Remodeling of the Lymph Node High Endothelial Venules Reflects Tumor Invasiveness in Breast Cancer and is Associated with Dysregulation of Perivascular Stromal Cells.
Remodeling of the Lymph Node High Endothelial Venules Reflects Tumor Invasiveness in Breast Cancer and is Associated with Dysregulation of Perivascular Stromal Cells.
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DOI：
10.3390/cancers13020211
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发表时间：
2021-01-08
期刊：
影响因子：
5.2
通讯作者：
Ulvmar MH
中科院分区：
文献类型：
--
作者：
Bekkhus T;Martikainen T;Olofsson A;Franzén Boger M;Vasiliu Bacovia D;Wärnberg F;Ulvmar MH
肿瘤引流淋巴结（TDLN）是人类癌症中最常见的转移部位，但也是诱导肿瘤免疫的重要部位。不同类型的原发性肿瘤如何影响LN中的抗肿瘤免疫应答尚未完全了解。通过分析乳腺癌患者的生物样本库组织，我们证明浸润性乳腺癌诱导显著的转移前LN变化，影响专门的LN脉管系统和相关的基质细胞的结构和功能，需要招募T淋巴细胞进入LN。这些变化在非侵袭性乳腺癌患者中看不到，并为侵袭性肿瘤如何破坏免疫系统的基本功能提供了新的见解。这些数据还显示LN基质和血管变化有望成为未来预测人类癌症疾病进展的生物标志物。肿瘤引流淋巴结（TDLN）是诱导肿瘤免疫的主要部位。它们也是常见的转移部位，表明肿瘤诱导的机制可以破坏抗肿瘤免疫应答并促进转移性播种。高内皮微静脉（HEVs）与CCL21表达的成纤维网状细胞（FRC）一起对于淋巴细胞募集到LN中是必不可少的。我们建立了抗HEVs抗体组，用于评估乳腺癌（BC）患者TDLN中的HEVs和FRC。我们的数据显示，侵袭性BC患者显示广泛的结构和分子重塑的HEV，包括血管扩张，内皮细胞变薄和不连续表达的HEV标记PNAd。HEV的重塑与血管周围FRC中CCL21的失调以及CCL21饱和淋巴细胞的积累相关，我们将其与FRC中CCL21结合硫酸乙酰肝素的丧失联系起来。这些变化在非侵袭性BC和无癌器官供体患者的淋巴结中是罕见或不存在的，并且观察到与淋巴结转移无关。因此，TDLN内核心基质和血管功能的转移前失调反映了BC中的原发性肿瘤侵袭性。这增加了对癌症诱导的免疫反应扰动的理解，并为TDLN中血管和基质变化作为潜在生物标志物的前景开辟了道路。
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.
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DOI：
10.1083/jcb.115.1.85
发表时间：
1991-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mebius RE;Streeter PR;Brevé J;Duijvestijn AM;Kraal G
通讯作者：
Kraal G
影响因子：
30.5
作者：
Riedel A;Shorthouse D;Haas L;Hall BA;Shields J
通讯作者：
Shields J
DOI：
10.1084/jem.20121462
发表时间：
2013-03-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Onder L;Danuser R;Scandella E;Firner S;Chai Q;Hehlgans T;Stein JV;Ludewig B
通讯作者：
Ludewig B
影响因子：
5.9
作者：
Blenman, Kim R. M.;He, Ting-Fang;Lee, Peter P.
通讯作者：
Lee, Peter P.
影响因子：
4.6
作者：
AuBuchon, J. P.;de Wildt-Eggen, J.;Dumont, L. J.
通讯作者：
Dumont, L. J.