Skip to main content
Erschienen in: Angiogenesis 2/2011

01.05.2011 | Original Paper

Immunohistochemical expression of VEGF predicts response to platinum based chemotherapy in patients with epithelial ovarian cancer

verfasst von: G. K. Siddiqui, A. B. Maclean, K. Elmasry, A. Wong te Fong, R. W. Morris, M. Rashid, R. H. J. Begent, G. M. Boxer

Erschienen in: Angiogenesis | Ausgabe 2/2011

Einloggen, um Zugang zu erhalten

Abstract

Purpose

For patients with epithelial ovarian cancer (EOC) cytoreduction, with a combination of taxane and platinum, is the standard of care. Despite this, approximately 50% of patients with advanced disease will relapse and moreover 15–20% of cases of EOC are resistant to platinum based chemotherapy. Vascular Endothelial Growth Factor (VEGF), an angiogenic factor, is associated with poor prognosis. This study was undertaken to examine whether there is an association between VEGF-A expression in the tumour of EOC patients and their response to platinum based chemotherapy.

Methods

The study cohort consisted of 66 patients with advanced stage EOC (FIGO III-IV). Ovarian cancer tissue was analysed for VEGF-A expression immunohistochemically. Protein expression was measured and correlated, with platinum sensitivity and overall patient survival.

Results

Median age of patients was 53 years, 45 patients had platinum sensitive disease (68%), the remaining patients being platinum resistant (32%). Of the platinum resistant group, 18 (86%) patients had high VEGF score compared to only 1 (2%) with high VEGF score in the platinum sensitive group. Median survival was 11 months in the patient group with high VEGF score versus 32 months in that cohort with low VEGF score. VEGF expression was significantly inversely correlated with overall survival (P < 0.0001).

Conclusion

We demonstrated that tumours of patients with platinum resistant EOC exhibit higher levels of VEGF expression compared to the platinum sensitive group. VEGF in EOC, may be of clinical and therapeutic relevance and suggests a role for first line anti-angiogenic therapy.
Literatur
1.
Zurück zum Zitat Berek J (2005) Epithelial ovarian cancer. In: Berek J (ed) Practical gynecolgical oncology, vol 4. Lippincott Wiliams and Wilkins, Philadelphia Berek J (2005) Epithelial ovarian cancer. In: Berek J (ed) Practical gynecolgical oncology, vol 4. Lippincott Wiliams and Wilkins, Philadelphia
2.
Zurück zum Zitat Friedlander ML (1998) Prognostic factors in ovarian cancer. Semin Oncol 25(3):305–314PubMed Friedlander ML (1998) Prognostic factors in ovarian cancer. Semin Oncol 25(3):305–314PubMed
3.
Zurück zum Zitat Duncan TJ, Al-Attar A, Rolland P, Scott IV, Deen S, Liu DT et al (2008) Vascular endothelial growth factor expression in ovarian cancer: a model for targeted use of novel therapies? Clin Cancer Res 14(10):3030–3035PubMedCrossRef Duncan TJ, Al-Attar A, Rolland P, Scott IV, Deen S, Liu DT et al (2008) Vascular endothelial growth factor expression in ovarian cancer: a model for targeted use of novel therapies? Clin Cancer Res 14(10):3030–3035PubMedCrossRef
4.
Zurück zum Zitat Battegay EJ (1995) Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med 73(7):333–346PubMedCrossRef Battegay EJ (1995) Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med 73(7):333–346PubMedCrossRef
5.
Zurück zum Zitat Boxer GM, Tsiompanou E, Levine T, Watson R, Begent RH (2005) Immunohistochemical expression of vascular endothelial growth factor and microvessel counting as prognostic indicators in node-negative colorectal cancer. Tumour Biol 26(1):1–8PubMedCrossRef Boxer GM, Tsiompanou E, Levine T, Watson R, Begent RH (2005) Immunohistochemical expression of vascular endothelial growth factor and microvessel counting as prognostic indicators in node-negative colorectal cancer. Tumour Biol 26(1):1–8PubMedCrossRef
6.
Zurück zum Zitat Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1(1):27–31PubMedCrossRef Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1(1):27–31PubMedCrossRef
7.
Zurück zum Zitat Fujimoto J, Sakaguchi H, Hirose R, Ichigo S, Tamaya T (1998) Biologic implications of the expression of vascular endothelial growth factor subtypes in ovarian carcinoma. Cancer 83(12):2528–2533PubMedCrossRef Fujimoto J, Sakaguchi H, Hirose R, Ichigo S, Tamaya T (1998) Biologic implications of the expression of vascular endothelial growth factor subtypes in ovarian carcinoma. Cancer 83(12):2528–2533PubMedCrossRef
8.
Zurück zum Zitat Berse B, Brown LF, Van de Water L, Dvorak HF, Senger DR (1992) Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 3(2):211–220PubMed Berse B, Brown LF, Van de Water L, Dvorak HF, Senger DR (1992) Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 3(2):211–220PubMed
9.
Zurück zum Zitat Dang DT, Chun SY, Burkitt K, Abe M, Chen S, Havre P et al (2008) Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition. Cancer Res 68(6):1872–1880PubMedCrossRef Dang DT, Chun SY, Burkitt K, Abe M, Chen S, Havre P et al (2008) Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition. Cancer Res 68(6):1872–1880PubMedCrossRef
10.
Zurück zum Zitat Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, Tong RK et al (2008) Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13(4):331–342PubMedCrossRef Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, Tong RK et al (2008) Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13(4):331–342PubMedCrossRef
11.
Zurück zum Zitat Neuhaus T, Pabst S, Stier S, Weber AA, Schror K, Sachinidis A et al (2004) Inhibition of the vascular-endothelial growth factor-induced intracellular signaling and mitogenesis of human endothelial cells by epigallocatechin-3 gallate. Eur J Pharmacol 483(2–3):223–227PubMedCrossRef Neuhaus T, Pabst S, Stier S, Weber AA, Schror K, Sachinidis A et al (2004) Inhibition of the vascular-endothelial growth factor-induced intracellular signaling and mitogenesis of human endothelial cells by epigallocatechin-3 gallate. Eur J Pharmacol 483(2–3):223–227PubMedCrossRef
12.
Zurück zum Zitat Mylona E, Nomikos A, Alexandrou P, Giannopoulou I, Keramopoulos A, Nakopoulou L (2007) Lymphatic and blood vessel morphometry in invasive breast carcinomas: relation with proliferation and VEGF-C and -D proteins expression. Histol Histopathol 22(8):825–835PubMed Mylona E, Nomikos A, Alexandrou P, Giannopoulou I, Keramopoulos A, Nakopoulou L (2007) Lymphatic and blood vessel morphometry in invasive breast carcinomas: relation with proliferation and VEGF-C and -D proteins expression. Histol Histopathol 22(8):825–835PubMed
13.
Zurück zum Zitat Roberts DL, Williams KJ, Cowen RL, Barathova M, Eustace AJ, Brittain-Dissont S et al (2009) Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells. Br J Cancer 101(8):1290–1297PubMedCrossRef Roberts DL, Williams KJ, Cowen RL, Barathova M, Eustace AJ, Brittain-Dissont S et al (2009) Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells. Br J Cancer 101(8):1290–1297PubMedCrossRef
14.
Zurück zum Zitat Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS et al (2006) Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 24(2):217–227PubMedCrossRef Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS et al (2006) Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 24(2):217–227PubMedCrossRef
15.
Zurück zum Zitat Yamamoto S, Konishi I, Tsuruta Y, Nanbu K, Mandai M, Kuroda H et al (1997) Expression of vascular endothelial growth factor (VEGF) during folliculogenesis and corpus luteum formation in the human ovary. Gynecol Endocrinol 11(6):371–381PubMedCrossRef Yamamoto S, Konishi I, Tsuruta Y, Nanbu K, Mandai M, Kuroda H et al (1997) Expression of vascular endothelial growth factor (VEGF) during folliculogenesis and corpus luteum formation in the human ovary. Gynecol Endocrinol 11(6):371–381PubMedCrossRef
16.
Zurück zum Zitat Abu-Jawdeh GM, Faix JD, Niloff J, Tognazzi K, Manseau E, Dvorak HF et al (1996) Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms. Lab Invest 74(6):1105–1115PubMed Abu-Jawdeh GM, Faix JD, Niloff J, Tognazzi K, Manseau E, Dvorak HF et al (1996) Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms. Lab Invest 74(6):1105–1115PubMed
17.
Zurück zum Zitat Byrne AT, Ross L, Holash J, Nakanishi M, Hu L, Hofmann JI et al (2003) Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 9(15):5721–5728PubMed Byrne AT, Ross L, Holash J, Nakanishi M, Hu L, Hofmann JI et al (2003) Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 9(15):5721–5728PubMed
18.
Zurück zum Zitat Markman M, Hoskins W (1992) Responses to salvage chemotherapy in ovarian cancer: a critical need for precise definitions of the treated population. J Clin Oncol 10(4):513–514PubMed Markman M, Hoskins W (1992) Responses to salvage chemotherapy in ovarian cancer: a critical need for precise definitions of the treated population. J Clin Oncol 10(4):513–514PubMed
19.
Zurück zum Zitat Alvarez AA, Krigman HR, Whitaker RS, Dodge RK, Rodriguez GC (1999) The prognostic significance of angiogenesis in epithelial ovarian carcinoma. Clin Cancer Res 5(3):587–591PubMed Alvarez AA, Krigman HR, Whitaker RS, Dodge RK, Rodriguez GC (1999) The prognostic significance of angiogenesis in epithelial ovarian carcinoma. Clin Cancer Res 5(3):587–591PubMed
20.
Zurück zum Zitat Hollingsworth HC, Kohn EC, Steinberg SM, Rothenberg ML, Merino MJ (1995) Tumor angiogenesis in advanced stage ovarian carcinoma. Am J Pathol 147(1):33–41PubMed Hollingsworth HC, Kohn EC, Steinberg SM, Rothenberg ML, Merino MJ (1995) Tumor angiogenesis in advanced stage ovarian carcinoma. Am J Pathol 147(1):33–41PubMed
21.
Zurück zum Zitat Paley PJ, Staskus KA, Gebhard K, Mohanraj D, Twiggs LB, Carson LF et al (1997) Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer 80(1):98–106PubMedCrossRef Paley PJ, Staskus KA, Gebhard K, Mohanraj D, Twiggs LB, Carson LF et al (1997) Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer 80(1):98–106PubMedCrossRef
22.
Zurück zum Zitat Gasparini G, Bonoldi E, Viale G, Verderio P, Boracchi P, Panizzoni GA et al (1996) Prognostic and predictive value of tumour angiogenesis in ovarian carcinomas. Int J Cancer 69(3):205–211PubMedCrossRef Gasparini G, Bonoldi E, Viale G, Verderio P, Boracchi P, Panizzoni GA et al (1996) Prognostic and predictive value of tumour angiogenesis in ovarian carcinomas. Int J Cancer 69(3):205–211PubMedCrossRef
23.
Zurück zum Zitat Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL et al (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349(5):427–434PubMedCrossRef Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL et al (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349(5):427–434PubMedCrossRef
24.
Zurück zum Zitat Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25(12):1539–1544PubMedCrossRef Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25(12):1539–1544PubMedCrossRef
25.
Zurück zum Zitat Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF et al (2003) A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 30(5 Suppl 16):117–124PubMedCrossRef Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF et al (2003) A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 30(5 Suppl 16):117–124PubMedCrossRef
26.
Zurück zum Zitat Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H et al (2007) Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25(33):5180–5186PubMedCrossRef Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H et al (2007) Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25(33):5180–5186PubMedCrossRef
28.
Zurück zum Zitat Engels K, du Bois A, Harter P, Fisseler-Eckhoff A, Kommoss F, Stauber R et al (2009) VEGF-A and i-NOS expression are prognostic factors in serous epithelial ovarian carcinomas after complete surgical resection. J Clin Pathol 62(5):448–454PubMedCrossRef Engels K, du Bois A, Harter P, Fisseler-Eckhoff A, Kommoss F, Stauber R et al (2009) VEGF-A and i-NOS expression are prognostic factors in serous epithelial ovarian carcinomas after complete surgical resection. J Clin Pathol 62(5):448–454PubMedCrossRef
29.
Zurück zum Zitat Han ES, Monk BJ (2007) Bevacizumab in the treatment of ovarian cancer. Expert Rev Anticancer Ther 7(10):1339–1345PubMedCrossRef Han ES, Monk BJ (2007) Bevacizumab in the treatment of ovarian cancer. Expert Rev Anticancer Ther 7(10):1339–1345PubMedCrossRef
30.
Zurück zum Zitat O’Toole SA, Sheppard BL, Laios A, O’Leary JJ, McGuinness EP, D’Arcy T et al (2007) Potential predictors of chemotherapy response in ovarian cancer–how do we define chemosensitivity? Gynecol Oncol 104(2):345–351PubMedCrossRef O’Toole SA, Sheppard BL, Laios A, O’Leary JJ, McGuinness EP, D’Arcy T et al (2007) Potential predictors of chemotherapy response in ovarian cancer–how do we define chemosensitivity? Gynecol Oncol 104(2):345–351PubMedCrossRef
31.
Zurück zum Zitat Hu L, Hofmann J, Holash J, Yancopoulos GD, Sood AK, Jaffe RB (2005) Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin Cancer Res 11(19 Pt 1):6966–6971PubMedCrossRef Hu L, Hofmann J, Holash J, Yancopoulos GD, Sood AK, Jaffe RB (2005) Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin Cancer Res 11(19 Pt 1):6966–6971PubMedCrossRef
32.
Zurück zum Zitat Bamias A, Koutsoukou V, Terpos E, Tsiatas ML, Liakos C, Tsitsilonis O et al (2008) Correlation of NK T-like CD3 + CD56 + cells and CD4 + CD25 + (hi) regulatory T cells with VEGF and TNFalpha in ascites from advanced ovarian cancer: association with platinum resistance and prognosis in patients receiving first-line, platinum-based chemotherapy. Gynecol Oncol 108(2):421–427PubMedCrossRef Bamias A, Koutsoukou V, Terpos E, Tsiatas ML, Liakos C, Tsitsilonis O et al (2008) Correlation of NK T-like CD3 + CD56 + cells and CD4 + CD25 + (hi) regulatory T cells with VEGF and TNFalpha in ascites from advanced ovarian cancer: association with platinum resistance and prognosis in patients receiving first-line, platinum-based chemotherapy. Gynecol Oncol 108(2):421–427PubMedCrossRef
33.
Zurück zum Zitat Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI (2007) Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol 25(33):5165–5171PubMedCrossRef Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI (2007) Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol 25(33):5165–5171PubMedCrossRef
34.
Zurück zum Zitat Raspollini MR, Amunni G, Villanucci A, Baroni G, Boddi V, Taddei GL (2004) Prognostic significance of microvessel density and vascular endothelial growth factor expression in advanced ovarian serous carcinoma. Int J Gynecol Cancer 14(5):815–823PubMedCrossRef Raspollini MR, Amunni G, Villanucci A, Baroni G, Boddi V, Taddei GL (2004) Prognostic significance of microvessel density and vascular endothelial growth factor expression in advanced ovarian serous carcinoma. Int J Gynecol Cancer 14(5):815–823PubMedCrossRef
35.
Zurück zum Zitat Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676PubMedCrossRef Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676PubMedCrossRef
Metadaten
Titel
Immunohistochemical expression of VEGF predicts response to platinum based chemotherapy in patients with epithelial ovarian cancer
verfasst von
G. K. Siddiqui
A. B. Maclean
K. Elmasry
A. Wong te Fong
R. W. Morris
M. Rashid
R. H. J. Begent
G. M. Boxer
Publikationsdatum
01.05.2011
Verlag
Springer Netherlands
Erschienen in
Angiogenesis / Ausgabe 2/2011
Print ISSN: 0969-6970
Elektronische ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-010-9199-4

Weitere Artikel der Ausgabe 2/2011

Angiogenesis 2/2011 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.