Next Article in Journal
Nuclear Localization of PTTG1 Promotes Migration and Invasion of Seminoma Tumor through Activation of MMP-2
Previous Article in Journal
Non-Invasive Mapping for Effective Preoperative Guidance to Approach Highly Language-Eloquent Gliomas—A Large Scale Comparative Cohort Study Using a New Classification for Language Eloquence
Open AccessArticle

Remodeling of the Lymph Node High Endothelial Venules Reflects Tumor Invasiveness in Breast Cancer and is Associated with Dysregulation of Perivascular Stromal Cells

1
The Beijer Laboratory, Department Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala University, 75185 Uppsala, Sweden
2
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, 41345 Gothenburg, Sweden
*
Author to whom correspondence should be addressed.
Cancers 2021, 13(2), 211; https://doi.org/10.3390/cancers13020211
Received: 16 October 2020 / Revised: 28 December 2020 / Accepted: 5 January 2021 / Published: 8 January 2021
(This article belongs to the Section Tumor Microenvironment)
Tumor draining lymph nodes (TDLNs) are the most common metastatic sites in human cancer but are also essential sites for induction of tumor immunity. How different types of primary tumors affect the anti-tumor immune response in the LNs is not fully understood. By analyzing biobank tissue from breast cancer patients, we demonstrate that invasive breast cancer induce dramatic pre-metastatic LN changes affecting the structure and function of the specialized LN vasculature and associated stromal cells, required for recruitment of T-lymphocytes into the LNs. These changes could not be seen in patients with non-invasive breast cancer and provide new insights of how invasive tumors can disrupt essential functions within the immune system. The data also shows promise of LN stromal and vascular changes as possible future biomarkers for prediction of disease progression in human cancer.
The tumor-draining lymph nodes (TDLNs) are primary sites for induction of tumor immunity. They are also common sites of metastasis, suggesting that tumor-induced mechanisms can subvert anti-tumor immune responses and promote metastatic seeding. The high endothelial venules (HEVs) together with CCL21-expressing fibroblastic reticular cells (FRCs) are essential for lymphocyte recruitment into the LNs. We established multicolor antibody panels for evaluation of HEVs and FRCs in TDLNs from breast cancer (BC) patients. Our data show that patients with invasive BC display extensive structural and molecular remodeling of the HEVs, including vessel dilation, thinning of the endothelium and discontinuous expression of the HEV-marker PNAd. Remodeling of the HEVs was associated with dysregulation of CCL21 in perivascular FRCs and with accumulation of CCL21-saturated lymphocytes, which we link to loss of CCL21-binding heparan sulfate in FRCs. These changes were rare or absent in LNs from patients with non-invasive BC and cancer-free organ donors and were observed independent of nodal metastasis. Thus, pre-metastatic dysregulation of core stromal and vascular functions within TDLNs reflect the primary tumor invasiveness in BC. This adds to the understanding of cancer-induced perturbation of the immune response and opens for prospects of vascular and stromal changes in TDLNs as potential biomarkers. View Full-Text
Keywords: lymph node; pre-metastatic changes; CCL21; high endothelial venule (HEV); T-lymphocytes; heparan sulfate; fibroblastic reticular cell (FRC); breast cancer; metastasis lymph node; pre-metastatic changes; CCL21; high endothelial venule (HEV); T-lymphocytes; heparan sulfate; fibroblastic reticular cell (FRC); breast cancer; metastasis
Show Figures

Graphical abstract

MDPI and ACS Style

Bekkhus, T.; Martikainen, T.; Olofsson, A.; Franzén Boger, M.; Vasiliu Bacovia, D.; Wärnberg, F.; Ulvmar, M.H. 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, 211. https://doi.org/10.3390/cancers13020211

AMA Style

Bekkhus T, Martikainen T, Olofsson A, Franzén Boger M, Vasiliu Bacovia D, Wärnberg F, Ulvmar MH. 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. https://doi.org/10.3390/cancers13020211

Chicago/Turabian Style

Bekkhus, Tove; Martikainen, Teemu; Olofsson, Anna; Franzén Boger, Mathias; Vasiliu Bacovia, Daniel; Wärnberg, Fredrik; Ulvmar, Maria H. 2021. "Remodeling of the Lymph Node High Endothelial Venules Reflects Tumor Invasiveness in Breast Cancer and is Associated with Dysregulation of Perivascular Stromal Cells" Cancers 13, no. 2: 211. https://doi.org/10.3390/cancers13020211

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop