Transcriptional profiling of breast cancer-associated lymphatic vessels reveals VCAM-1 as regulator of lymphatic invasion and permeability.

Dieterich, Lothar C; Kapaklikaya, Kübra; Cetintas, Timur; Proulx, Steven Thomas; Commerford, Catharina D; Ikenberg, Kristian; Bachmann, Samia B; Scholl, Jeannette; Detmar, Michael (2019). Transcriptional profiling of breast cancer-associated lymphatic vessels reveals VCAM-1 as regulator of lymphatic invasion and permeability. International journal of cancer, 145(10), pp. 2804-2815. Wiley-Blackwell 10.1002/ijc.32594

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Tumor-associated lymphangiogenesis and lymphatic invasion of tumor cells correlate with poor outcome in many tumor types, including breast cancer. Various explanations for this correlation have been suggested in the past, including the promotion of lymphatic metastasis and an immune-inhibitory function of lymphatic endothelial cells (LECs). However, the molecular features of tumor-associated lymphatic vessels and their implications for tumor progression have been poorly characterized. Here, we report the first transcriptional analysis of tumor-associated LECs directly isolated from the primary tumor in an orthotopic mouse model of triple negative breast cancer (4T1). Gene expression analysis showed a strong upregulation of inflammation-associated genes, including endothelial adhesion molecules such as VCAM-1, in comparison to LECs derived from control tissue. In vitro experiments demonstrated that VCAM-1 is not involved in the adhesion of tumor cells to LECs but unexpectedly promoted lymphatic permeability by weakening of lymphatic junctions, most likely through a mechanism triggered by interactions with integrin α4 which was also induced in tumor-associated LECs. In line with this, in vivo blockade of VCAM-1 reduced lymphatic invasion of 4T1 cells. Taken together, our findings suggest that disruption of lymphatic junctions and increased permeability via tumor-induced lymphatic VCAM-1 expression may represent a new target to block lymphatic invasion and metastasis.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Proulx, Steven Thomas

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0020-7136

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

13 Nov 2019 12:35

Last Modified:

13 Nov 2019 12:35

Publisher DOI:

10.1002/ijc.32594

PubMed ID:

31344266

Uncontrolled Keywords:

breast cancer lymphangiogenesis lymphatic invasion metastasis

BORIS DOI:

10.7892/boris.134687

URI:

https://boris.unibe.ch/id/eprint/134687

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