Increased expression of placental growth factor in high-grade endometrial carcinoma

Abstract

Placental growth factor (PlGF), a homolog of vascular endothelial growth factor (VEGF), exerts pleiotropic functions in cancer by affecting tumor cells as well as endothelial and inflammatory cells. Moreover, PlGF expression correlates with tumor stage, recurrence, metastasis and patient outcome in different types of cancer. Recently, administration of anti-PlGF therapy reduced tumor growth and metastasis in preclinical tumor models. In the present study, we evaluated the diagnostic and prognostic value of systemic and local expression of PlGF in primary endometrial carcinomas. PlGF levels in tumor lysates (n=128) and serum (n=88) of patients with primary endometrial cancer were determined using ELISA. PlGF mRNA expression in endometrial carcinoma tissues was quantified by quantitative qRT-PCR. Results were compared to endometrial cancer stage and grade. Systemic PlGF levels were not altered in patients with endometrial cancer (FIGO stage I-II-III) as compared to healthy controls. Only in FIGO stage IV patients, serum PlGF levels were slightly increased. Local PlGF mRNA and protein expression in endometrial tumors progressively increased with tumor grade. In endometrioid carcinomas, PlGF mRNA expression was significantly increased in endometrioid grade 3 tumors as compared to normal endometrial tissue. PlGF protein expression was significantly increased in endometrioid grade 2 and 3 carcinomas and in serous carcinomas as compared to normal endometrial tissue. Our study showed that systemic/serum PlGF levels cannot be used as a diagnostic or prognostic marker in endometrial cancer. However, the increased local expression of PlGF, primarily in high-grade carcinomas, underscores the possibility for preclinical assessment of anti-PlGF therapy in endometrial cancer.

Figure 1

Serum PlGF concentrations in healthy controls and endometrial cancer patients (according to FIGO stage). Horizontal bars represent median values. ^**P<0.01 vs. normal using one-way ANOVA followed by a Tukey-Kramer multiple comparison test; n=10–37.

Figure 2

PlGF mRNA expression in normal endometrial tissue, endometrioid and serous carcinomas. PlGF mRNA expression, corrected for expression of the housekeeping gene GUSB, was quantified in endometrial carcinoma samples and normal endometrial tissue samples. All values are expressed relative to the expression levels in normal endometrial tissue. Horizontal bars represent median values. ^*P<0.05 vs. normal using one-way ANOVA followed by a Tukey-Kramer multiple comparison test; n=9–30.

Figure 3

PlGF protein expression in normal endometrial tissue, endometrioid and serous carcinomas. PlGF protein expression levels were quantified by ELISA and corrected for total protein content. Horizontal bars represent median values. ^*P<0.05, ^**P<0.01, ^***P<0.001 vs. normal using one-way ANOVA followed by a Tukey-Kramer multiple comparison test; n=9–30.

Figure 4

Kaplan-Meier survival curves of disease-free survival for patients with endometrial carcinoma according to low (median) levels of PlGF protein expression.

Figure 5

Kaplan-Meier survival curves of cancer-specific overall survival for patients with endometrial carcinoma according to low (median) levels of PlGF protein expression.