침샘 선양낭성암종의 세포학적, 분자생물학적 특성에 관한 연구 = CELLULAR AND MOLECULAR CHARACTERIZATION OF ADENOID CYSTIC CARCINOMA OF THE SALIVARY GLANDS

다국어 초록 (Multilingual Abstract)

Adenoid cystic carcinoma (ACC) of salivary glands has a protracted clinical course with perineural invasion, delayed onset of hematogenous metastasis, and poor responses to classical cytotoxic chemotherapic agents. Most deaths from salivary ACC are caused by lung metastases that are resistant to conventional therapy. Therefore, knowledge of cellular properties and tumor-host interactions that influence the dissemination of metastatic cells is important for the design of more effective therapy of salivary cancer. I determined in vitro expression of epidermal growth factor receptor (EGFR) and its downstream effectors and vascular endothelial growth factor receptor (VEGFR)-2 on a human salivary ACC cell line (ACC2). I also evaluated the expression of EGF and VEGF signaling molecules and metastasis-related proteins on human salivary ACC cells orthotopically growing in nude mice. In Western blot and immunohistochemical analyses, EGFR and VEGFR-2 were presented and phosphorylated in ACC2 cells. In human parotid cancer xenografts in nude mice, EGF and VEGF signaling molecules, IL-8, and MMP-9 were expressed at markedly higher levels than in normal parotid tissues. Moreover, tumor-associated endothelial cells of this orthotopic parotid tumor expressed phosphorylated VEGFR-2 and phosphorylated Akt, which is a cell-survival protein. These data show that those biomarkers can be molecular targets for therapy of salivary ACC, which has a propensity for delayed lung metastasis.

참고문헌 (Reference)

1 "overview of a 35 year experience with 2" 807-, 1986

2 "overview of a 35 year experience with 2" 807-, 1986

3 "and pharmacodynamic trial of ZD1839 in patients with five selected solid tumor types" 2002

4 "and microvessel density in squamous cell carcinomas of the larynx Influence of microvessel density and vascular permeability factor/ vascular endothelial growth factor expression on prognosis in vulvar cancer" 19991996

5 "Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinoma of the head and neck" Clin Cancer Res 5 : 775-82, 1999

6 "Vascular endothelial growth factor induces endothelial fenestrations in vitro" 140 : 947-, 1998

7 "Tumor cell and endothelial cell therapy of oral cancer by dual tyrosine kinase receptor blockade" 64 : 7977-, 2004

8 "Transforming growth factor-alpha-induced transcriptional activation of the vascular permeability factor" 1997

9 "The many faces of metalloproteases Trends in Cell Biol 11" 2001

10 "Suppression of epidermal growth factor receptor and Pak1 pathway and invasiveness of human cutaneous squamous cancer cells by the tyrosine kinase inhibitor ZD1839" 2003

11 "Rationale and methods for the use of nude mice to study the biology and therapy of human cancer metastasis" 5 : 29-, 1986

12 "Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck" 21 : 1980-, 2003

13 "Paclitaxel and carboplatin for recurrent salivary gland malignancies" (5) : 3781-, 2000

14 "Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression" 3 : 515-, 1997

15 "Orthotopic models are necessary to predict therapy of transplantable tumors in mice" 17 : 279-, 1999

16 "Organ-specific modulation of steady-state mdr gene expression and drug resistance in murine colon carcinoma cell line" 86 : 913-, 1994

17 "Molecular and biological properties of the vascular endothelial growth factor family of proteins" 13 : 18-, 1992

18 "Modulation of tumor cell reponse to chemotherapy by the organ environment" 13 : 209-, 1994

19 "Microvessel density and expression of vascular endothelial growth factor in adenoid cystic carcinoma of salivary gland" 12 : 443-, 2003

20 "Metastatic models of human cancer xenografted in mice:the importance of orthotopic transplantation" 4-, 1994

21 "Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis Successful induction of B16-BL6 melanoma in the parotid gland of C57BL/6 black mouse Orthotopic implantaion of ACC2 cell suspension into the parotid gland A well-localized bleb confirmed a successful injection without leakage of the tumor cells The primary tumor in the parotid gland of nude mou" -200, 2000

22 "Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis Successful induction of B16-BL6 melanoma in the parotid gland of C57BL/6 black mouse Orthotopic implantaion of ACC2 cell suspension into the parotid gland A well-localized bleb confirmed a successful injection without leakage of the tumor cells The primary tumor in the parotid gland of nude mou" -200, 2000

23 "Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells" 1 : 19-, 1995

24 "Interleukin-8 as a macrophage derived mediator of angiogenesis" 258 : 1798-, 1992

25 "Immunohistochemical study of epidermal growth factor receptor in adenoid cystic carcinoma of salivary gland origin" 24 : 632-, 2002

26 "Hypoxia-induced angiogenesis of cultured human salivary gland carcinoma cells enhances vascular endothelial growth factor production and basic fibroblast growth factor release" 37 : 77-, 2001

27 "Extensive multi-organ metastasis following orthotopic implantation of histologically-intact human bladder carcinoma tissue in nude mice" 49 : 938-, 1991

28 "Expression of vascular endothelial growth factor in basal cell carcinoma and cutaneous squamous cell carcinoma of the head and neck" 29 : 585-, 2002

29 "Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis" 151 : 41-, 1997

30 "Expression of growth factors and their receptors in invasive breast cancer Correlations with proliferation and angiogenesis" 1998

31 "Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells:a model of glioblastoma multiforme pathophysiology" 121-, 1993

32 "Epidermal growth factor receptors as a target for cancer treatment:the emerging role of IMC-C225 in the treatment of lung and head and neck cancers" 27-, 2002

33 "Epidermal growth factor receptor blockade potentiates apoptosis mediated by paclitaxel and leads to prolonged survival in a murine model of oral cancer" Clin Cancer Res 9 : 3183-9, 2003

34 "Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy" 58 : 959-, 2004

35 "EGF receptor in neoplasia and metastasis" 12 : 255-, 1993

36 "Chemoradiotherapy for head and neck cancer:current status and perspectives" 421-, 2004

37 "Adenoid cystic carcinoma of the head and neck:predictors of morbidity and mortality" 149-, 1999

38 "A decade of tyrosine kinases:from gene discovery to therapeutics" 39-, 2003