Vascular endothelial growth factor (VEGF) expression in locally advanced prostate cancer: secondary analysis of radiation therapy oncology group (RTOG) 8610

Abstract

BackgroundAngiogenesis is a key element in solid-tumor growth, invasion, and metastasis. VEGF is among the most potent angiogenic factor thus far detected. The aim of the present study is to explore the potential of VEGF (also known as VEGF-A) as a prognostic and predictive biomarker among men with locally advanced prostate cancer.MethodsThe analysis was performed using patients enrolled on RTOG 8610, a phase III randomized control trial of radiation therapy alone (Arm 1) versus short-term neoadjuvant and concurrent androgen deprivation and radiation therapy (Arm 2) in men with locally advanced prostate carcinoma. Tissue samples were obtained from the RTOG tissue repository. Hematoxylin and eosin slides were reviewed, and paraffin blocks were immunohistochemically stained for VEGF expression and graded by Intensity score (0–3). Cox or Fine and Gray’s proportional hazards models were used.ResultsSufficient pathologic material was available from 103 (23%) of the 456 analyzable patients enrolled in the RTOG 8610 study. There were no statistically significant differences in the pre-treatment characteristics between the patient groups with and without VEGF intensity data. Median follow-up for all surviving patients with VEGF intensity data is 12.2 years. Univariate and multivariate analyses demonstrated no statistically significant correlation between the intensity of VEGF expression and overall survival, distant metastasis, local progression, disease-free survival, or biochemical failure. VEGF expression was also not statistically significantly associated with any of the endpoints when analyzed by treatment arm.ConclusionsThis study revealed no statistically significant prognostic or predictive value of VEGF expression for locally advanced prostate cancer. This analysis is among one of the largest sample bases with long-term follow-up in a well-characterized patient population. There is an urgent need to establish multidisciplinary initiatives for coordinating further research in the area of human prostate cancer biomarkers.

The Role of Vascular Endothelial Growth Factor in Metastatic Prostate Cancer to the Skeleton

“…As prostate cancer cells are initially dependant on androgens, suppressing the levels of testosterone and dihydrotestosterone decreases the growth rate of prostate cancer cells [ 74 ]. However, after this initial response these cells can become castrate-resistant and develop a more aggressive phenotype, with increased VEGF expression and proliferative potential [ 74 , 75 ]. The commonest conventional treatments for bone metastases secondary to prostate cancer are chemotherapy, radiation, and surgery.…”

Influence of stromal–epithelial interactions on androgen action

“…Therefore, it is not surprising that ADT downregulates the expression of stromal VEGF (Cheng et al 2004). This improvement is not long lasting, however, and the expression of VEGF is upregulated again in CRPC cells (Pan et al 2013). IGF and TGFb upregulate the expression of VEGF transcriptionally (Eisermann et al 2013, Li et al 2013.…”

Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy

“…8 The amount of VEGF-A expressed by tumor cells correlates with poor prognosis in many types of tumors including lung, gastric, colon, prostate, ovary and melanoma. [9][10][11][12][13][14] Of the 3 closely related members of the VEGFR family (VEGFR1, 2, 3), VEGFR2 (also named as KDR or Flk1) and VEGFR3 mainly expressed in vascular and lymphatic endothelial cells, plays major roles in VEGF-A and VEGF-C induced angiogenesis and lymphangiogenesis. 15,16 Binding VEGF ligands to the extracellular domain of VEGFRs on the cell surface of the endothelial cells leads to dimerization of the receptor, and consequently, phosphorylation of the intracellular kinase domain of VEGFRs and triggers activation of downstream cell signaling cascades, including PI3K/AKT, PKC, Raf/Ras and ERK pathways, resulting in vascular/lymphatic endothelial cell proliferation and formation of new vessel branches.…”