Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils

Liu, Yanfang; Gu, Yan; Yun, Han; Zhang, Qian; Jiang, Zhengping; Zhang, Xiang; Huang, Bo; Xu, Xiaoqing; Zheng, Jianming; Cao, Xuetao

doi:10.1016/j.ccell.2016.06.021

Cited by 482 publications

(406 citation statements)

References 60 publications

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“…TLR3 activation in lung epithelial cells by tumor-exosomal non-coding snRNA enhances expression of S100A8, A100A9, MMP9, Bv8 and fibronectin which, in turn, contributes to lung PMN formation (Liu et al, 2016). Upregulation of TLR3 promotes secretion of chemokines that mobilize neutrophils (CD45 + CD11b + Ly6G + Ly6C int cKit + VEGFR1 + ), as well as macrophages (F4/80 + ) and monocytes (VEGFR1 + Ly6G − Ly6C + ) that further support PMN formation (Liu et al, 2016).…”

Section: Tumor Evs Path Through the Extracellular Compartmentmentioning

confidence: 99%

“…Upregulation of TLR3 promotes secretion of chemokines that mobilize neutrophils (CD45 + CD11b + Ly6G + Ly6C int cKit + VEGFR1 + ), as well as macrophages (F4/80 + ) and monocytes (VEGFR1 + Ly6G − Ly6C + ) that further support PMN formation (Liu et al, 2016). Interestingly, tumor-secreted exosomes have their own protein “zip-codes”, namely specific integrin profiles, that address them to specific target organs, thus determining metastatic organotropism (Hoshino et al, 2015).…”

Section: Tumor Evs Path Through the Extracellular Compartmentmentioning

confidence: 99%

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Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis

et al. 2016

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Summary Tumor-secreted extracellular vesicles (EVs) are critical mediators of intercellular communication between tumor cells and stromal cells in local and distant microenvironments. Accordingly, EVs play an essential role in both primary tumor growth and metastatic evolution. EVs orchestrate multiple systemic pathophysiological processes, such as coagulation, vascular leakiness, and reprogramming of stromal recipient cells to support pre-metastatic niche formation and subsequent metastasis. Clinically, EVs may be biomarkers and novel therapeutic targets for cancer progression, particularly for predicting and preventing future metastatic development.

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Section: Tumor Evs Path Through the Extracellular Compartmentmentioning

confidence: 99%

Section: Tumor Evs Path Through the Extracellular Compartmentmentioning

confidence: 99%

Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis

et al. 2016

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“…Also TLRs have been shown to be involved in premetastatic niche formation in the lung. The role of TLR3 in the formation of a PMN in the lung was shown with TLR3 knock-out mice (94). TLR3 activation in lung epithelial cells by tumorderived exosomal RNAs triggers neutrophil recruitment by induction of PMN markers such as S100A8, S100A9, MMP9, Bv8 and FN and secretion of cytokines such as CXCL1, CXCL2, CXCL5 and CXCL12 (94).…”

Section: Metastatic Niche Of Melanoma In the Lungmentioning

confidence: 99%

The Multiple Roles of Exosomes in Metastasis

Weidle

Birzele

Kollmorgen

et al. 2017

CGP

159

124

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Abstract. Exosomes are important contributors to cellMetastases are responsible for the death of a large majority of cancer patients despite considerable progress in surgical techniques, radiotherapy, chemotherapy and targeted therapies including immuno-therapy (1). A dramatic reduction of metastatic burden has been observed, however, tumor elimination is almost always incomplete. This phenomenon is based on drug resistance, which is due to adaptation of intracellular pathways or on activation of survival-supporting autocrine and paracrine pathways and several secreted factors expressed by drug-sensitive tumor cells after therapy (2). Metastasis can occur through release of cancer cells from the primary tumor into body cavities that holds true for ovarian and CNS tumors, or via hematogeneous and lymphatic vessels of the circulatory system (3). Metastases of some tumors are directed besides to lymph nodes to mainly one type of organ only, such as prostate cancer to the bones, pancreatic cancer and uveal melanoma to the liver, whereas tumors such as melanoma, breast-and lung cancer can colonize several types of organs (3). Tumor cells have been found in the blood of patients with early-stage cancer and in some cases even before the primary tumor has been diagnosed (4, 5). Recently, making use of single-cell expression profiling, it has been shown that early metastatic cells possess a stem-like gene signature and give rise to heterogeneous metastases (6). The metastatic process is characterized by a defined sequence of events (7,8). Initial steps are detachment from the extracellular matrix (ECM), invasion into the surrounding tissue and proteolysis of the basement membrane. After intravasation, survival of circulating tumor cells (CTCs) is achieved by forming clusters, binding to platelets and immune evasion. Subsequently, they arrest in distal microvascular beds and extravasation can be achieved either by migration through intercellular junctions of endothelial cells (EC) or penetration of a single EC (9). CTCs can also colonize their tumors of origin, a process referred to as "tumor self-seeding", selecting for cancer cell populations more aggressive than those present in the primary tumor (10). After extravasation, colonization and outgrowth in the parenchyma of distant organs are the following steps. A common theme of the metastatic process is settlement of disseminated tumor cells (DTCs) into latency (dormancy), which can last from several months to decades (11). It has been observed that DTCs are recruited into pre-metastatic niches that support their survival by interactions with endothelial, myeloid cells, fibroblasts and other types of cells. After adaptation to the host microenvironment and suppression of an anti-tumoral immune response, DTCs are activated by not yet completely resolved mechanisms. Finally their outgrowth is based on an angiogenic switch mediated by pro-angiogenic factors and establishment of a vascular network to support the metabolic demands of colonizing tumor cells (12). In the follo...

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“…The impact of TEX on niche resident cells supporting recruitment was recently described in an elegant report. The authors noted that lung epithelial cells become triggered by TEX via activation of TLR3 to secret chemokines promoting neutrophil recruitment (Liu Y. et al, 2016). In a similar study it was elaborated that TEX support TGFß, TLR and Stat3 upregulation in BMC and LNC, which is accompanied by upregulation of Notch.…”

Section: Cic Cd44 and Texmentioning

confidence: 99%

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Wang

Zhao

Hackert

et al. 2018

Front. Cell Dev. Biol.

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Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker. Knockdown and knockout models accompanied by loss of tumor progression despite unaltered primary tumor growth unraveled that these markers are indispensable for CIC. The unexpected contribution of marker molecules to CIC-related activities prompted research on underlying molecular mechanisms. This review outlines the contribution of CD44, particularly CD44v6 to CIC activities. A first focus is given to the impact of CD44/CD44v6 to inherent CIC features, including the crosstalk with the niche, apoptosis-resistance, and epithelial mesenchymal transition. Following the steps of the metastatic cascade, we report on supporting activities of CD44/CD44v6 in migration and invasion. These CD44/CD44v6 activities rely on the association with membrane-integrated and cytosolic signaling molecules and proteases and transcriptional regulation. They are not restricted to, but most pronounced in CIC and are tightly regulated by feedback loops. Finally, we discuss on the engagement of CD44/CD44v6 in exosome biogenesis, loading and delivery. exosomes being the main acteurs in the long-distance crosstalk of CIC with the host. In brief, by supporting the communication with the niche and promoting apoptosis resistance CD44/CD44v6 plays an important role in CIC maintenance. The multifaceted interplay between CD44/CD44v6, signal transducing molecules and proteases facilitates the metastasizing tumor cell journey through the body. By its engagement in exosome biogenesis CD44/CD44v6 contributes to disseminated tumor cell settlement and growth in distant organs. Thus, CD44/CD44v6 likely is the most central CIC biomarker.

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Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils

Cited by 482 publications

References 60 publications

Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis

Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis

The Multiple Roles of Exosomes in Metastasis

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

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