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Dysfunctional roads and loss of the lymphocyte guiding road signs in tumor draining lymph nodes

By Tove Bekkhus
20 January, 2021

Vectra Polaris image of remodeled (i.e. dilated) high endothelial venules (HEVs) (white) and perivascular fibroblastic reticular cells (FRCs) (green) with disrupted immobilization of the T-lymphocyte attracting chemokine CCL21 (magenta) resulting in accumulation of CCL21 saturated lymphocytes (magenta). Picture taken from a lymph node draining the malignant breast cancer tumor; invasive ductal carcinoma.

Microscope imag of vessels in a lymph node


Our body’s lymphocytes need to find their way to the lymph node in order to become activated to fight cancer cells. The lymph nodes' specialized blood vessels; the high endothelial venules (HEVs) and the vessel lining fibroblastic reticular cells (FRCs) form the roads and road signs, respectively, allowing them to do so.

Our studies have revealed that patients with invasive breast cancer have dramatic changes both of the HEVs and surrounding FRCs. In patients with non-invasive breast cancer (ductal carcinoma in situ, DCIS), these changes are in contrast rare, or when present, very limited. This demonstrates that invasive breast cancer differs from non-invasive in its ability to affect the function of the lymph nodes.

While remodeling of HEVs, including dilation of the vessels, have been indicated in earlier studies, it was earlier not known if and how they were linked to changes in perivascular FRCs or to different types of human cancer, which we can now clearly demonstrate. A further unexpected finding was an accumulation of CCL21 saturated lymphocytes around the dilated HEVs, which was associated with loss of the glycosaminoglycan heparan sulphate (HS) on the perivascular FRCs. HS is needed for immobilization of chemokines to the extra cellular matrix and to the surface of cells, which is important for effective immune cell migration. Without HS the ability of immune cells to navigate will be affected. 

Our analysis also shows that the changes to the HEVs are present even before the spread of the cancer to the lymph nodes (i.e. pre-metastatic changes). The latter could be a contributing factor to why lymph node metastasis is so common in breast cancer patients.

We are now working to understand the detailed mechanisms behind dysregulation of the lymph node vasculature, in breast cancer and other tumor types and are evaluating if changes in LN HEVs and FRCs will be useful as biomarkers in human cancer by using AI-driven image analysis.

Further reading

Bekkhus et al., Remodeling of the lymph node high endothelial venules reflects tumor invasiveness in breast cancer and is associated with dysregulation of perivascular stromal cells, Cancers 2021, 13(2), 211.

About the author:

Tove is a PhD student in Maria Ulvmar’s group at the Rudbeck Laboratory. She studies the role of the lymph node specialized vasculature and stroma in disease and homeostasis by image analysis using human biobank material and mouse models.

Tove Bekkhus
Uppsala University
Dept. Immunology, Genetics and Pathology
Rudbeck Laboratory C11
Dag Hammarskjölds Väg 20
751 85 Uppsala


Last modified: 2021-01-20