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. 2017 Feb;77(3):255-262.
doi: 10.1002/pros.23244. Epub 2016 Aug 16.

Changes in Lymphangiogenesis and Vascular Endothelial Growth Factor Expression by Neo-Adjuvant Hormonal Therapy in Prostate Cancer Patients

Akihiro Asai  1 , Yasuyoshi Miyata  1 , Tomohiro Matsuo  1 , Yohei Shida  1 , Tomoaki Hakariya  1 , Kojiro Ohba  1 , Hideki Sakai  1
Affiliations

Changes in Lymphangiogenesis and Vascular Endothelial Growth Factor Expression by Neo-Adjuvant Hormonal Therapy in Prostate Cancer Patients

Akihiro Asai et al. Prostate. 2017 Feb.

Abstract

Background: The anti-cancer mechanism of neo-adjuvant hormonal therapy (NHT) is not well understood. Lymphangiogenesis plays an important role in cancer progression and is regulated by a complex mechanism that includes vascular endothelial growth factor (VEGF) signaling. However, there is little information regarding relationship between lymphangiogenesis and androgen deprivation. The aim of this study was to clarify changes in lymphangiogenesis and VEGF expression induced by androgen deprivation in prostate cancer in vivo and in vitro.

Methods: Patients who had undergone a radical prostatectomy were enrolled in the study (NHT, n = 60 and non-NHT, n = 64). Lymph vessels were identified by D2-40 immunoreactivity and lymph vessel density and lymph vessel area (LVD and LVA, respectively) were measured from micrographs. The expression of VEGF-A, -B, -C, and -D was evaluated by immunohistochemistry. The prognostic value of LVD and LVA for biochemical recurrence was also investigated.

Results: Mean LVD ± SD was higher in the NHT than in the non-NHT group (11.3 ± 3.0 vs. 7.1 ± 3.4 per high power field; P < 0.001). LVA was larger in the NHT than in the non-NHT group (512.8 ± 174.9 vs. 202.7 ± 72.8 µm2 ; P < 0.001). VEGF-A expression was lower whereas VEGF-C and -D levels were higher in the NHT than in the non-NHT group. VEGF-B expression in specimens with NHT was lower than that in biopsy specimens at diagnosis. These results were confirmed by in vitro studies used androgen-sensitive prostate cancer cell line. LVA was found to be an independent predictor of biochemical recurrence in patients who received NHT.

Conclusions: Our results demonstrate that NHT stimulates lymphangiogenesis via upregulation of VEGF-C and -D, which may increase LVA and affect the outcome of prostate cancer patients. This findings were supported by in vitro data of prostate cancer cell. Prostate 77:255-262, 2017. © 2016 The Authors. The Prostate Published by Wiley Periodicals, Inc.

Keywords: androgen deprivation; lymphangiogenesis; neo-adjuvant hormonal therapy; prostate cancer; vascular endothelial growth factors.

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Figures

Figure 1
Figure 1
Representative micrographs of D2‐40‐positive lymph vessels in prostate cancer tissue samples with/without NHT. Most lymph vessels were relapsed and the intra‐luminal space was narrow in non‐NHT specimens (A: magnification ×200). Lymph vessels had a relatively wide inner cavity in NHT specimens (B: magnification ×200, C: ×400). Some cells were detected within D2‐40‐positive lymph vessels in some NHT specimens (D: magnification ×400).
Figure 2
Figure 2
(A) LVD was higher and (B) LVA is greater in the NHT than in the non‐NHT group. (C and D) The IRS for VEGF‐A (C) and VEGF‐B (D) was lower in the NHT than in the non‐NHT group, although the difference was statistically significant only for VEGF‐A. (E and F) The IRS of VEGF‐C (E) and VEGF‐D (F) was higher in the NHT than in the non‐NHT group.
Figure 3
Figure 3
Expressions of VEGF‐A and ‐B were reduced by androgen depletion, as determined by western blotting. In contrast, expressions of VEGF‐C and VEGF‐D were increased in cancer cells cultured in androgen‐deficient as compared to standard medium.
Figure 4
Figure 4
Kaplan–Meier curves of BCR in patients treated with NHT. (A) Higher LVD was associated with shorter time to BCR (P = 0.037, log‐rank test). (B) Larger LVA predicted BCR (P = 0.004, log‐rank test).
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