The online version of this article (doi:10.1186/1476-9255-9-46) contains supplementary material, which is available to authorized users.
Authors declare no conflict of interest.
THG had the overall responsibilities of the experiment design and statistical analysis, the concept and wrote the manuscript. CdO carried out chemical induction of squamous cell carcinoma, histological experiments and counting of inflammatory infiltration in the lesions. LTdF carried out chemical induction of squamous cell carcinoma and counting of inflammatory infiltration in the lesions. CRP and RNR carried out chemical induction of squamous cell carcinoma. ALdScarried out histological experiments and counting of inflammatory infiltration in the lesions. GPG, JSdS and APC had shared the concept and supported the manuscript. APC had overall responsibilities of fund management, experimental design and wrote the manuscript. All the authors have read and approved the final manuscript.
Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. In SCC, tumour development is accompanied by an immune response that leads to massive tumour infiltration by inflammatory cells, and consequently, local and systemic production of cytokines, chemokines and other mediators. Studies in both humans and animal models indicate that imbalances in these inflammatory mediators are associated with cancer development.
We used a multistage model of SCC to examine the involvement of elastase (ELA), myeloperoxidase (MPO), nitric oxide (NO), cytokines (IL-6, IL-10, IL-13, IL-17, TGF-β and TNF-α), and neutrophils and macrophages in tumour development. ELA and MPO activity and NO, IL-10, IL −17, TNF-α and TGF-β levels were increased in the precancerous microenvironment.
ELA and MPO activity and NO, IL-10, IL −17, TNF-α and TGF-β levels were increased in the precancerous microenvironment. Significantly higher levels of IL-6 and lower levels of IL-10 were detected at 4 weeks following 7,12-Dimethylbenz(a)anthracene (DMBA) treatment. Similar levels of IL-13 were detected in the precancerous microenvironment compared with control tissue. We identified significant increases in the number of GR-1+ neutrophils and F4/80+/GR-1- infiltrating cells in tissues at 4 and 8 weeks following treatment and a higher percentage of tumour-associated macrophages (TAM) expressing both GR-1 and F4/80, an activated phenotype, at 16 weeks. We found a significant correlation between levels of IL-10, IL-17, ELA, and activated TAMs and the lesions. Additionally, neutrophil infiltrate was positively correlated with MPO and NO levels in the lesions.
Our results indicate an imbalance of inflammatory mediators in precancerous SCC caused by neutrophils and macrophages and culminating in pro-tumour local tissue alterations.
Mika D, Guruvayoorappan C: Myeloperoxidase: the yin and yang in tumour progression. J Exp Ther Oncol. 2011, 9: 93-100. PubMed
Sansone P, Bromberg J: Environment, inflammation, and cancer. Cur Opin Gen Develop. 2011, 21: 80-85. 10.1016/j.gde.2010.11.001. CrossRef
Fortina AB, Piaserico S, Caforio AL, Abeni D, Alaibac M, Angelini A, Iliceto S, Peserico A: Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients. Arch Dermatol. 2004, 140: 1079-1085. 10.1001/archderm.140.9.1079. CrossRefPubMed
Lee KD, Lee HS, Jeon CH: Body fluid biomarkers for early detection of head and neck squamous cell carcinomas. Anticancer Res. 2011, 31: 1161-1167. PubMed
Blumberg PM: Protein kinase C as the receptor for the phorbol ester tumor promoters: sixth Rhoads memorial award lecture. Cancer Res. 1988, 48: 1-8. PubMed
Tauber AI: Protein kinase C and the activation of the human neutrophil NADPH-oxidase. Blood. 1987, 69: 711-720. PubMed
Gasparoto TH, Sipert CR, de Oliveira CE, Porto VC, Santos CF, Campanelli AP, Lara VS: Salivary immunity in elderly individuals presented with Candida-related denture stomatitis. Gerodontology. 2012, 47: 741-748.
Ziech D, Franco R, Georgakilas AG, Georgakila S, Malamou-Mitsi V, Schoneveld O, Pappa A, Panayiotidis MI: The role of reactive oxygen species and oxidative stress in environmental carcinogenesis and biomarker development. Chem Biol Interact. 2010, 188: 334339-
London SJ, Lehman TA, Taylor JA: Myeloperoxidase genetic polymorphism and lung cancer risk. Cancer Res. 1997, 57: 5001-5003. PubMed
Cascorbi I, Henning S, Brockmöller J, Gephart J, Meisel C, Müller JM, Loddenkemper R, Roots I: Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant–463A of the myeloperoxidase gene. Cancer Res. 2009, 60: 644-649.
Ambrosone CB, Barlow WE, Reynolds W, Livingston RB, Yeh IT, Choi JY, Davis W, Rae JM, Tang L, Hutchins LR, Ravdin PM, Martino S: Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897. J Clin Oncol. 2009, 27: 4973-4979. 10.1200/JCO.2009.21.8669. PubMedCentralCrossRefPubMed
Lanza F, Fietta A, Spisani S, Castoldi GL, Traniello S: Does a relationship exist between neutrophil myeloperoxidase deficiency and the occurrence of neoplasms?. J Clin Lab Immunol. 1987, 22: 175-180. PubMed
Lanza F, Giuliani AL, Amelotti F, Spisani S, Traniello S, Castoldi G: Depressed neutrophil-mediated tumor cell cytotoxicity in subjects affected by hereditary myeloperoxidase deficiency and secondary neoplasia. Haematologica. 1998, 73: 355-358.
Weitzman SA, Gordon LI: Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood. 1990, 76: 655-663. PubMed
Liotta LA, Stetler-Stevenson WG: Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res. 1991, 51: 5054-5059.
Nakajima M, Chop AM: Tumor invasion and extracellular matrix degradative enzymes: regulation of activity by organ factors. Semin Cancer Biol. 1991, 2: 115-127. PubMed
Zeydel M, Nakagawa S, Biempica L, Takahashi S: Collagenase and elastase production by mouse mammary adenocarcinoma primary cultures and cloned cells. Cancer Res. 1986, 46: 6438-6445. PubMed
Grant AJ, Lerro KA, Wu CW: Cell associated elastase activities of rat mammary tumour cells. Bioch. Int. 1990, 22: 1077-1084.
Banda MJ, Werb Z: Mouse macrophage elastase. Bioc J. 1981, 193: 589-605. CrossRef
Kohno T, Mizukami H, Suzuki M, Saga Y, Takei Y, Shimpo M, Matsushita T, Okada T, Hanazono Y, Kume A, Sato I, Ozawa K: Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer. Cancer Res. 2003, 63: 5091-5094. PubMed
Cervenak L, Morbidelli L, Donati D, Donnini S, Kambayashi T, Wilson JL, Axelson H, Castaños-Velez E, Ljunggren HG, Malefyt RD, Granger HJ, Ziche M: Abolished angiogenicity and tumorigenicity of Burkitt lymphoma by interleukin-10. Blood. 2000, 96: 2568-2573. PubMed
Alas S, Emmanouilides C, Bonavida B: Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin’s lymphoma to apoptosis. Clin Cancer Res. 2001, 7: 709-723. PubMed
Sredni B, Weil M, Khomenok G, Lebenthal I, Teitz S, Mardor Y, Ram Z, Orenstein A, Kershenovich A, Michowiz S, Cohen YI, Rappaport ZH: Ammonium trichloro(dioxoethylene-o, o’)tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop. Cancer Res. 2004, 64: 1843-1852. 10.1158/0008-5472.CAN-03-3179. CrossRefPubMed
Alas S, Bonavida B: Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin’s lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res. 2001, 61: 5137-5144. PubMed
- Inflammatory events during murine squamous cell carcinoma development
Thais Helena Gasparoto
Carine Ervolino de Oliveira
Luisa Thomazini de Freitas
Claudia Ramos Pinheiro
Rodrigo Nalio Ramos
André Luis da Silva
Gustavo Pompermaier Garlet
João Santana da Silva
Ana Paula Campanelli
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II