Suppression of Prostate Cancer Nodal and Systemic Metastasis by Blockade of the Lymphangiogenic Axis

Abstract

Lymph node involvement denotes a poor outcome for patients with prostate cancer. Our group, along with others, has shown that initial tumor cell dissemination to regional lymph nodes via lymphatics also promotes systemic metastasis in mouse models. The aim of this study was to investigate the efficacy of suppressive therapies targeting either the angiogenic or lymphangiogenic axis in inhibiting regional lymph node and systemic metastasis in subcutaneous and orthotopic prostate tumor xenografts. Both androgen-dependent and more aggressive androgen-independent prostate tumors were used in our investigations. Interestingly, we observed that the threshold for dissemination is lower in the vascular-rich prostatic microenvironment compared with subcutaneously grafted tumors. Both vascular endothelial growth factor-C (VEGF-C) ligand trap (sVEGFR-3) and antibody directed against VEGFR-3 (mF4-31C1) significantly reduced tumor lymphangiogenesis and metastasis to regional lymph nodes and distal vital organs without influencing tumor growth. Conversely, angiogenic blockade by short hairpin RNA against VEGF or anti-VEGFR-2 antibody (DC101) reduced tumor blood vessel density, significantly delayed tumor growth, and reduced systemic metastasis, although it was ineffective in reducing lymphangiogenesis or nodal metastasis. Collectively, these data clarify the utility of vascular therapeutics in prostate tumor growth and metastasis, particularly in the context of the prostate microenvironment. Our findings highlight the importance of lymphangiogenic therapies in the control of regional lymph node and systemic metastasis.

Interaction of tumor cells and lymphatic vessels in cancer progression

“…76,78,86 Use of different prostate cancer models has shown a VEGF-C dependency of intratumoral lymphatic vessels. 75,89 Furthermore, in a VEGF-C-expressing prostate cancer model (PC3), ablation of intratumoral vessels by a VEGF-C and VEGF-D binding decoy receptor did not decrease metastasis, suggesting that peritumoral lymphatic vessels were sufficient for tumor metastasis in this model. 89 Some imaging studies have shown that intratumorally injected tracers may be deposited in tumors instead of being cleared by lymphatic drainage.…”

“…74 VEGF-C-induced dilation of collecting vessels around tumors may allow the entry of clusters of metastatic tumor cells. 78,79 Even tumors that rarely metastasize through the lymphatic vessels, for example, the fibrosarcoma T241 and the prostate cancer cell line LAPC9, have been observed to do so when manipulated to overexpress VEGF-C. 20,65,75 Although VEGF-D overexpression in mouse models resulted in increased lymphangiogenesis and metastasis, 72,80 correlation between VEGF-D expression levels and lymph node metastasis in patients has been found only in less than half of the studies. 73 VEGF-D may play a limited role in tumor lymphangiogenesis, as low expression levels have been found in most patient-derived cell lines and Figure 2.…”

“…26 Inhibition of the VEGF-C and VEGF-D receptor VEGFR-3, either by blocking antibodies or by a soluble receptor acting as a ligand trap, has been shown to inhibit lymphangiogenesis, and to a moderate degree angiogenesis, and is also found to restrict lymph node metastasis without effects on mature vessels in surrounding tissues. 26,74,75,81 In addition to VEGF-C and VEGF-D, overexpression of VEGF-A may also lead to the activation of lymphangiogenesis. We have observed intratumoral lymphatic vessels and enlargement of peritumoral lymphatic vessels in VEGF-C-or VEGF-A-overexpressing squamous cell carcinomas.…”

“…This target has provided promise of efficacy, although not complete blockage of metastasis, in several pre-clinical models. 69,74,75,81,112 Thus, there is a need to identify additional mediators of pathological lymphangiogenesis.…”

Regulation of vascular endothelial growth factor in prostate cancer

“…VEGF isoforms exhibit distinct receptor affinities and activate the intracellular receptor tyrosine kinase signaling cascade. The VEGFs and their receptors also play a role in PCa lymphangiogenesis (Wong et al 2005, Burton et al 2008. In the present review, we focus on the regulation and function of VEGFA (also referred to as simply VEGF) in angiogenesis.…”