The expression of Platelet-derived Growth factor receptors (PDGFRs) and their correlation with overall survival of patients with ovarian cancer
Abstract
Objectives: The main aim of the study was to investigate the expression of Platelet-Derived Growth Factor Receptors alpha (PDGFR-alpha) and beta (PDGFR-beta) in malignant and benign ovarian tumors. We performed an analysis of the correlation of PDGFRs expression and stage of the disease, tumor grade and histopathological type of epithelial ovarian cancer (EOC). Additionally, we evaluated patient prognosis according to PDGFR expression.
Material and methods: Our study group was composed of 52 samples of EOCs, 35 samples of benign ovarian tumors (BOTs), and 21 samples of unchanged ovaries (UOs). The samples were collected from patients who had been operated on in the Division of Gynecological Surgery of the Poznan University of Medical Sciences.
Results: PDGFR-alpha was found to be expressed more frequently in cancer cells of EOCs, when compared with tumor cells of BOTs and epithelium of UOs. On the other hand, PDGFR-alpha receptors were present less frequently in the stroma of EOCs, when compared with the stroma of BOTs and UOs. Comparing the studied groups, there were no statistically significant differences in the expression of PDGFR-beta. The expression of both PDGFRs was not related to the FIGO stage, grade or histopathological type of EOCs. The expression of the PDGFR-beta receptor in cancer cells was associated with an improved overall survival among patients with EOCs. Patient prognosis was not affected by either PDGFR-alpha expres- sion or by PDGFR-beta tumor stroma expression.
Conclusions: The expression of PDGFR-alpha is significantly different when comparing EOCs, BOTs and UOs. However, the prognosis of EOC only seems to be affected by PDGFR-beta expression in cancer cells.
Keywords: platelet-derived growth factorplatelet-derived growth factor receptorovarian malignanciesepithelial ovarian cancer
References
- Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin. 2010; 60(5): 277–300.
- Bois Adu. A Randomized Clinical Trial of Cisplatin/Paclitaxel Versus Carboplatin/Paclitaxel as First-Line Treatment of Ovarian Cancer. CancerSpectrum Knowledge Environment. 2003; 95(17): 1320–1329.
- Szymankiewicz M, Dziobek K, Sznajdorwska M, et al. An analysis of the influence of infection on overall survival rates, following modified posterior pelvic exenteration for advanced ovarian cancer. Ginekol Pol. 2018; 89(11): 618–626.
- Burger RA. Overview of anti-angiogenic agents in development for ovarian cancer. Gynecol Oncol. 2011; 121(1): 230–238.
- Perren TJ, Swart AM, Pfisterer J, et al. ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011; 365(26): 2484–2496.
- Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008; 8(8): 592–603.
- Nowak-Sliwinska P, Griffioen AW. Angiogenesis inhibitors in combinatorial approaches. Angiogenesis. 2017; 20(2): 183–184.
- Li WL, Yamada Y, Ueno M, et al. Platelet derived growth factor receptor alpha is essential for establishing a microenvironment that supports definitive erythropoiesis. J Biochem. 2006; 140(2): 267–273.
- Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Communication and Signaling. 2013; 11(1): 97.
- Biedka M, Nowikiewicz T, Dziobek K, et al. The analysis of Treg lymphocytes in the blood of patients with breast cancer during the combined oncological treatment. Breast J. 2019; 26(1).
- Walentowicz-Sadlecka M, Dziobek K, Grabiec M, et al. The analysis of human leukocyte antigen-G level in patients with endometrial cancer by Western blot technique. American Journal of Reproductive Immunology. 2018; 81(1): e13070.
- Koper K, Dziobek K, Makarewicz R, et al. The analysis of the long-term outcomes in elderly women treated for locally advanced cervical cancer. J Contemp Brachytherapy. 2018; 10(5): 411–417.
- Matei D, Emerson RE, Lai YC, et al. Autocrine activation of PDGFRalpha promotes the progression of ovarian cancer. Oncogene. 2006; 25(14): 2060–2069.
- Lassus H, Sihto H, Leminen A, et al. Genetic alterations and protein expression of KIT and PDGFRA in serous ovarian carcinoma. Br J Cancer. 2004; 91(12): 2048–2055.
- Apte SM, Fan D, Killion JJ, et al. Targeting the platelet-derived growth factor receptor in antivascular therapy for human ovarian carcinoma. Clin Cancer Res. 2004; 10(3): 897–908.
- Matsuo K, Nishimura M, Komurov K, et al. Platelet-derived growth factor receptor alpha (PDGFRα) targeting and relevant biomarkers in ovarian carcinoma. Gynecol Oncol. 2014; 132(1): 166–175.
- Apte SM, Bucana CD, Killion JJ, et al. Expression of platelet-derived growth factor and activated receptor in clinical specimens of epithelial ovarian cancer and ovarian carcinoma cell lines. Gynecol Oncol. 2004; 93(1): 78–86.
- Lu C, Shahzad MMK, Moreno-Smith M, et al. Targeting pericytes with a PDGF-B aptamer in human ovarian carcinoma models. Cancer Biol Ther. 2010; 9(3): 176–182.
- Czekierdowska S, Stachowicz N, Chróściel M, et al. Proliferation and maturation of intratumoral blood vessels in women with malignant ovarian tumors assessed with cancer stem cells marker nestin and platelet derived growth factor PDGF-B. Ginekol Pol. 2017; 88(3): 120–128.
- Schatteman GC, Motley ST, Effmann EL, et al. Platelet-derived growth factor receptor alpha subunit deleted Patch mouse exhibits severe cardiovascular dysmorphogenesis. Teratology. 1995; 51(6): 351–366.
- Wang X, Liu P, Tang J. PDGF Gene Therapy Enhances Expression of VEGF and bFGF Genes and Activates the NF-??B Gene in Signal Pathways in Ischemic Flaps. Plastic and Reconstructive Surgery. 2006; 117(1): 129–137.
- Cimpean AM, Raica M. Lymphangiogenesis and Inflammation-Looking for the "Missing Pieces" of the Puzzle. Arch Immunol Ther Exp (Warsz). 2015; 63(6): 415–426.
- Merz H, Malisius R, Mannweiler S, et al. ImmunoMax. A maximized immunohistochemical method for the retrieval and enhancement of hidden antigens. Lab Invest. 1995; 73(1): 149–156.
- Henriksen R, Funa K, Wilander E, et al. Expression and prognostic significance of platelet-derived growth factor and its receptors in epithelial ovarian neoplasms. Cancer Res. 1993; 53(19): 4550–4554.
- Madsen CV, Dahl Steffensen K, Waldstrøm M, et al. Immunohistochemical expression of platelet-derived growth factor receptors in ovarian cancer patients with long-term follow-up. Patholog Res Int. 2012; 2012: 851432.
- Wilczynski SP, Chen YY, Chen W, et al. Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian cancers. Hum Pathol. 2005; 36(3): 242–249.
- Dabrow MB, Francesco MR, McBrearty FX, et al. The effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium. Gynecol Oncol. 1998; 71(1): 29–37.
- Avril S, Dincer Y, Malinowsky K, et al. Increased PDGFR-beta and VEGFR-2 protein levels are associated with resistance to platinum-based chemotherapy and adverse outcome of ovarian cancer patients. Oncotarget. 2017; 8(58): 97851–97861.
- Schauer IG, Sood AK, Mok S, et al. Cancer-associated fibroblasts and their putative role in potentiating the initiation and development of epithelial ovarian cancer. Neoplasia. 2011; 13(5): 393–405.
- Szubert S, Koper K, Dutsch-Wicherek MM, et al. High tumor cell vimentin expression indicates prolonged survival in patients with ovarian malignant tumors. Ginekol Pol. 2019; 90(1): 11–19.
- Chen Y, Zhang L, Liu W, et al. Prognostic Significance of the Tumor-Stroma Ratio in Epithelial Ovarian Cancer. Biomed Res Int. 2015; 2015: 589301.
- Thijssen VL, Paulis YWj, Nowak-Sliwinska P, et al. Targeting PDGF-mediated recruitment of pericytes blocks vascular mimicry and tumor growth. J Pathol. 2018; 246(4): 447–458.
- Holzer TR, O'Neill Reising L, Credille KM, et al. Variability in Platelet-Derived Growth Factor Receptor Alpha Antibody Specificity May Impact Clinical Utility of Immunohistochemistry Assays. J Histochem Cytochem. 2016; 64(12): 785–810.
- Ntanasis-Stathopoulos I, Fotopoulos G, Tzanninis IG, et al. The Emerging Role of Tyrosine Kinase Inhibitors in Ovarian Cancer Treatment: A Systematic Review. Cancer Invest. 2016; 34(7): 313–339.
- Ledermann JA, Embleton AC, Raja F, et al. ICON6 collaborators. Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; 387(10023): 1066–1074.
