Angiogenic co‐operation of VEGF and stromal cell TP in endometrial carcinomas

Vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) are important angiogenic enzymes, inducing new blood vessel formation in many human malignancies. In this study, the immunohistochemical expression of the two molecules was analysed in a series of 121 endometrial carcinomas. VEGF was expressed exclusively in cancer cells, while TP expression was shown in cancer cells (TPcc) and in stromal cells (TPsc) of both fibroblastic and myometrial origin. In all cases, enzymatic detection was particularly evident at the invading tumour front. At this site, TPsc, but not VEGF, expression was associated with non‐endometrioid‐type carcinomas, high tumour grade, deep myometrial invasion, and advanced stage. VEGF, but not TP, expression was related to increased angiogenesis (p=0.01). Double stratification of the two factors, however, marked VEGF/TPsc co‐expression as the most potent angiogenic phenotype (p=0.008), suggesting a synergistic function. Survival analysis revealed that VEGF and TPsc, whether expressed alone or in combination, define poor prognosis. In multivariate analysis, however, stage of disease (p<0.0001, t‐ratio 4.4) and VEGF expression (p=0.01, t‐ratio 2.4) were the most important prognostic variables. Furthermore, VEGF expression emerged as the only independent prognostic variable in stage I endometrial carcinomas (p=0.04, t‐ratio 1.9). This was not shown for TP, probably because of its close association with histopathological parameters. In conclusion, VEGF is a major angiogenic factor in endometrial carcinomas and an independent prognostic factor in stage I endometrial disease. TP is not an effective contributor to the angiogenic process, but is associated with aggressive histological features. The two factors, when co‐expressed, play a co‐operative role in the induction of angiogenesis. Copyright © 2002 John Wiley & Sons, Ltd.

[1]  A. Harris,et al.  Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors. , 2000, Cancer research.

[2]  M Ancukiewicz,et al.  Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. , 2000, Cancer research.

[3]  A. Harris,et al.  ‘Invading edge vs. inner’ (edvin) patterns of vascularization: an interplay between angiogenic and vascular survival factors defines the clinical behaviour of non‐small cell lung cancer , 2000, The Journal of pathology.

[4]  A. Giatromanolaki,et al.  Cancer vascularization: implications in radiotherapy? , 2000, International journal of radiation oncology, biology, physics.

[5]  L. Ellis,et al.  Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases , 2000, Cancer.

[6]  A. Harris,et al.  Serum vascular endothelial growth factor load and interleukin-6 in cancer patients , 2000, British Journal of Cancer.

[7]  K. O'Byrne,et al.  Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer , 2000, British Journal of Cancer.

[8]  A. Giatromanolaki,et al.  Angiogenesis, thymidine phosphorylase, and resistance of squamous cell head and neck cancer to cytotoxic and radiation therapy. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  H. Ito,et al.  Thymidine phosphorylase expression is associated with both increase of intratumoral microvessels and decrease of apoptosis in human colorectal carcinomas. , 1999, Cancer research.

[10]  N. Tsopanoglou,et al.  On the Mechanism of Thrombin-induced Angiogenesis , 1999, The Journal of Biological Chemistry.

[11]  K. Miyazaki,et al.  Co-expression of vascular endothelial growth factor and thymidine phosphorylase in endometrial cancer. , 1999, Acta obstetricia et gynecologica Scandinavica.

[12]  R. Weichselbaum,et al.  Blockade of the Vascular Endothelial Growth Factor Stress Response Increases the Antitumor Effects of Ionizing Radiation , 1999 .

[13]  A. Harris,et al.  Thymidine phosphorylase expression in endometrial carcinomas , 1999, Clinical & Experimental Metastasis.

[14]  M. Volm,et al.  Inverse correlation between apoptotic (Fas ligand, caspase-3) and angiogenic factors (VEGF, microvessel density) in squamous cell lung carcinomas. , 1999, Anticancer research.

[15]  D. Hanahan,et al.  Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. , 1999, Cancer research.

[16]  H. Watanabe,et al.  Histochemical study of vascular endothelial growth factor in squamous cell carcinoma of the esophagus. , 1999, Hepato-gastroenterology.

[17]  K. Alitalo,et al.  Vascular endothelial growth factor (VEGF)‐C synergizes with basic fibroblast growth factor and VEGF in the induction of angiogenesis in vitro and alters endothelial cell extracellular proteolytic activity , 1998, Journal of cellular physiology.

[18]  Vishva Dixit,et al.  Vascular Endothelial Growth Factor Regulates Endothelial Cell Survival through the Phosphatidylinositol 3′-Kinase/Akt Signal Transduction Pathway , 1998, The Journal of Biological Chemistry.

[19]  A. Harris,et al.  Neo-angiogenesis in locally advanced squamous cell head and neck cancer correlates with thymidine phosphorylase expression and p53 nuclear oncoprotein accumulation , 1998, Clinical & Experimental Metastasis.

[20]  A. Harris,et al.  Validation of anti‐vascular endothelial growth factor (anti‐VEGF) antibodies for immunohistochemical localization of VEGF in tissue sections: expression of VEGF in the human endometrium , 1998, The Journal of pathology.

[21]  V. Dixit,et al.  Vascular Endothelial Growth Factor Induces Expression of the Antiapoptotic Proteins Bcl-2 and A1 in Vascular Endothelial Cells* , 1998, The Journal of Biological Chemistry.

[22]  K. O'Byrne,et al.  Platelet-derived endothelial cell growth factor expression correlates with tumour angiogenesis and prognosis in non-small-cell lung cancer. , 1997, British Journal of Cancer.

[23]  N. Ferrara,et al.  The biology of vascular endothelial growth factor. , 1997, Endocrine reviews.

[24]  M. Brizzi,et al.  Activation of JAK2 in human vascular endothelial cells by granulocyte-macrophage colony-stimulating factor. , 1997, Blood.

[25]  S. Akiba,et al.  Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. , 1996, Journal of the National Cancer Institute.

[26]  A. Harris,et al.  Platelet‐derived endothelial cell growth factor/thymidine phosphorylase expression in normal tissues: An immunohistochemical study , 1995, The Journal of pathology.

[27]  H. Ishitsuka,et al.  Expression of platelet‐derived endothelial cell growth factor/thymidine phosphorylase in human breast cancer , 1995, International journal of cancer.

[28]  S. Fox,et al.  Thymidine phosphorylase is angiogenic and promotes tumor growth. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[29]  J. Pearson Tumors of the Uterine Corpus and Gestational Trophoblastic Disease , 1993 .

[30]  L. Copeland,et al.  Stage I endometrial adenocarcinoma: treatment results in 835 patients. , 1983, American journal of obstetrics and gynecology.

[31]  B. Fine,et al.  VEGF, flt-1, and KDR/flk-1 as prognostic indicators in endometrial carcinoma. , 2000, Gynecologic oncology.

[32]  A. Giatromanolaki,et al.  Angiogenic interactions of vascular endothelial growth factor, of thymidine phosphorylase, and of p53 protein expression in locally advanced gastric cancer. , 2000, Oncology research.

[33]  A. Giatromanolaki,et al.  Intratumoral angiogenesis: a new prognostic indicator for stage I endometrial adenocarcinomas? , 1999, Oncology research.

[34]  R. Weichselbaum,et al.  Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. , 1999, Cancer research.

[35]  Sandra R. Smith,et al.  Growth factor effects on cells of the vascular wall: a survey. , 1993, Growth factors.

[36]  Carcinoma of the endometrium. ACOG Technical Bulletin Number 162--December 1991. , 1993, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[37]  H. Fox,et al.  Biopsy pathology of the endometrium , 1989 .