Lymphatic Metastasis in Breast Cancer: Importance and New Insights into Cellular and Molecular Mechanisms

Overview

Journal Clin Exp Metastasis

Specialty Oncology

Date 2007 Nov 7

PMID 17985200

Citations 19

Authors

Suzanne Eccles

Lenaic Paon

Jonathan Sleeman

Affiliations

Soon will be listed here.

Abstract

Lymph node metastasis is the main prognosis factor in a number of malignancies, including breast carcinomas. The means by which lymph node metastases arise is not fully understood, and many questions remain about their importance in the further spread of breast cancer. Nevertheless, a number of key cellular and molecular mechanisms of lymphatic metastasis have been identified. These include induction of intra- or peri-tumoral lymphangiogenesis or co-option of existing lymphatic vessels to allow tumour cells to enter the lymphatics, although it remains to be established whether this is primarily an active or passive process. Gene expression microarrays and functional studies in vitro and in vivo, together with detailed clinical observations have identified a number of molecules that can play a role in the genesis of lymph node metastases. These include the well-recognised lymphangiogenic cytokines VEGF-C and VEGF-D as well as chemokine-receptor interactions, integrins and downstream signalling pathways. This paper briefly reviews current clinical and experimental evidence for the underlying mechanisms and significance of lymphatic metastasis in breast cancer and highlights questions that still need to be addressed.

Citing Articles

PAIP2 is a potential diagnostic and prognostic biomarker of breast cancer and is associated with immune infiltration.

Wang C, Jiang X, Qi J, Xu J, Yang G, Mi C Front Genet. 2022; 13:1009056.

PMID: 36437922 PMC: 9685164. DOI: 10.3389/fgene.2022.1009056.

Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis.

Lopez A, Mazariegos M, Capuano A, Ximenez-Embun P, Hergueta-Redondo M, Recio J Int J Mol Sci. 2021; 22(14).

PMID: 34299025 PMC: 8303474. DOI: 10.3390/ijms22147406.

Increased expression of miR-155 and miR-222 is associated with lymph node positive status.

Chernyy V, Pustylnyak V, Kozlov V, Gulyaeva L J Cancer. 2018; 9(1):135-140.

PMID: 29290778 PMC: 5743720. DOI: 10.7150/jca.22181.

In Vivo Dual-Modality Fluorescence and Magnetic Resonance Imaging-Guided Lymph Node Mapping with Good Biocompatibility Manganese Oxide Nanoparticles.

Zhan Y, Zhan W, Li H, Xu X, Cao X, Zhu S Molecules. 2017; 22(12).

PMID: 29231865 PMC: 6149721. DOI: 10.3390/molecules22122208.

The role of lymphangiogenesis and angiogenesis in tumor metastasis.

Paduch R Cell Oncol (Dordr). 2016; 39(5):397-410.

PMID: 27126599 PMC: 5052283. DOI: 10.1007/s13402-016-0281-9.

References

van der Schaft D, Pauwels P, Hulsmans S, Zimmermann M, van de Poll-Franse L, Griffioen A . Absence of lymphangiogenesis in ductal breast cancer at the primary tumor site. Cancer Lett. 2007; 254(1):128-36. DOI: 10.1016/j.canlet.2007.03.001. View

Fukumoto S, Morifuji M, Katakura Y, Ohishi M, Nakamura S . Endostatin inhibits lymph node metastasis by a down-regulation of the vascular endothelial growth factor C expression in tumor cells. Clin Exp Metastasis. 2005; 22(1):31-8. DOI: 10.1007/s10585-005-3973-5. View

Stacker S, Hughes R, Williams R, Achen M . Current strategies for modulating lymphangiogenesis signalling pathways in human disease. Curr Med Chem. 2006; 13(7):783-92. DOI: 10.2174/092986706776055625. View

van Trappen P, Pepper M . Lymphatic dissemination of tumour cells and the formation of micrometastases. Lancet Oncol. 2002; 3(1):44-52. DOI: 10.1016/s1470-2045(01)00621-0. View

Kumar S, Singh J, Xia G, Krasnoperov V, Hassanieh L, Ley E . Receptor tyrosine kinase EphB4 is a survival factor in breast cancer. Am J Pathol. 2006; 169(1):279-93. PMC: 1698769. DOI: 10.2353/ajpath.2006.050889. View

Qian C, Berghuis B, Tsarfaty G, Bruch M, Kort E, Ditlev J . Preparing the "soil": the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Res. 2006; 66(21):10365-76. DOI: 10.1158/0008-5472.CAN-06-2977. View

Al-Rawi M, Watkins G, Mansel R, Jiang W . Interleukin 7 upregulates vascular endothelial growth factor D in breast cancer cells and induces lymphangiogenesis in vivo. Br J Surg. 2005; 92(3):305-10. DOI: 10.1002/bjs.4832. View

Schoppmann S, Fenzl A, Nagy K, Unger S, Bayer G, Geleff S . VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. Surgery. 2006; 139(6):839-46. DOI: 10.1016/j.surg.2005.12.008. View

Xi L, Lyons-Weiler J, Coello M, Huang X, Gooding W, Luketich J . Prediction of lymph node metastasis by analysis of gene expression profiles in primary lung adenocarcinomas. Clin Cancer Res. 2005; 11(11):4128-35. PMC: 2211271. DOI: 10.1158/1078-0432.CCR-04-2525. View

10.

Padera T, Kadambi A, Tomaso E, Carreira C, Brown E, Boucher Y . Lymphatic metastasis in the absence of functional intratumor lymphatics. Science. 2002; 296(5574):1883-6. DOI: 10.1126/science.1071420. View

11.

ODonnell R, Kupferman M, Wei S, Singhal S, Weber R, OMalley B . Gene expression signature predicts lymphatic metastasis in squamous cell carcinoma of the oral cavity. Oncogene. 2004; 24(7):1244-51. DOI: 10.1038/sj.onc.1208285. View

12.

Brader S, Eccles S . Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori. 2004; 90(1):2-8. DOI: 10.1177/030089160409000102. View

13.

Roberts N, Kloos B, Cassella M, Podgrabinska S, Persaud K, Wu Y . 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. DOI: 10.1158/0008-5472.CAN-05-1843. View

14.

Irigoyen M, Anso E, Martinez E, Garayoa M, Martinez-Irujo J, Rouzaut A . Hypoxia alters the adhesive properties of lymphatic endothelial cells. A transcriptional and functional study. Biochim Biophys Acta. 2007; 1773(6):880-90. DOI: 10.1016/j.bbamcr.2007.03.001. View

15.

McColl B, Loughran S, Davydova N, Stacker S, Achen M . Mechanisms of lymphangiogenesis: targets for blocking the metastatic spread of cancer. Curr Cancer Drug Targets. 2005; 5(8):561-71. DOI: 10.2174/156800905774932833. View

16.

He Y, Rajantie I, Ilmonen M, Makinen T, Karkkainen M, Haiko P . Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res. 2004; 64(11):3737-40. DOI: 10.1158/0008-5472.CAN-04-0088. View

17.

Kinoshita J, Kitamura K, Kabashima A, Saeki H, Tanaka S, Sugimachi K . Clinical significance of vascular endothelial growth factor-C (VEGF-C) in breast cancer. Breast Cancer Res Treat. 2001; 66(2):159-64. DOI: 10.1023/a:1010692132669. View

18.

He Y, Karpanen T, Alitalo K . Role of lymphangiogenic factors in tumor metastasis. Biochim Biophys Acta. 2004; 1654(1):3-12. DOI: 10.1016/j.bbcan.2003.07.003. View

19.

Cronin-Fenton D, Ries L, Clegg L, Edwards B . Rising incidence rates of breast carcinoma with micrometastatic lymph node involvement. J Natl Cancer Inst. 2007; 99(13):1044-9. DOI: 10.1093/jnci/djm026. View

20.

Kubo H, Fujiwara T, Jussila L, Hashi H, Ogawa M, Shimizu K . Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis. Blood. 2000; 96(2):546-53. View