G., Jung, K. H., & Min Ku, O. (2002) · International Journal of Experimental Pathology · doi:10.1046/j.1365-2613.2002.00228.x · Cited by 21
Mammary tumor growth and metastasis are reduced in c‐Kit mutant Sash mice
He, L., Zhu, Z., Chen, S., Wang, Y., & Gu, H. (2016) · Cancer Medicine · doi:10.1002/cam4.696 · Cited by 20
“However, in the last 15 years, studies mainly using mouse models for various types of cancers, including squamous carcinoma [2], neurofibromatosis [3, 4], and pancreatic islet tumor [5], reveal the tumor- promoting role of mast cells in different cancers.”
Background
Severe pan-sensory neuropathy in leprosy.
Pandya, S. S., & Ws, B. (1994) · PubMed · Cited by 20
Thrombosis Increases Circulatory Hepatocyte Growth Factor by Degranulation of Mast Cells
Kinoshita, M., Miyamoto, T., Ohashi, N., Sasayama, S., & Matsumori, A. (2002) · Circulation · doi:10.1161/01.cir.0000039344.98537.be · Cited by 20
Oncogenes and Tumor Angiogenesis
Rak, J. W., & Kerbel, R. S. (2003) · Humana Press eBooks · doi:10.1007/978-1-59259-313-2_10 · Cited by 20
Expression of human papillomavirus type 16 E7 is sufficient to significantly increase expression of angiogenic factors but is not sufficient to induce endothelial cell migration
Walker, J. L., Smiley, L. C., Ingram, D. A., & Roman, A. (2010) · Virology · doi:10.1016/j.virol.2010.11.010 · Cited by 20
Polyps Wrap Mast Cells and Treg within Tumorigenic Tentacles
Colombo, M. P., & Piconese, S. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1351 · Cited by 19
“Lisa Coussens and coworkers (21, 22) first showed that mast cells, recruited early into skin cancer, support tumor growth by”
Background
The Role of Mouse Mast Cell Proteases in the Proliferative Phase of Wound Healing in Microdeformational Wound Therapy
Succar, J., Douaiher, J., Lancerotto, L., Li, Q., Yamaguchi, R., Younan, G. J., Pejler, G., & Orgill, D. P. (2014) · Plastic & Reconstructive Surgery · doi:10.1097/prs.0000000000000432 · Cited by 19
IgE crosslinkage of Fcε receptor I induces both production and activation of matrix metalloproteinase-9 in mast cells
Tanaka, A., & Matsuda, H. (2004) · Cellular Immunology · doi:10.1016/j.cellimm.2004.03.009 · Cited by 19
Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid
Chen, R., Ning, G., Zhao, M., Fleming, M. G., Diaz, L. A., Werb, Z., & Liu, Z. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200111494 · Cited by 19
Self-citation
The ecology of brain tumors: lessons learned from neurofibromatosis-1
Pong, W. W., & Gutmann, D. H. (2010) · Oncogene · doi:10.1038/onc.2010.519 · Cited by 18
“Recruited mast cells activate fibroblast collagen synthesis and induce angiogenesis through the secretion of the mast cell serine proteases monocyte chemoattractant protein-4 and monocyte chemoattractant protein-6 (Coussens et al., 1999).”
Background
Peripheral Thyroid Hormone Conversion and Its Impact on TSH and Metabolic Activity
Holtorf, K. (2014) · Journal of Restorative Medicine · doi:10.14200/jrm.2014.3.0103 · Cited by 18
Inhibition of thrombosis in melanoma allografts in mice by endogenous mast cell heparin
Corwin, M. A., Yu, H., Wang, J., Nalcioğlu, O., Su, M., & Samoszuk, M. K. (2003) · Thrombosis and Haemostasis · doi:10.1160/th03-02-0088 · Cited by 18
“They have been implicated in promoting tumor metastasis (34, 36) and angiogenesis (34-39) and are generally associated with a poor prognosis (38, 39).”
Background
Conjugated Linoleic Acid Induces Mast Cell Recruitment during Mouse Mammary Gland Stromal Remodeling1
Russell, J. S., McGee, S. O., Ip, M. M., Kuhlmann, D., & Masso‐Welch, P. A. (2007) · Journal of Nutrition · doi:10.1093/jn/137.5.1200 · Cited by 18
“Although 10,12-CLA has been associated with decreased angiogenesis and apoptosis of the adipose vasculature (23), mast cells are usually associated with increased angiogenesis (37,38).”
Background
Mast Cell Proteases 6 and 7 Stimulate Angiogenesis by Inducing Endothelial Cells to Release Angiogenic Factors
de Souza, D. A., Borges, A. C., Santana, A. C., Oliver, C., & Jamur, M. C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0144081 · Cited by 19
NGR-TNF, a novel vascular-targeting agent, does not induce cytokine recruitment of proangiogenic bone marrow-derived cells
Matteo, P. D., Hackl, C., Jedeszko, C., Valentinis, B., Bordignon, C., Traversari, C., Kerbel, R. S., & Gp, R. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.347 · Cited by 17
“…(Lin et al, 2006), Tie2-expressing monocytes (TEMs) (De Palma et al, 2003, 2005), dendritic cell precursors (Conejo-Garcia et al, 2004), mast cells (Coussens et al, 1999) and CD11bþGr1þ cells, including neutrophils (Nozawa et al, 2006) and myeloid-derived suppressor cells (MDSCs) (Yang et al,…”
Background
Mast cell chymase is present in uterine cervical carcinoma and it detaches viable and growing cervical squamous carcinoma cells from substratum in vitro
Diaconu, N.-C., Rummukainen, J. K., Naukkarinen, A., Mättö, M., Harvima, R. J., Pelkonen, J., & Harvima, I. T. (2011) · Archives of Dermatological Research · doi:10.1007/s00403-011-1121-4 · Cited by 17
Targeting Inflammatory Cells to Improve Anti-VEGF Therapies in Oncology
Gerber, H., Olazoglu, E., & Grewal, I. S. (2009) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-540-78281-0_11 · Cited by 17
Expression of matrix metalloproteinase-9 (MMP-9) and blood vessel density in laryngeal squamous cell carcinomas
Wittekindt, C., Jovanovic, N., & Guntinas‐Lichius, O. (2010) · Acta Oto-Laryngologica · doi:10.3109/00016489.2010.506886 · Cited by 17
“The contribution of hematopoietic-derived inflammatory cells like monocytes, macrophages, mast cells, and neutrophils to the expression of MMPs and in particular MMP-9 in the tumor environment has been emphasized [14].”
Background
The Angiogenic Switch in Tumorigenesis
WICKI, A. N., & Christofori, G. (2007) · Springer eBooks · doi:10.1007/978-3-540-33177-3_4 · Cited by 17
Stable Overexpression of miRNAs in Bone Marrow-Derived Murine Mast Cells Using Lentiviral Expression Vectors
Mayoral, R. J., & Monticelli, S. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-811-9_14 · Cited by 17
EVALUATION OF CD31 EXPRESSION AND MAST CELL COUNT IN DYSPLASTIC LESIONS AND SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY
Jaafari‐Ashkavandi, Z., Moshref, M., Abbas, F. M., Sargolzaei, S., & Taghavi, N. (2010) · Iranian Red Crescent Medical Journal · Cited by 17
Equine Chorionic Gonadotropin Modulates the Expression of Genes Related to the Structure and Function of the Bovine Corpus Luteum
Sousa, L. M. M. D. C., Mendes, G. P., Campos, D. B., Baruselli, P. S., & Papa, P. D. C. (2016) · PLoS ONE · doi:10.1371/journal.pone.0164089 · Cited by 17
Inonotus obliquus attenuates histamine-induced microvascular inflammation
Javed, S., Mitchell, K., Sidsworth, D., Sellers, S., Reutens-Hernandez, J., Massicotte, H. B., Egger, K. N., Lee, C. H., & Payne, G. W. (2019) · PLoS ONE · doi:10.1371/journal.pone.0220776 · Cited by 18
Basic Concepts of Inflammation and its Role in Carcinogenesis
Maher, S. G., & Reynolds, J. V. (2011) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-642-03503-6_1 · Cited by 17
Preoperative Prognostic Nutritional Index Is a Prognostic Indicator of Cancer-Specific Survival in Patients Undergoing Endometrial Cancer Surgery
Kim, Y. J., Park, H., Kim, H. S., & Park, S. (2023) · Journal of Korean Medical Science · doi:10.3346/jkms.2023.38.e163 · Cited by 16
Prognostic value of immune-related cells and genes in the tumor microenvironment of ovarian cancer, especially CST4
Wang, S., Wang, C., Liu, O., Hu, Y., Li, X., & Lin, B. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119461 · Cited by 16
MMP9 is protective against lethal inflammatory mass lesions in the mouse colon
Hald, A., Rønø, B., Melander, M. C., Ding, M. L., Holck, S., & Lund, L. R. (2010) · Disease Models & Mechanisms · doi:10.1242/dmm.005801 · Cited by 15
“It is interesting to note that, whereas the colon mucosa gets inflamed in Plg–/– and MMP9–/–:Plg–/– mice, the number of mast cells, which have previously been shown to assist the development of benign neoplastic skin lesion into malignant tumors (Coussens et al., 1999), is decreased.”
Background
Context-dependent regulation of cutaneous immunological responses by TGF 1 and its role in skin carcinogenesis
Glick, A. B., Pérez‐Lorenzo, R., & Mohammed, J. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm215 · Cited by 17
“In this model, the skin pro- 195 gresses through a hyperplastic and dysplastic state to SCC that is dependent on B cell-driven infiltration of mast cells ( 69 ,70).”
Background
Imatinib Spares cKit-Expressing Prostate Neuroendocrine Tumors, whereas Kills Seminal Vesicle Epithelial–Stromal Tumors by Targeting PDGFR-β
Jachetti, E., Rigoni, A., Bongiovanni, L., Arioli, I., Botti, L., Parenza, M., Cancila, V., Chiodoni, C., Festinese, F., Bellone, M., et al. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0466 · Cited by 16
“In this scenario, mast cells (MCs) have been recognized capable of proangiogenic (15) and protumorigenic activities (16, 17).”
Background
Surface association of secreted matrix metalloproteinases
Fridman, R. A. (2003) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(03)54005-4 · Cited by 16
The novel protein PTPIP51 is expressed in human keratinocyte carcinomas and their surrounding stroma
Reiners-Koch, P.-S., Stenzinger, A., Viard, M., Marker, D., Mayser, P., Nilles, M., Schreiner, D., Steger, K., & Wimmer, M. A. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00198.x · Cited by 16
“Furthermore, mast cells of the innate immune system seem to be crucial for keratinocytes to achieve hyperproliferative growth characteristics during neoplastic development [48, 49, 50].”
Background
Increased Blood Clotting, Microvascular Density, and Inflammation in Eotaxin-Secreting Tumors Implanted into Mice
Samoszuk, M. K., Deng, T., Hamamura, M. J., Su, M., Asbrock, N., & Nalcioğlu, O. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63310-x · Cited by 16
A Pulmonary Perspective on GASPIDs: Granule-Associated Serine Peptidases of Immune Defense
Caughey, G. H. (2006) · Current Respiratory Medicine Reviews · doi:10.2174/157339806778019024 · Cited by 16
Self-citation
Unimpeded skin carcinogenesis in K14‐HPV16 transgenic mice deficient for plasminogen activator inhibitor
Masset, A., Maillard, C., Sounni, N. E., Jacobs, N., Bruyére, F., Delvenne, P., Tacke, M., Reinheckel, T., Foidart, J., Coussens, L. M., et al. (2010) · International Journal of Cancer · doi:10.1002/ijc.25326 · Cited by 16
Self-citation

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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