Skip to main content
Top
Published in: Cancer Microenvironment 1/2009

Open Access 01-12-2009 | Original Paper

Stromal Myofibroblasts Accompany Modifications in the Epithelial Phenotype of Tongue Dysplastic and Malignant Lesions

Authors: Marilena Vered, Irit Allon, Amos Buchner, Dan Dayan

Published in: Cancer Microenvironment | Issue 1/2009

Login to get access

Abstract

Stromal myofibroblasts (SMF) associated with various types of carcinomas are believed to emerge under the influence of the tumor cells. Recent studies have shown that SMF may originate from fibroblasts within the tumor stroma or even from carcinoma cells by the process of epithelial-mesenchymal transition. The aim of this study was to investigate the concomitant expression of epithelial membrane antigen and α-smooth muscle actin in cells at the tumor-connective tissue interface in human tongue carcinoma, as a possible reflection of epithelial-mesenchymal transition. Given its key role in this process, expression of transforming growth factor-β in the malignant cells was assessed as well. Immunostaining with α-smooth muscle actin was performed on cases of hyperplasia (n = 16), mild dysplasia (n = 12), moderate-to-severe dysplasia (n = 11) and carcinoma (n = 22). Transforming growth factor-β assessment and double immunostaining with epithelial membrane antigen and α-smooth muscle actin were performed only in cases of carcinoma. SMF were significantly associated with carcinomas, while their number in pre-malignant lesions (hyperplasia and dysplasia) was significantly lower (P < 0.001). Although SMF were found in all carcinomas, they were heterogeneous in their frequency and patterns of distribution. In addition, 95% of the carcinomas expressed transforming growth factor-β and 41% exhibited cells positive for both epithelial membrane antigen and α-smooth muscle actin. SMF were almost exclusively associated with established carcinomas and not with pre-malignant lesions. Cells that co-expressed epithelial membrane antigen and α-smooth muscle actin can be a manifestation of epithelial-mesenchymal transition and, as such, may serve as a source for SMF in these tumors. These findings appear to be linked to the frequent expression of transforming growth factor-β by the malignant cells.
Literature
1.
go back to reference Kademani D (2007) Oral Cancer. Mayo Clin Proc 82(7):878–887 (erratum: Mayo Clin Proc 2007 82(8):1017) Kademani D (2007) Oral Cancer. Mayo Clin Proc 82(7):878–887 (erratum: Mayo Clin Proc 2007 82(8):1017)
2.
go back to reference Choi S, Myers JN (2008) Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. J Dent Res 87(1):14–32CrossRefPubMed Choi S, Myers JN (2008) Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. J Dent Res 87(1):14–32CrossRefPubMed
4.
go back to reference Tlsty TD, Hein PW (2001) Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev 11(1):54–59CrossRefPubMed Tlsty TD, Hein PW (2001) Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev 11(1):54–59CrossRefPubMed
5.
go back to reference Elenbaas B, Weinberg RA (2001) Heterotopic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 264(1):169–184CrossRefPubMed Elenbaas B, Weinberg RA (2001) Heterotopic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 264(1):169–184CrossRefPubMed
6.
go back to reference Mueller MM, Fusening NE (2004) Friends or foes–bipolar effects of the tumor stroma in cancer. Nat Rev Cancer 4(11):839–849CrossRefPubMed Mueller MM, Fusening NE (2004) Friends or foes–bipolar effects of the tumor stroma in cancer. Nat Rev Cancer 4(11):839–849CrossRefPubMed
7.
go back to reference Zeisberg EM, Potenta S, Xie L et al (2007) Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67(21):10123–10128CrossRefPubMed Zeisberg EM, Potenta S, Xie L et al (2007) Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67(21):10123–10128CrossRefPubMed
8.
go back to reference Tomasek JJ, Gabbiani G, Hinz B et al (2002) Myofibroblasts and mechano-regulation of connective tissue remodeling. Nat Rev Mol Cell Biol 3(5):349–363CrossRefPubMed Tomasek JJ, Gabbiani G, Hinz B et al (2002) Myofibroblasts and mechano-regulation of connective tissue remodeling. Nat Rev Mol Cell Biol 3(5):349–363CrossRefPubMed
9.
go back to reference Lohr M, Schimdt C, Ringel J et al (2001) Transforming growth factor β-1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res 61(2):550–555PubMed Lohr M, Schimdt C, Ringel J et al (2001) Transforming growth factor β-1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res 61(2):550–555PubMed
10.
go back to reference Aoyagi Y, Oda T, Kinoshita T et al (2004) Overexpression of TGF- β by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cells. Br J Cancer 91(7):1316–1326CrossRefPubMed Aoyagi Y, Oda T, Kinoshita T et al (2004) Overexpression of TGF- β by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cells. Br J Cancer 91(7):1316–1326CrossRefPubMed
11.
go back to reference De Wever O, Mareel M (2003) Role of tissue stroma in cancer cell invasion. J Pathol 200(4):429–447CrossRefPubMed De Wever O, Mareel M (2003) Role of tissue stroma in cancer cell invasion. J Pathol 200(4):429–447CrossRefPubMed
12.
go back to reference Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142CrossRefPubMed Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142CrossRefPubMed
13.
go back to reference Nawshad A, LaGamba D, Polad A et al (2005) Transforming growth factor-β signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs 179(1–2):11–23CrossRefPubMed Nawshad A, LaGamba D, Polad A et al (2005) Transforming growth factor-β signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs 179(1–2):11–23CrossRefPubMed
14.
go back to reference Trelstad RL, Hay ED, Revel JD (1967) Cell contact during early morphogenesis in the chick embryo. Dev Biol 16(1):78–106CrossRefPubMed Trelstad RL, Hay ED, Revel JD (1967) Cell contact during early morphogenesis in the chick embryo. Dev Biol 16(1):78–106CrossRefPubMed
15.
go back to reference Yang J, Mani SA, Donaher JL et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939CrossRefPubMed Yang J, Mani SA, Donaher JL et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939CrossRefPubMed
16.
go back to reference Radisky DC, Kenny PA, Bissell MJ (2007) Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem 101(4):830–839CrossRefPubMed Radisky DC, Kenny PA, Bissell MJ (2007) Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem 101(4):830–839CrossRefPubMed
17.
go back to reference Takkunen M, Grenman R, Hakkunen M et al (2006) Snail-dependent and–independent epithelial-mesenchymal transition in oral squamous carcinoma cells. J Histochem Cytochem 54(11):1263–1275CrossRefPubMed Takkunen M, Grenman R, Hakkunen M et al (2006) Snail-dependent and–independent epithelial-mesenchymal transition in oral squamous carcinoma cells. J Histochem Cytochem 54(11):1263–1275CrossRefPubMed
18.
go back to reference Yokoyama K, Kamata N, Hayashi E et al (2001) Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma in vitro. Oral Oncol 37(1):65–71CrossRefPubMed Yokoyama K, Kamata N, Hayashi E et al (2001) Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma in vitro. Oral Oncol 37(1):65–71CrossRefPubMed
19.
go back to reference Diniz-Freitas M, Garcia-Caballero T, Antunez-Lopez J et al (2006) Reduced E-cadherin is an indicator of unfavorable prognosis in oral squamous cell carcinoma. Oral Oncol 42(2):190–200CrossRefPubMed Diniz-Freitas M, Garcia-Caballero T, Antunez-Lopez J et al (2006) Reduced E-cadherin is an indicator of unfavorable prognosis in oral squamous cell carcinoma. Oral Oncol 42(2):190–200CrossRefPubMed
20.
go back to reference Vered M, Allon I, Buchner A et al (2007) Stromal myofibroblasts and malignant transformation in a 4NQO rat tongue carcinogenesis model. Oral Oncol 43(10):999–1006CrossRefPubMed Vered M, Allon I, Buchner A et al (2007) Stromal myofibroblasts and malignant transformation in a 4NQO rat tongue carcinogenesis model. Oral Oncol 43(10):999–1006CrossRefPubMed
21.
go back to reference Vered M, Polak-Charcon S, Babushkin T et al (2008) 4NQO-induced tongue carcinoma: an ultrastructural study. Ultrastruct Pathol 32(5):199–205CrossRefPubMed Vered M, Polak-Charcon S, Babushkin T et al (2008) 4NQO-induced tongue carcinoma: an ultrastructural study. Ultrastruct Pathol 32(5):199–205CrossRefPubMed
22.
go back to reference Gale N, Pilch BZ, Sidransky D et al (2005) Epithelial precursor lesions. In: Barnes L, Eveson JW, Reichart P et al (eds) WHO classification of tumours. Pathology and genetics. Head and neck tumours. IARC, Lyon, pp 177–179 Gale N, Pilch BZ, Sidransky D et al (2005) Epithelial precursor lesions. In: Barnes L, Eveson JW, Reichart P et al (eds) WHO classification of tumours. Pathology and genetics. Head and neck tumours. IARC, Lyon, pp 177–179
23.
go back to reference Pinkus GS, Kurtin PJ (1985) Epithelial membrane antigen–a diagnostic discriminant in surgical pathology: immunohistochemical profile in epithelial, mesenchymal, and hematopoietic neoplasms using paraffin sections and monoclonal antibodies. Hum Pathol 16(9):929–940CrossRefPubMed Pinkus GS, Kurtin PJ (1985) Epithelial membrane antigen–a diagnostic discriminant in surgical pathology: immunohistochemical profile in epithelial, mesenchymal, and hematopoietic neoplasms using paraffin sections and monoclonal antibodies. Hum Pathol 16(9):929–940CrossRefPubMed
24.
go back to reference Logullo AF, Nonogaki S, Miguel RE et al (2003) Transforming growth factor beta1 (TGFbeta1) expression in head and neck squamous cell carcinoma patients as related to prognosis. J Oral Pathol Med 32(3):139–145CrossRefPubMed Logullo AF, Nonogaki S, Miguel RE et al (2003) Transforming growth factor beta1 (TGFbeta1) expression in head and neck squamous cell carcinoma patients as related to prognosis. J Oral Pathol Med 32(3):139–145CrossRefPubMed
25.
go back to reference Lewis MP, Lygoe KA, Nystrom ML et al (2004) Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br J Cancer 90(4):822–832CrossRefPubMed Lewis MP, Lygoe KA, Nystrom ML et al (2004) Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br J Cancer 90(4):822–832CrossRefPubMed
26.
go back to reference Barth PJ, Schenck zu Schweinsberg T, Ramaswamy A et al (2004) CD34+ fibrocytes, alpha-smooth muscle antigen-positive myofibroblasts, and CD117 expression in the stroma of invasive squamous cell carcinomas of the oral cavity, pharynx, and larynx. Virchows Arch 444(3):231–234CrossRefPubMed Barth PJ, Schenck zu Schweinsberg T, Ramaswamy A et al (2004) CD34+ fibrocytes, alpha-smooth muscle antigen-positive myofibroblasts, and CD117 expression in the stroma of invasive squamous cell carcinomas of the oral cavity, pharynx, and larynx. Virchows Arch 444(3):231–234CrossRefPubMed
27.
go back to reference Vered M, Shohat I, Buchner A et al (2005) Myofibroblasts in stroma of odontogenic cysts and tumors can contribute to variations in the biological behavior of lesions. Oral Oncol 41(10):1028–1033CrossRefPubMed Vered M, Shohat I, Buchner A et al (2005) Myofibroblasts in stroma of odontogenic cysts and tumors can contribute to variations in the biological behavior of lesions. Oral Oncol 41(10):1028–1033CrossRefPubMed
28.
go back to reference Kellermann MG, Sobral LM, da Silva SD et al (2007) Myofibroblasts in the stroma of oral squamous cell carcinoma are associated with poor prognosis. Histopathology 51(6):849–852CrossRefPubMed Kellermann MG, Sobral LM, da Silva SD et al (2007) Myofibroblasts in the stroma of oral squamous cell carcinoma are associated with poor prognosis. Histopathology 51(6):849–852CrossRefPubMed
29.
go back to reference Lynch CC, Matrisian LM (2002) Matrix metalloproteinases in tumor-host cell communication. Differentiation 70(9–10):561–573CrossRefPubMed Lynch CC, Matrisian LM (2002) Matrix metalloproteinases in tumor-host cell communication. Differentiation 70(9–10):561–573CrossRefPubMed
30.
go back to reference Patel PB, Shah PM, Rawal UM et al (2005) Activation of MMP-2 and MMP-9 in patients with oral squamous cell carcinoma. J Surg Oncol 90(2):81–88CrossRefPubMed Patel PB, Shah PM, Rawal UM et al (2005) Activation of MMP-2 and MMP-9 in patients with oral squamous cell carcinoma. J Surg Oncol 90(2):81–88CrossRefPubMed
31.
go back to reference de Vicente GJ, Fresno MF, Villalain L et al (2005) Expression and clinical significance of matrix metalloproteinase-2 and matrix metalloproteinase-9 in oral squamous cell carcinoma. Oral Oncol 41(3):283–293CrossRefPubMed de Vicente GJ, Fresno MF, Villalain L et al (2005) Expression and clinical significance of matrix metalloproteinase-2 and matrix metalloproteinase-9 in oral squamous cell carcinoma. Oral Oncol 41(3):283–293CrossRefPubMed
32.
go back to reference Prime SS, Davies M, Pring M et al (2004) The role of TGF-β I epithelial malignancy and its relevance to the pathogenesis of oral cancer (part II). Crit Rev Oral Biol Med 15(6):337–347CrossRefPubMed Prime SS, Davies M, Pring M et al (2004) The role of TGF-β I epithelial malignancy and its relevance to the pathogenesis of oral cancer (part II). Crit Rev Oral Biol Med 15(6):337–347CrossRefPubMed
33.
go back to reference Maeda G, Chiba T, Okazaki M et al (2005) Expression of SIP1 in oral squamous cell carcinomas: implications for E-cadherin expression and tumor progression. Int J Oncol 27(6):1535–1541PubMed Maeda G, Chiba T, Okazaki M et al (2005) Expression of SIP1 in oral squamous cell carcinomas: implications for E-cadherin expression and tumor progression. Int J Oncol 27(6):1535–1541PubMed
34.
go back to reference Pyo SW, Hashimoto M, Kim YS et al (2007) Expression of E-cadherin, P-cadherin and N-cadherin in oral squamous cell carcinoma: correlation with the clinicopathologic features and patient outcome. J Craniomaxillofac Surg 35(1):1–9PubMed Pyo SW, Hashimoto M, Kim YS et al (2007) Expression of E-cadherin, P-cadherin and N-cadherin in oral squamous cell carcinoma: correlation with the clinicopathologic features and patient outcome. J Craniomaxillofac Surg 35(1):1–9PubMed
35.
go back to reference Lim SC, Zhang S, Ishii G et al (2004) Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res 10(1 Pt 1):166–172CrossRefPubMed Lim SC, Zhang S, Ishii G et al (2004) Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res 10(1 Pt 1):166–172CrossRefPubMed
36.
go back to reference Huang Y, Fernandez SV, Goodwin S et al (2007) Epithelial to mesenchymal transition in human breast epithelial cells transformed by 17beta-estradiol. Cancer Res 67(23):11147–11157CrossRefPubMed Huang Y, Fernandez SV, Goodwin S et al (2007) Epithelial to mesenchymal transition in human breast epithelial cells transformed by 17beta-estradiol. Cancer Res 67(23):11147–11157CrossRefPubMed
37.
go back to reference Guarino M (2007) Epithelial-mesenchymal transition and tumor invasion. Int J Biochem Cell Biol 39(12):2153–2160CrossRefPubMed Guarino M (2007) Epithelial-mesenchymal transition and tumor invasion. Int J Biochem Cell Biol 39(12):2153–2160CrossRefPubMed
Metadata
Title
Stromal Myofibroblasts Accompany Modifications in the Epithelial Phenotype of Tongue Dysplastic and Malignant Lesions
Authors
Marilena Vered
Irit Allon
Amos Buchner
Dan Dayan
Publication date
01-12-2009
Publisher
Springer Netherlands
Published in
Cancer Microenvironment / Issue 1/2009
Print ISSN: 1875-2292
Electronic ISSN: 1875-2284
DOI
https://doi.org/10.1007/s12307-009-0020-0

Other articles of this Issue 1/2009

Cancer Microenvironment 1/2009 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine