The correlation of vascular endothelial growth factor with angiogenesis and p53 gene in laryngeal squamous celi carcinoma

Yıl 2006, Cilt: 16 Sayı: 3, 105 - 111, 30.06.2006

Atılay Yaylacı Salih Çakır Pembegül Güneş Adil Çınar Akkaynak Barış Naiboğlu Tanju Gökçeer

Öz

Objectives: Angiogenesis is a fundamental process in tumour growth and metastasis. VEGF Vascular endothelial growth factor is a key regülatör of angiogenesis and it has been identified in a wide variety of malignancies, including head and neck squamous celi carcinoma.Hovvever, the regulation of VEGF expression in tumour angiogenesis is not well defined. The tumour-suppressor gene p53 has been thought to regulate VEGF. İn this study, we examined the role of p53 gene on VEGF expression.Patients and Methods: Clinical records of patients’ who undervvent total or partial laryngectomy betvveen 1999-2002 years were revievved. Of these, ali paraffin-embedded specimens of 27 patients 27 males; mean age 55 years; range 39 to 74 years with diagnosis of larynx epidermoid carcinoma were immunostained to evaluate VEGF expression, p53 gene status and microvessel density MVD .Variables were statistically examined.Results: Vascular endothelial growth factor positive staining was detected in 11 40.7% and p53 mutations were identified in 16 60% of 27 tumours. No association was detected betvveen p53 mutations and VEGF expression level p>0.05 . Statistical analysis gave a clear correlation betvveen the tumour vascularity and the VEGF protein expression p<0.05 . Vascular endothelial grovvth factor negative tumours shovved a lovver mean number of microvessels per micro- scopic field 29.6±6.6 than VEGF positive tumours 40.8±15.2 . P53 and VEGF expression levels and MVD did not correlate with the T- stage, N-status, tumour localization and histological grading p>0.05 .Conclusion: The higher microvessel density in VEGF positive tumours supports the importance of VEGF for tumour angiogenesis in laryngeal carcinoma. Hovvever, our result does not support the hypothesis of a p53 regulation on the angiogenic process through a VEGF up-regulation.

Anahtar Kelimeler

Carcinoma, sguamous cell/genetics/metabolism, DNA mutational analy­sis, endothelium, vascular/metabolism/pathology, genes, p53/genetics, grovvth substances/genetics/metabolism, head and neck neoplasms/genetics/metabolism/pathology, immunohistochemistry

Larenksin skuamöz hücreli kanserlerinde vasküler endotelyal büyüme faktörünün anjiyogenez ve p53 geni ile ilişkisi

Öz

Amaç: Anjiyogenez tümör büyümesi ve metastazındaki temel süreçlerden biridir. VEGF Vascular endothelial growth factor , anjiyogenezin temel düzenleyicisidir ve baş-boyun skuamöz hücreli karsinomunun da içerisinde bulunduğu birçok malignitede saptanmıştır. Fakat,tümör anjiyogenezinde VEGF ekspresyonunun düzenlenmesi tamolarak aydınlatılamamıştır. Bir tümör-süpressör gen olan p53 genininVEGF ekspresyonunun düzenleyicisi olduğu düşünülmektedir. Bu çalışmada, p53 geninin VEGF ekspresyonu üzerindeki etkisi incelendi.Hastalar ve Yöntemler: 1999 ve 2002 yılları arasında, total veya parsiyel larenjektomi ameliyatı uygulanan hastalara ait klinik kayıtlar gözden geçirildi. Bunlardan larenks epidermoid karsinomu tanısı konmuş27 hastanın parafine batırılmışspesimenleri çalışmaya alındı. Örnek dokularda, VEGF ekspresyonu,p53 gen durumu ve mikrodamar yoğunluğu MDY immünhistokimyasal yöntemle incelendi. Değişkenler istatistiksel olarak değerlendirildi.Bulgular: Vascular endothelial growth factor pozitifliği 11 tümörde %40.7 ve p53 mutasyonları 16 tümörde %60 saptandı. P53 mutasyonları ile VEGF ekspresyon derecesi arasında bir ilişki bulunamadı p>0.05 . İstatistiksel olarak tümör vaskülarizasyonu ile VEGF proteinekspresyonu arasında anlamlı bir ilişki vardı p0.05 .Sonuç: Vascular endothelial growth factor pozitif tümörlerde MDY’ninyüksek olması larenks karsinomu anjiyogenezinde VEGF’nin öneminiortaya koymaktadır. Fakat sonuçlarımız, p53 geninin VEGF ekspresyonunu değiştirerek anjiyogenezi düzenlediği hipotezini desteklememektedir

Anahtar Kelimeler

Skuamöz hücreli karsinom/genetik/metabolizma, DNA mutasyon analizi, vasküler endotel/metabolizma/patoloji, p53 geni, büyüme maddesi/genetik/metabolizma, baş boyun tümörleri/genetik/metabolizma/patoloji, immünhistokimya

Kaynakça

• Riedel F, Gotte K, Schwalb J, Schafer C, Hormann K. Vascular endothelial growth factor expression corre- lates with p53 mutation and angiogenesis in squamous cell carcinoma of the head and neck. Acta Otolaryngol 2000;120:105-11.
• Shibusa T, Shijubo N, Abe S. Tumor angiogenesis and vascular endothelial growth factor expression in stage I lung adenocarcinoma. Clin Cancer Res 1998;4:1483-7.
• Poljak M, Gale N, Kambic V, Ferluga D, Fischinger J. Overexpression of p53 protein in benign and malig- nant laryngeal epithelial lesions. Anticancer Res 1996; 16:1947-51.
• Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med 1991;324:1-8.
• Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memor- ial Award lecture. Cancer Res 1986;46:467-73.
• Folkman J. What is the evidence that tumors are angio- genesis dependent? J Natl Cancer Inst 1990;82:4-6.
• Hanahan D, Folkman J. Patterns and emerging mecha- nisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353-64.
• Ferrara N. Vascular endothelial growth factor. Eur J Cancer 1996;32:2413-22.
• Conn G, Soderman DD, Schaeffer MT, Wile M, Hatcher VB, Thomas KA. Purification of a glycoprotein vascu- lar endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci U S A 1990;87:1323-7.
• Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995;146:1029-39.
• Vincenti V, Cassano C, Rocchi M, Persico G. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation 1996; 93:1493-5.
• Robinson CJ, Stringer SE. The splice variants of vascu- lar endothelial growth factor (VEGF) and their recep- tors. J Cell Sci 2001;114(Pt 5):853-65.
• Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vas- cular endothelial cells. Biochem Biophys Res Commun 1989;161:851-8.
• Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 1994;269:26988-95.
• Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999;13:9-22.
• Senger DR, Perruzzi CA, Feder J, Dvorak HF. A high- ly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res 1986;46:5629-32.
• Ferrara N. Molecular and biological properties of vas- cular endothelial growth factor. J Mol Med 1999; 77:527-43.
• Maeda T, Matsumura S, Hiranuma H, Jikko A, Furukawa S, Ishida T, et al. Expression of vascular endothelial growth factor in human oral squamous cell carcinoma: its association with tumour progres- sion and p53 gene status. J Clin Pathol 1998;51:771-5.
• Kieser A, Weich HA, Brandner G, Marme D, Kolch W. Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 1994;9:963-9.
• Mukhopadhyay D, Tsiokas L, Sukhatme VP. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res 1995;55:6161-5.
• Salven P, Heikkila P, Anttonen A, Kajanti M, Joensuu H. Vascular endothelial growth factor in squamous cell head and neck carcinoma: expression and prognostic significance. Mod Pathol 1997;10:1128-33.
• Eisma RJ, Spiro JD, Kreutzer DL. Vascular endothelial growth factor expression in head and neck squamous cell carcinoma. Am J Surg 1997;174:513-7.
• Mineta H, Miura K, Ogino T, Takebayashi S, Misawa K, Ueda Y, et al. Prognostic value of vascular endothe- lial growth factor (VEGF) in head and neck squamous cell carcinomas. Br J Cancer 2000;83:775-81.
• Neuchrist C, Quint C, Pammer A, Burian M. Vascular endothelial growth factor (VEGF) and microvessel density in squamous cell carcinomas of the larynx: an immunohistochemical study. Acta Otolaryngol 1999; 119:732-8.
• Burian M, Quint C, Neuchrist C. Angiogenic factors in laryngeal carcinomas: do they have prognostic rele- vance? Acta Otolaryngol 1999;119:289-92.
• Ünal A, Özcan M, Albayrak L, Çetin MA, Tuncel Ü, Nalça Y. Larinks kanserlerinde CD34 ve p53’ün klinikopatolojik parametrelerle ilişkisi. KBB ve Baş Boyun Cerrahisi Dergisi 1999;7:104-9.
• Gorgoulis V, Rassidakis G, Karameris A, Giatromanolaki A, Barbatis C, Kittas C. Expression of p53 protein in laryngeal squamous cell carcinoma and dysplasia: pos- sible correlation with human papillomavirus infection and clinicopathological findings. Virchows Arch 1994;425:481-9.
• Caruso ML, Valentini AM. Localization of p53 protein and human papillomavirus in laryngeal squamous lesions. Anticancer Res 1997;17:4671-5.
• Kropveld A, Slootweg PJ, Blankenstein MA, Terhaard CH, Hordijk GJ. Ki-67 and p53 in T2 laryngeal cancer. Laryngoscope 1998;108:1548-52.
• Field JK, Pavelic ZP, Spandidos DA, Stambrook PJ, Jones AS, Gluckman JL. The role of the p53 tumor sup- pressor gene in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1993; 119:1118-22.
• Dolcetti R, Doglioni C, Maestro R, Gasparotto D, Barzan L, Pastore A, et al. p53 over-expression is an early event in the development of human squamous- cell carcinoma of the larynx: genetic and prognostic implications. Int J Cancer 1992;52:178-82.
• Gasparini G, Weidner N, Maluta S, Pozza F, Boracchi P, Mezzetti M, et al. Intratumoral microvessel density and p53 protein: correlation with metastasis in head- and-neck squamous-cell carcinoma. Int J Cancer 1993; 55:739-44.
• Hücümenoğlu S, Özağar A, Hücümenoğlu M, Erdem G, Şiriner Gİ. Larenks kanserlerinde anjiogenezin p53, histolojik evre ve nodal metastaz ile korelasyonu. KBB ve Baş Boyun Cerrahisi Dergisi 2000;8:129-34.
• Kaiser TN, Spector GJ. Tumours of the larynx and laryngopharynx. In: Ballenger JJ, editor. Diseases of the nose, thorat, ear, head and neck. Pennsylvania: Lea and Febiger, Malvern; 1991. p. 682-746.
• Leedy DA, Trune DR, Kronz JD, Weidner N, Cohen JI. Tumor angiogenesis, the p53 antigen, and cervical metastasis in squamous carcinoma of the tongue. Otolaryngol Head Neck Surg 1994;111:417-22.
• Narayana A, Vaughan AT, Gunaratne S, Kathuria S, Walter SA, Reddy SP. Is p53 an independent prognos- tic factor in patients with laryngeal carcinoma? Cancer 1998;82:286-91.
• Augustin HG. Antiangiogenic tumour therapy: will it work? Trends Pharmacol Sci 1998;19:216-22.