肺のプロトロンボティックニッチからの細胞外膀は,インテグリンβ2を介して,がんに関連した血栓形成と転移を誘導する

Serena Lucotti¹, Yusuke Ogitani¹, Candia M Kenific¹

¹Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.

Cell

|February 12, 2025

まとめ

癌の進行は,特定の肺マクロファージからの小さな細胞外膀 (sEVs) を介して血栓を誘発する. これらのsEVにインテグリンβ2を標的にすることで,がん患者の血栓形成と転移を防ぐことができる.

科学分野:

腫瘍学
血液学
細胞生物学

背景:

血栓形成は,がん患者,特に臓管内腺がん (PDAC) の患者の主要な死因です.
癌の進行は,血栓前状態を含む全身的な合併症につながる可能性があります.
がんと血栓形成を結びつけるメカニズムは完全に理解されていません.

研究の目的:

癌に関連した血栓形成における小細胞外小胞 (sEVs) の役割を調査する.
血栓性SEVの細胞源と分子メカニズムを特定する.
血栓形成リスクと治療目標のバイオマーカーとしてsEV-β2を評価する.

主な方法:

肺の微環境におけるC-X-Cモチーフケモキン13 (CXCL13) によって再プログラムされたインタースティシャルマクロファージによって分泌されるsEVの特徴化.
sEV内のインテグリンβ2包装とインテグリンαXとの二酸化分析.
血小板糖タンパク質 (GP) IbとsEVの相互作用の評価と血小板凝集の誘導
血栓形成と肺転移に対する影響を評価するために,インビオ試験でインテグリンβ2を阻害する.
血血栓症とないPDAC患者におけるsEV-β2濃度の測定

主要な成果:

CXCL13で再プログラムされたマクロファージは,肺内のプロトロンボティックニッチ (PTN) を確立して,プロトロンボティックSEVを分泌する.
これらのsEVは,血小板のGPIbと相互作用して血小板の集積を促進する,集積されたインテグリンβ2を包み込む.
インテグリンβ2を阻害することで,sEVによる血栓形成と肺転移が著しく減少した.
PDAC患者では,血栓性イベントの前のsEV-β2の血値上昇が観察されました.

結論:

癌の進行は,肺のPTNを系統的に確立し,プロトロンボ性SEVによって特徴付けられます.
sEVのインテグリンβ2は,がんに関連した血栓形成と転移の重要な媒介です.
sEV- β2は,血栓形成リスクの予後バイオマーカーであり,潜在的な治療標的である.

キーワード:

さらに関連する動画

07:39

The Establishment of a Lung Colonization Assay for Circulating Tumor Cell Visualization in Lung Tissues

Published on: June 16, 2018

9.2K

07:35

A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer

Published on: December 26, 2016

40.5K

関連する概念動画

02:30

Metastasis

5.5K

Metastasis is the spread of cancer cells from the original site to distant locations in the body. Cancer cells can spread via blood vessels (hematogenous) as well as lymph vessels in the body.
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...

5.5K

01:17

Intracellular Signaling Affects Focal Adhesions

2.5K

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...

2.5K

01:35

Cancer Cell Migration through Invadopodia

2.3K

Invadosome is a broad category of cell surface structures with proteolytic activity that degrades the extracellular matrix (ECM). Invadosomes are present in normal cell types, including macrophages, endothelial cells, and neurons, as well as tumor cells. Although the macrophage podosomes and tumor cell invadopodia are classified as invadosomes, they have different structures, molecular pathways, and functions. Podosomes are short structures that last for a few minutes. However,...

2.3K

02:17

The Tumor Microenvironment

6.5K

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...

6.5K

01:10

Integrins

3.7K

Animal and protozoan cells do not have cell walls to help maintain shape and provide structural stability. Instead, these eukaryotic cells secrete a sticky mass of carbohydrates and proteins into the spaces between adjacent cells. This network of proteins and molecules is called an extracellular matrix or ECM.
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...

3.7K

01:25

Selectins

3.2K

Cell adhesion is an essential aspect of multicellularity. While stable cell interactions usually occur between cells of the same type, transient cell interactions occur between cells of different tissue types, such as between neutrophils and endothelial cells. Selectins are one class of cell adhesion molecules (CAMs) that bind carbohydrate ligands to form transient cell adhesion. They are rod-like proteins with a long extracellular part of variable length ending with the lectin domain,...