[en] BACKGROUND: Lymphatic 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. METHODS: We 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. RESULTS: AD0157 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. CONCLUSIONS: These 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.
Ramos-Medina R, Moreno F, Lopez-Tarruella S, Lopez-Tarruella S, Del Monte-Millán M, Márquez-Rodas I, Durán E, Jerez Y, Garcia-Saenz JA, Ocaña I, Andrés S, et al. Review: circulating tumor cells in the practice of breast cancer oncology. Clin Transl Oncol. 2016;18(8):749-59.
Paduch R. The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol. 2016;39(5):397-410.
Rovera F, Fachinetti A, Rausei S, Chiappa C, Lavazza M, Arlant V, Marelli M, Boni L, Dionigi G, Dionigi R. Prognostic role of micrometastases in sentinel lymph node in patients with invasive breast cancer. Int J Surg. 2013;11 Suppl 1:S73-78.
Stacker SA, Baldwin ME, Achen MG. The role of tumor lymphangiogenesis in metastatic spread. FASEB J. 2002;16(9):922-34.
Alitalo K. The lymphatic vasculature in disease. Nat Med. 2011;17(11):1371-80.
Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer. 2014;14(3):159-72.
Saffar B, Bennett M, Metcalf C, Burrows S. Retrospective preoperative assessment of the axillary lymph nodes in patients with breast cancer and literature review. Clin Radiol. 2015;70(9):954-9.
Dieterich LC, Detmar M. Tumor lymphangiogenesis and new drug development. Adv Drug Deliv Rev. 2016;99(Pt B):148-60.
Ran S, Volk L, Hall K, Flister MG. Lymphangiogenesis and lymphatic metastasis in breast cancer. Pathophysiology. 2010;17(4):229-51.
Kerbel RS. Reappraising antiangiogenic therapy for breast cancer. Breast. 2011;20 Suppl 3:S56-60.
Martin M. Understanding the value of antiangiogenic therapy in metastatic breast cancer. Curr Opin Oncol. 2011;23(Suppl):S1.
Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220-31.
Ribatti D. Antiangiogenic therapy accelerates tumour metastasis. Leuk Res. 2011;35(1):24-6.
Saif MW, Knost JA, Chiorean EG, Kambhampati SR, Yu D, Pytowski B, Qin A, Kauh JS, O'Neil BH. Phase 1 study of the anti-vascular endothelial growth factor receptor 3 monoclonal antibody LY3022856/IMC-3C5 in patients with advanced and refractory solid tumors and advanced colorectal cancer. Cancer Chemother Pharmacol. 2016;78(4):815-24.
García-Caballero M, Cañedo L, Fernández-Medarde A, Medina MA, Quesada AR. The marine fungal metabolite, AD0157, inhibits angiogenesis by targeting the Akt signaling pathway. Mar Drugs. 2014;12(1):279-99.
Sounni NE, Cimino J, Blacher S, Primac I, Truong A, Mazzucchelli G, Paye A, Calligaris D, Debois D, De Tulllio P, et al. Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab. 2014;20(2):280-94.
Blacher S, Detry B, Bruyère F, Foidart JM, Noël A. Additional parameters for the morphometry of angiogenesis and lymphangiogenesis in corneal flat mounts. Exp Eye Res. 2009;89(2):274-76.
García-Caballero M, Blacher S, Paupert J, Quesada AR, Medina MA, Noël A. Novel application assigned to toluquinol: inhibition of lymphangiogenesis by interfering with VEGF-C/VEGFR-3 signaling pathway. Br J Pharmacol. 2016;173(12):1966-87.
Bruyère F, Melen-Lamalle L, Blacher S, Roland G, Thiry M, Moons L, Frankenne F, Carmeliet P, Alitalo K, Libert C, et al. Modeling lymphangiogenesis in a three-dimensional culture system. Nat Methods. 2008;5(5):431-37.
Sweat RS, Sloas DC, Murfee WL. VEGF-C induces lymphangiogenesis and angiogenesis in the rat mesentery culture model. Microcirculation. 2014;21(6):532-40.
Blacher S, Erpicum C, Lenoir B, Paupert J, Moraes G, Ormenese S, Bullinger E, Noel A. Cell invasion in the spheroid sprouting assay: a spatial organisation analysis adaptable to cell behaviour. PLoS One. 2014;9(5):e97019.
Yoshimatsu Y, Miyazaki H, Watabe T. Roles of signaling and transcriptional networks in pathological lymphangiogenesis. Adv Drug Deliv Rev. 2016;99(Pt B):161-71.
Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001;7(2):192-8.
Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumor metastasis. EMBO J. 2001;20(4):672-82.
Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Ylä-Herttuala S, Jäättelä M, Alitalo K. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res. 2001;61(5):1786-90.
Timoshenko AV, Chakraborty C, Wagner GF, Lala PK. COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. Br J Cancer. 2006;94(8):1154-63.
Tekedereli I, Alpay SN, Tavares CD, Cobanoglu ZE, Kaoud TS, Sahin I, Sood AK, Lopez-Berestein G, Dalby KN, Ozpolat B. Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer. PLoS One. 2012;7(7):e41171.
Cheng P, Dai W, Wang F, Lu J, Shen M, Chen K, Li J, Zhang Y, Wang C, Yang J, et al. Ethyl pyruvate inhibits proliferation and induces apoptosis of hepatocellular carcinoma via regulation of the HMGB1-RAGE and AKT pathways. Biochem Biophys Res Commun. 2014;443(4):1162-8.
He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, Alitalo K. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst. 2002;94(11):819-25.
Roberts N, Kloos B, Cassella M, Podgrabinska S, Persaud K, Wu Y, Pytowski B, Skobe M. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res. 2006;66(5):2650-7.
Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14(17):5459-65.
Heckman CA, Holopainen T, Wirzenius M, Keskitalo S, Jeltsch M, Ylä-Herttuala S, Wedge SR, Jürgensmeier JM, Alitalo K. The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis. Cancer Res. 2008;68(12):4754-62.
Schomber T, Zumsteg A, Strittmatter K, Crnic I, Antoniadis H, Littlewood-Evans A, Wood J, Christofori G. Differential effects of the vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 on tumor angiogenesis and tumor lymphangiogenesis. Mol Cancer Ther. 2009;8(1):55-63.
Burton JB, Priceman SJ, Sung JL, Brakenhielm E, An DS, Pytowski B, Alitalo K, Wu L. Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res. 2008;68(19):7828-37.
Yu J, Zhang Y, Leung LH, Liu L, Yang F, Yao X. Efficacy and safety of angiogenesis inhibitors in advanced gastric cancer: a systematic review and meta-analysis. J Hematol Oncol. 2016;9(1):111.
Sun Y, Niu W, Du F, Du C, Li S, Wang J, Li L, Wang F, Hao Y, Li C, et al. Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol. 2016;9(1):105.
Rutkowski P, Bylina E, Klimczak A, Switaj T, Falkowski S, Kroc J, Lugowska I, Brzeskwiniewicz M, Melerowicz W, Osuch C, et al. The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study. BMC Cancer. 2012;12:107.
Zhang S. Adjuvant sunitinib in renal-cell carcinoma. N Engl J Med. 2017;376(9):893.
Yeh CN, Wang SY, Tsai CY, Chen YY, Liu CT, Chiang KC, Chen TW, Liu YY, Yeh TS. Surgical management of patients with progressing metastatic gastrointestinal stromal tumors receiving sunitinib treatment: a prospective cohort study. Int J Surg. 2017;39:30-6.