scholarly journals The pre-metastatic niche in lymph nodes: formation and characteristics

2021 ◽  
Author(s):  
Lionel Gillot ◽  
Louis Baudin ◽  
Loïc Rouaud ◽  
Frédéric Kridelka ◽  
Agnès Noël
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Current Knowledge ◽  
Lymphatic Vessels ◽  
Matrix Composition ◽  
Matrix Remodeling ◽  
Metastatic Niche ◽  
Future Directions ◽  
Metastatic Cells ◽  
Immunosuppressive Cell

AbstractLymph node metastasis is a crucial prognostic parameter in many different types of cancers and a gateway for further dissemination to distant organs. Prior to metastatic dissemination, the primary tumor prepares for the remodeling of the draining (sentinel) lymph node by secreting soluble factors or releasing extracellular vesicles that are transported by lymphatic vessels. These important changes occur before the appearance of the first metastatic cell and create what is known as a pre-metastatic niche giving rise to the subsequent survival and growth of metastatic cells. In this review, the lymph node structure, matrix composition and the emerging heterogeneity of cells forming it are described. Current knowledge of the major cellular and molecular processes associated with nodal pre-metastatic niche formation, including lymphangiogenesis, extracellular matrix remodeling, and immunosuppressive cell enlisting in lymph nodes are additionally summarized. Finally, future directions that research could possibly take and the clinical impact are discussed.

scholarly journals Tumor Microenvironment of Metastasis (TMEM) Doorways Are Restricted to the Blood Vessel Endothelium in Both Primary Breast Cancers and Their Lymph Node Metastases

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1507 ◽  
Author(s):  
Ginter ◽  
Karagiannis ◽  
Entenberg ◽  
Lin ◽  
Condeelis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Tumor Microenvironment ◽  
Lymph Nodes ◽  
Lymph Node Metastases ◽  
Lymphatic Vessels ◽  
Breast Tumors ◽  
Primary Tumors ◽  
Hematogenous Dissemination ◽  
Node Metastases

Cancer cells metastasize from primary tumors to regional lymph nodes and distant sites via the lymphatic and blood vascular systems, respectively. Our prior work has demonstrated that in primary breast tumors, cancer cells utilize a three-cell complex (known as tumor microenvironment of metastasis, or TMEM) composed of a perivascular macrophage, a tumor cell expressing high levels of the actin-regulatory protein mammalian enabled (Mena), and an endothelial cell as functional “doorways” for hematogenous dissemination. Here, we studied a well-annotated case–control cohort of human invasive ductal carcinoma of the breast and metastatic lymph nodes from a separate breast cancer cohort. We demonstrate that in primary breast tumors, blood vessels are always present within tumor cell nests (TCNs) and tumor-associated stroma (TAS), while lymphatic vessels are only occasionally present in TCN and TAS. Furthermore, TMEM doorways not only exist in primary tumors as previously reported but also in lymph node metastases. In addition, we show that TMEM intravasation doorways are restricted to the blood vascular endothelium in both primary tumors and lymph node metastases, suggesting that breast cancer dissemination to distant sites from both primary tumors and metastatic foci in lymph nodes occurs hematogenously at TMEM doorways. TMEMs are very rarely detected at lymphatic vessels and do not confer clinical prognostic significance, indicating they are not participants in TMEM-associated hematogenous dissemination. These findings are consistent with recent observations that hematogenous dissemination from lymph nodes occurs via blood vessels.

scholarly journals Lymph-migrating, tissue-derived dendritic cells are minor constituents within steady-state lymph nodes

2008 ◽  
Vol 205 (12) ◽  
pp. 2839-2850 ◽  
Author(s):  
Claudia Jakubzick ◽  
Milena Bogunovic ◽  
Anthony J. Bonito ◽  
Emma L. Kuan ◽  
Miriam Merad ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Node ◽  
Steady State ◽  
Lymph Nodes ◽  
Lymphatic Vessels ◽  
Inflammatory Stimulus ◽  
Major Fraction ◽  
Reporter Mouse ◽  
Relationship Of ◽  
The Relationship

Observations that dendritic cells (DCs) constitutively enter afferent lymphatic vessels in many organs and that DCs in some tissues, such as the lung, turnover rapidly in the steady state have led to the concept that a major fraction of lymph node DCs are derived from migratory DCs that enter the lymph node through upstream afferent lymphatic vessels. We used the lysozyme M–Cre reporter mouse strain to assess the relationship of lymph node and nonlymphoid organ DCs. Our findings challenge the idea that a substantial proportion of lymph node DCs derive from the upstream tissue during homeostasis. Instead, our analysis suggests that nonlymphoid organ DCs comprise a major population of DCs within lymph nodes only after introduction of an inflammatory stimulus.

scholarly journals VEGF-C–induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1010-1017 ◽  
Author(s):  
Satoshi Hirakawa ◽  
Lawrence F. Brown ◽  
Shohta Kodama ◽  
Karri Paavonen ◽  
Kari Alitalo ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Cancer Metastasis ◽  
Fluorescent Protein ◽  
Sentinel Lymph Nodes ◽  
Primary Tumors ◽  
Metastatic Cells ◽  
Good Target ◽  
Green Fluorescent ◽  
Factor C

Abstract The mechanisms by which tumors metastasize to sentinel and distant lymph nodes, and beyond, are poorly understood. We developed transgenic mice that overexpress vascular endothelial growth factor-C (VEGF-C) and green fluorescent protein specifically in the skin and studied the effects of chemically-induced skin carcinogenesis in this model. We found that in contrast to VEGF-A, VEGF-C does not increase the growth of primary tumors, but instead induces expansion of lymphatic networks within sentinel lymph nodes, even before the onset of metastasis. Once the metastatic cells arrived at the sentinel lymph nodes, the extent of lymphangiogenesis at these sites increased. Of importance, in mice with metastasis-containing sentinel lymph nodes, tumors that expressed VEGF-C were more likely to metastasize to additional organs, such as distal lymph nodes and lungs. No metastases were observed in distant organs in the absence of lymph node metastases. These findings indicate an important role of VEGF-C–induced lymph node lymphangiogenesis in the promotion of cancer metastasis beyond the sentinel lymph nodes. VEGF-C is therefore a good target to slow or even prevent the onset of metastasis.

scholarly journals Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses

2013 ◽  
Vol 210 (8) ◽  
pp. 1509-1528 ◽  
Author(s):  
Suvendu Das ◽  
Eliana Sarrou ◽  
Simona Podgrabinska ◽  
Melanie Cassella ◽  
Sathish Kumar Mungamuri ◽  
...  
Keyword(s):  
Cell Migration ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Lymphatic Vessels ◽  
Cell Entry ◽  
Human Malignant Melanoma ◽  
Tumor Cell Migration ◽  
Mouse Tissues

Lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation system. It is widely believed that tumor cells enter lymph nodes passively by the flow of lymph. We demonstrate that lymph node lymphatic sinuses control tumor cell entry into the lymph node, which requires active tumor cell migration. In human and mouse tissues, CCL1 protein is detected in lymph node lymphatic sinuses but not in the peripheral lymphatics. CCR8, the receptor for CCL1, is strongly expressed by human malignant melanoma. Tumor cell migration to lymphatic endothelial cells (LECs) in vitro is inhibited by blocking CCR8 or CCL1, and recombinant CCL1 promotes migration of CCR8+ tumor cells. The proinflammatory mediators TNF, IL-1β, and LPS increase CCL1 production by LECs and tumor cell migration to LECs. In a mouse model, blocking CCR8 with the soluble antagonist or knockdown with shRNA significantly decreased lymph node metastasis. Notably, inhibition of CCR8 led to the arrest of tumor cells in the collecting lymphatic vessels at the junction with the lymph node subcapsular sinus. These data identify a novel function for CCL1–CCR8 in metastasis and lymph node LECs as a critical checkpoint for the entry of metastases into the lymph nodes.

scholarly journals Morphological and radiological study of lymph nodes in dromedaries in Algeria

2020 ◽  
Vol 11 (2) ◽  
pp. 330-337
Author(s):  
D. E. Rahmoun ◽  
M. A. Lieshchova ◽  
M. A. Fares
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
General Structure ◽  
Lymphatic Vessels ◽  
Conventional Radiography ◽  
Farm Animals ◽  
Relative Mass ◽  
Linear Measurements ◽  
X Ray ◽  
The One

Despite significant progress in the study of the subtle mechanisms of interaction between cellular and molecular elements in immune responses, the general structure of the organs of the immune system, including the lymph node, has not been sufficiently studied, in particular in large farm animals. The lymph nodes of sexually mature camels have been studied anatomically and morphologically and advanced studies conducted using an X-ray system and a computer densitometer scanner with injection of a contrast medium. The topography and characteristics of the morphometric parameters (absolute and relative mass, linear measurements, volume) of certain somatic and visceral lymph nodes were determined. The mass of the lymph nodes studied varies according to the location and the interest of the organ in the satellite defense of the lymphoid system, For part of the x-ray examination of the lymph nodes, organs of large inguinal and axillary shape were selected after passing through a solution of tetraethyl-4,4-diamino-triphenylmethane oxalate, the lymph vessels were dilated and darkened, then iodine injections were made into the afferent lymphatic vessel of two lymph nodes; they were placed on the radiological cassette, a photograph taken on conventional radiography, for computer densitometer, the examination was made without preparation of the organs. A capsule encompasses the parenchyma of the lymph node, whose internal structure is composed of different zones, cortical, paracortical and medullary, on the one hand the lymphatic vessels were very clear especially with the conventional radiography with preparation of the organs, while the computer densitometer clearly revealed the deep texture of the parenchyma, basing it on the intensity of emission saturation from the use of computer densitometer.

scholarly journals Morphogenesis lymph node of domestic pig

2020 ◽  
pp. 102-109
Author(s):  
E. Gavrilina ◽  
A. Kolesnyk
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Lymphatic Vessels ◽  
Linear Measurements ◽  
Domestic Pig ◽  
Newborn Piglets ◽  
Connective Tissue Capsule ◽  
Degree Of Consolidation ◽  
Number Of Segments ◽  
Tissue Capsule

The visceral and somatic lymph nodes of a pig of domestic 1-120 day old were examined. Found that the lymph nodes have a common connective tissue capsule and different levels of fusion of individual subunits. In the center of each subunit, the capsule forms invaginations of the capsular trabecula, dividing the parenchyma of each structural unit into «Ʊ»-shaped structures, fused with lateral and lower parts. The number and degree of fusion of subunits is different and depends on the age of the animals and the location of the lymph node. The greatest degree of fusion of individual units of the lymph node was found in the superficial cervical and axillary I ribs. In the mandibular, superficial parotid and superficial inguinal lymph nodes, the segments are clearly contoured already in newborn piglets. Segments are predominantly bean-spherical in shape with a wide base. The fusion of the segments occurs in their central part, and on the surface the gates of the subunits are clearly contoured in the form of numerous depressions. In the visceral lymph nodes, the portal and splenic lymph nodes have the smallest segmentation, and the gastric, tracheobronchial, and iliocolic lymph nodes are the largest. The number of segments varies from two in newborn piglets to five in 120-day-old pigs. The variability of the morphometric parameters of the lymph nodes of a domestic pig is due to a different number of afferent lymphatic vessels, and, accordingly, to different scales of the lymphatic basins. Thus, the lymph nodes of the domestic pig are complexes of subunits fused to varying degrees. Somatic lymph nodes are highly segmented. The degree of consolidation of subunits in the visceral lymph nodes is less pronounced. Linear measurements of organs vary depending on the age of the animals, gradually increasing up to 120 days with a tendency for these indicators to prevail in the somatic lymph nodes. Key words: domestic pig, lymph node, subunit, topography, morphometry

scholarly journals MXRA8 is differentially expressed in lymph node metastasis in human breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Lymph Node Metastases ◽  
Metastatic Breast ◽  
Matrix Remodeling ◽  
Primary Tumors ◽  
Node Metastases ◽  
The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). Between the breast and the brain reside the secondary lymphoid organ, the lymph nodes. We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with metastasis to the lymph nodes in humans with metastatic breast cancer. We found that matrix remodeling associated 8, MXRA8, was among the genes whose expression was most different in the lymph node metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. MXRA8 mRNA was present at decreased quantities in lymph node metastases as compared to primary tumors of the breast. Importantly, expression of MXRA8 in primary tumors of the breast was correlated with patient post-progression survival, in lymph node positive patients but not in lymph node negative patients. Modulation of MXRA8 expression may be relevant to the biology by which tumor cells metastasize from the breast to the lymph nodes and the brain in humans with metastatic breast cancer.

scholarly journals IL-1α secreted by subcapsular sinus macrophages promotes melanoma metastasis in the sentinel lymph node by upregulating STAT3 signaling in the tumor.

2021 ◽  
Author(s):  
Tommaso Virgilio ◽  
Joy Bordini ◽  
Giulio Sartori ◽  
Irene Latino ◽  
Daniel Molina-Romero ◽  
...  
Keyword(s):  
Lymph Node ◽  
Sentinel Lymph Node ◽  
Tumor Antigens ◽  
Inflammatory Responses ◽  
Lymphatic Vessels ◽  
The Body ◽  
Melanoma Metastasis ◽  
Metastatic Cells ◽  
Subcapsular Sinus ◽  
Metastatic Microenvironment

During melanoma metastasization, tumor cells originated in the skin migrate via lymphatic vessels to the sentinel lymph node (sLN) in a process that facilitates their spread across the body. Here, we characterized the innate inflammatory responses to melanoma metastasis in the sLN. For this purpose, we confirmed the migration of fluorescent metastatic melanoma cells to the sLN and we characterized the inflammatory response in the metastatic microenvironment. We found that macrophages located in the subcapsular sinus (SSM), produce pro-tumoral IL-1α after recognition of tumor antigens. Moreover, we confirmed that the administration of an anti-IL-1α depleting antibody reduced metastasis. Conversely, the administration of recombinant IL-1α accelerated the lymphatic spreading of the tumor. Additionally, the elimination of the macrophages significantly reduced the progression of the metastatic spread. To understand the mechanism of action of IL-1α in the context of the lymph node microenvironment, we applied single-cell RNA sequencing to dissected metastases obtained from animals treated with an anti-IL-1α blocking antibody. Amongst the different pathways affected, we identified STAT3 as one of the main targets of IL-1α signaling in metastatic cells. Moreover, we found that the anti-IL-1α anti-tumoral effect was not mediated by lymphocytes, as IL-1R1 KO mice did not show any improvement in metastasis growth. Finally, we found a synergistic anti-metastatic effect of the combination of IL-1α blocking and the STAT3 inhibitor (STAT3i) stattic. In summary, we described a new mechanism by which SSM support melanoma metastasis, highlighting a new target for immunotherapy.

scholarly journals Decellularised scaffolds: just a framework? Current knowledge and future directions

2020 ◽  
Vol 11 ◽  
pp. 204173142094290 ◽  
Author(s):  
Elena García-Gareta ◽  
Yousef Abduldaiem ◽  
Prasad Sawadkar ◽  
Christos Kyriakidis ◽  
Ferdinand Lali ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Ex Vivo ◽  
Three Dimensional ◽  
Scaling Up ◽  
Matrix Composition ◽  
Minor Components ◽  
Future Directions ◽  
Great Progress ◽  
Cancer Modelling ◽  
Made In

The use of decellularised matrices as scaffolds offers the advantage of great similarity with the tissue to be replaced. Moreover, decellularised tissues and organs can be repopulated with the patient’s own cells to produce bespoke therapies. Great progress has been made in research and development of decellularised scaffolds, and more recently, these materials are being used in exciting new areas like hydrogels and bioinks. However, much effort is still needed towards preserving the original extracellular matrix composition, especially its minor components, assessing its functionality and scaling up for large tissues and organs. Emphasis should also be placed on developing new decellularisation methods and establishing minimal criteria for assessing the success of the decellularisation process. The aim of this review is to critically review the existing literature on decellularised scaffolds, especially on the preparation of these matrices, and point out areas for improvement, finishing with alternative uses of decellularised scaffolds other than tissue and organ reconstruction. Such uses include three-dimensional ex vivo platforms for idiopathic diseases and cancer modelling.

scholarly journals Lymph Nodes-On-Chip: Promising Immune Platforms for Pharmacological and Toxicological Applications

2021 ◽  
Vol 12 ◽  
Author(s):  
Aya Shanti ◽  
Nicholas Hallfors ◽  
Georg A Petroianu ◽  
Lourdes Planelles ◽  
Cesare Stefanini
Keyword(s):  
Lymph Node ◽  
Drug Discovery ◽  
Lymph Nodes ◽  
Chip Design ◽  
Future Directions ◽  
Drug Discovery And Development ◽  
Design And Implementation ◽  
Physiological Relevance ◽  
Main Determinants ◽  
On Chip

Organs-on-chip are gaining increasing attention as promising platforms for drug screening and testing applications. However, lymph nodes-on-chip options remain limited although the lymph node is one of the main determinants of the immunotoxicity of newly developed pharmacological drugs. In this review, we describe existing biomimetic lymph nodes-on-chip, their design, and their physiological relevance to pharmacology and shed the light on future directions associated with lymph node-on-chip design and implementation in drug discovery and development.

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