Targeting VEGFR-3/-2 signaling pathways with AD0157: a potential strategy against tumor-associated lymphangiogenesis and lymphatic metastases

Abstract

BackgroundLymphatic metastasis is one of the leading causes of death in patients with different types of cancer and is the main prognostic factor for the disease survival. The formation of new lymphatic vessels (lymphangiogenesis) in primary tumors facilitates tumor cell dissemination to regional lymph nodes and correlates with distant metastases. Lymphangiogenesis has thus emerged as a suitable therapeutic target to block metastases, but no anti-lymphangiogenic compounds have been approved for clinical use to date. Therefore, new or improved therapies blocking lymphatic metastases are urgently required.MethodsWe established murine breast tumors to assess the effect of AD0157 on tumor growth, lymphangiogenesis, and lymphatic dissemination. Then, a battery of in vivo (mouse corneal neovascularization and ear sponges), ex vivo (mouse lymphatic rings and rat mesentery explants), and in vitro (proliferation, tubulogenesis, wound-healing, Boyden chambers, and spheroids) assays was used to give insight into the lymphangiogenic steps affected by AD0157. Finally, we investigated the molecular pathways controlled by this drug.ResultsAD0157 was found to inhibit the growth of human breast cancer xenografts in mice, to strongly reduce tumor-associated lymphangiogenesis and to block metastatic dissemination to both lymph nodes and distant organs. The high anti-lymphangiogenic potency of AD0157 was further supported by its inhibitory activity at low micromolar range in two in vivo pathological models and in two ex vivo assays. In addition, AD0157 inhibited lymphatic endothelial cell proliferation, migration and invasion, cellular sprouting, and tube formation. Mechanistically, this compound induced apoptosis in lymphatic endothelial cells and decreased VEGFR-3/-2, ERK1/2, and Akt phosphorylations.ConclusionsThese findings demonstrate the suitability of AD0157 to suppress tumor-associated lymphangiogenesis. Beyond discovering a new potent anti-lymphangiogenic drug that is worth considering in future clinical settings, our study supports the interest of designing anti-lymphangiogenic therapies to avoid distant metastatic processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0484-1) contains supplementary material, which is available to authorized users.

Hedyotis diffusa willd extract suppresses colorectal cancer growth through multiple cellular pathways

“…Constitutive activation of STAT3 is associated with the development of various types of cancer including CRC and represents poor disease prognosis (40)(41)(42)(43). These molecular pathways modulate the expression of key genes involved in the regulation of cell proliferation, apoptosis and angiogenesis, and are therefore important in the induction, progression and metastasis of colorectal cancer (44).…”

Stromal cells in breast cancer as a potential therapeutic target

“…Currently, there are no clinical agents that selectively target lymph endothelial cells. Preclinical agents for anti-lymph angiogenesis target molecules such as VEGFR2/3, VEGF-C/D, neuropillin-2 (NRP2), and Plexin-A1/D1 [ 99 – 103 ]. These molecular targets are not specific for lymph angiogenesis, but also target blood vessel angiogenesis.…”

“…These molecular targets are not specific for lymph angiogenesis, but also target blood vessel angiogenesis. Still, in vitro and in vivo preclinical studies of such agents demonstrate that inhibition of lymph angiogenesis reduces lymph node and distant metastases [ 98 – 100 , 103 ]. This line of investigation may have particular relevance in inflammatory breast cancer (IBC), a rare form of aggressive breast cancer characterized by a rapid onset of erythema, rigidity, and edema of the skin of the breast [ 104 , 105 ].…”

Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies—A review

“…There is also good reason to pursue lymphangiogenesis targets for therapeutic applications, as some cancer patients have shown increased lymphangiogenic activity and subsequent recurrence of secondary tumors despite antiangiogenic therapy. It is theorized that the regression of blood vessels leads to hypoxia‐induced overexpression of lymphangiogenic factors that counteractively heighten the risk of tumor metastasis . Preliminary studies in mouse models show promising results by knockdown of vascular endothelial growth factor C (VEGFC) or soluble vascular endothelial growth factor receptor 2 in mammary cancer and lung cancer .…”

“…It is theorized that the regression of blood vessels leads to hypoxia-induced overexpression of lymphangiogenic factors that counteractively heighten the risk of tumor metastasis. 93 Preliminary studies in mouse models show promising results by knockdown of vascular endothelial growth factor C (VEGFC) or soluble vascular endothelial growth factor receptor 2 in mammary cancer 94 and lung cancer. 95 To date, however, no antilymphangiogenic cancer therapies have been approved by FDA due to our limited knowledge of the complex interactions between antiangiogenic drugs, lymphangiogenesis, and cancer metastasis.…”