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

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.

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Lymph-Borne Chemokines and Other Low Molecular Weight Molecules Reach High Endothelial Venules via Specialized Conduits While a Functional Barrier Limits Access to the Lymphocyte Microenvironments in Lymph Node Cortex

Journal of Experimental Medicine ◽

10.1084/jem.192.10.1425 ◽

2000 ◽

Vol 192 (10) ◽

pp. 1425-1440 ◽

Cited By ~ 408

Author(s):

J. Elizabeth Gretz ◽

Christopher C. Norbury ◽

Arthur O. Anderson ◽

Amanda E.I. Proudfoot ◽

Stephen Shaw

Keyword(s):

Lymph Node ◽

Basement Membranes ◽

High Endothelial Venules ◽

Reticular Fibers ◽

Lymph Node Enlargement ◽

Subcapsular Sinus ◽

Sinus Floor ◽

Draining Lymph Node ◽

Reticular Cells ◽

Draining Lymph Nodes

Lymph-borne, soluble factors (e.g., chemokines and others) influence lymphocyte recirculation and endothelial phenotype at high endothelial venules (HEVs) in lymph node cortex. Yet the route lymph-borne soluble molecules travel from the subcapsular sinus to the HEVs is unclear. Therefore, we injected subcutaneously into mice and rats a wide variety of fluorophore-labeled, soluble molecules and examined their distribution in the draining lymph nodes. Rather than percolating throughout the draining lymph node, all molecules, including microbial lipopolysaccharide, were very visible in the subcapsular and medullary sinuses but were largely excluded from the cortical lymphocyte microenvironments. Exclusion prevailed even during the acute lymph node enlargement accompanying viral infection. However, low molecular mass (MW) molecules, including chemokines, did gain entry into the cortex, but in a very defined manner. Low MW, fluorophore-labeled molecules highlighted the subcapsular sinus, the reticular fibers, and the abluminal and luminal surfaces of the associated HEVs. These low MW molecules were in the fibers of the reticular network, a meshwork of collagen fibers ensheathed by fibroblastic reticular cells that connects the subcapsular sinus floor and the HEVs by intertwining with their basement membranes. Thus, low MW, lymph-borne molecules, including chemokines, traveled rapidly from the subcapsular sinus to the HEVs using the reticular network as a conduit.

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Galectin-1 expression in cancer-associated stromal cells correlates tumor invasiveness and tumor progression in breast cancer

International Journal of Cancer ◽

10.1002/ijc.22434 ◽

2007 ◽

Vol 120 (11) ◽

pp. 2331-2338 ◽

Cited By ~ 96

Author(s):

Eun-Jung Jung ◽

Hyeong-Gon Moon ◽

Bok Im Cho ◽

Chi-Young Jeong ◽

Young-Tae Joo ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Stromal Cells ◽

Tumor Invasiveness

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Radiomics for Tumor Characterization in Breast Cancer Patients: A Feasibility Study Comparing Contrast-Enhanced Mammography and Magnetic Resonance Imaging

Diagnostics ◽

10.3390/diagnostics10070492 ◽

2020 ◽

Vol 10 (7) ◽

pp. 492

Author(s):

Maria Adele Marino ◽

Doris Leithner ◽

Janice Sung ◽

Daly Avendano ◽

Elizabeth A. Morris ◽

...

Keyword(s):

Breast Cancer ◽

Magnetic Resonance Imaging ◽

Tumor Grade ◽

Hormone Receptor Status ◽

Breast Cancers ◽

Resonance Imaging ◽

Dce Mri ◽

Tumor Invasiveness ◽

Non Invasive ◽

Contrast Enhanced

The aim of our intra-individual comparison study was to investigate and compare the potential of radiomics analysis of contrast-enhanced mammography (CEM) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the breast for the non-invasive assessment of tumor invasiveness, hormone receptor status, and tumor grade in patients with primary breast cancer. This retrospective study included 48 female patients with 49 biopsy-proven breast cancers who underwent pretreatment breast CEM and MRI. Radiomics analysis was performed by using MaZda software. Radiomics parameters were correlated with tumor histology (invasive vs. non-invasive), hormonal status (HR+ vs. HR−), and grading (low grade G1 + G2 vs. high grade G3). CEM radiomics analysis yielded classification accuracies of up to 92% for invasive vs. non-invasive breast cancers, 95.6% for HR+ vs. HR− breast cancers, and 77.8% for G1 + G2 vs. G3 invasive cancers. MRI radiomics analysis yielded classification accuracies of up to 90% for invasive vs. non-invasive breast cancers, 82.6% for HR+ vs. HR− breast cancers, and 77.8% for G1+G2 vs. G3 cancers. Preliminary results indicate a potential of both radiomics analysis of DCE-MRI and CEM for non-invasive assessment of tumor-invasiveness, hormone receptor status, and tumor grade. CEM may serve as an alternative to MRI if MRI is not available or contraindicated.

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Characterization of Leptin Receptor+ Stromal Cells in Lymph Node

Frontiers in Immunology ◽

10.3389/fimmu.2021.730438 ◽

2022 ◽

Vol 12 ◽

Author(s):

Liwei Jiang ◽

Mine Yilmaz ◽

Mayuko Uehara ◽

Cecilia B. Cavazzoni ◽

Vivek Kasinath ◽

...

Keyword(s):

Lymph Node ◽

Stromal Cells ◽

Leptin Receptor ◽

Inflammatory Responses ◽

Conditional Knockout ◽

High Endothelial Venules ◽

Stromal Compartment ◽

Leptin Signaling ◽

Cell Dysfunction ◽

Reticular Cells

Lymph node (LN)-resident stromal cells play an essential role in the proper functioning of LNs. The stromal compartment of the LN undergoes significant compensatory changes to produce a milieu amenable for regulation of the immune response. We have identified a distinct population of leptin receptor-expressing (LepR+) stromal cells, located in the vicinity of the high endothelial venules (HEVs) and lymphatics. These LepR+ stromal cells expressed markers for fibroblastic reticular cells (FRCs), but they lacked markers for follicular dendritic cells (FDCs) and marginal reticular cells (MRCs). Leptin signaling deficiency led to heightened inflammatory responses within the LNs of db/db mice, leakiness of HEVs, and lymphatic fragmentation. Leptin signaling through the JAK/STAT pathway supported LN stromal cell survival and promoted the anti-inflammatory properties of these cells. Conditional knockout of the LepR+ stromal cells in LNs resulted in HEV and extracellular matrix (ECM) abnormalities. Treatment of ob/ob mice with an agonist leptin fusion protein restored the microarchitecture of LNs, reduced intra-LN inflammatory responses, and corrected metabolic abnormalities. Future studies are needed to study the importance of LN stomal cell dysfunction to the pathogenesis of inflammatory responses in type 2 diabetes (T2D) in humans.

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