Interactions in the (Pre)metastatic Niche Support Metastasis Formation

Doglioni, Ginevra; Parik, Sweta; Fendt, Sarah-Maria

doi:10.3389/fonc.2019.00219

Cited by 116 publications

(94 citation statements)

References 89 publications

(103 reference statements)

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“…The process of tumor metastasis involves the interaction of primary tumor cells with the environment of distant organs (the premetastatic niche). Also important is the interaction of cancer cells with their environment after arriving in a distant organ (metastatic niche) . A premetastatic niche creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs …”

Section: Introductionmentioning

confidence: 99%

“…Also important is the interaction of cancer cells with their environment after arriving in a distant organ (metastatic niche). 3 A premetastatic niche creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs. 4 The C-C motif chemokine 2 (CCL2, also known as monocyte chemoattractant protein-1 [MCP-1]) and the signaling pathway modulated by its receptor (CCR2) play a crucial role in the recruitment of monocytes to the sites of inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Phase I dose‐escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer

et al. 2020

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The formation of premetastatic niches creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs. This is crucial for the development of metastasis in various malignancies, including breast cancer (BC). We previously reported that the loss of FBXW7 in bone marrow‐derived stromal cells promoted cancer metastasis by increasing the production of the chemokine CCL2, which attracts myeloid‐derived suppressor cells and macrophages to the premetastatic niche. Furthermore, treatment with the CCL2 inhibitor propagermanium (PG), which has been used in Japan as a therapeutic agent against chronic hepatitis B, was shown to block the enhancement of metastasis in FBXW7‐deficient mice through inhibiting the formation of premetastatic niches. Here, we describe a phase I dose‐escalation study of PG used as an antimetastatic drug for perioperative patients with primary BC. The primary end‐point was the percentage of patients who experience dose‐limiting toxicity. Twelve patients were enrolled in the study. Dose‐limiting toxicity was not observed, and the maximum dose was determined to be 90 mg/body/day. The serum concentrations of PG were nearly within the normal range in all observation days. We observed an inverse correlation between FBXW7 mRNA levels in blood and the serum concentrations of CCL2 and interleukin (IL)‐6, in agreement with our previous mouse model. Also, IL‐6 was downregulated in a PG dose‐dependent manner, as observed in mice. Thus, PG was given safely and it is expected to have antimetastatic potential in BC. This trial is registered in the UMIN Clinical Trials Registry as UMIN000022494.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase I dose‐escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer

et al. 2020

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“…In addition to genetic redirection and expression of increasingly 3 malignant traits 1,2 , disseminating TCs can highjack the normal function of platelets and immune cells 4 like neutrophils to survive hemodynamic forces and immune clearance while traversing the blood 5 circulation [3][4][5] . A growing body of evidence indicates that TCs can also modify distant 6 microenvironments to facilitate survival and proliferation in the later stages of metastasis [6][7][8] . 7 However, the formation of a vascular pre-metastatic niche, which may facilitate TC escape from the 8 circulation 9,10 , remains largely unexplored, and much is still unknown about how TCs achieve 9 vascular egress (extravasation) 11,12 .…”

Section: Introductionmentioning

confidence: 99%

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Offeddu

Hajal

Foley

et al. 2020

Preprint

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The glycocalyx on tumor cells has been recently identified as an important driver for cancer progression, possibly providing critical opportunities for treatment. Metastasis, in particular, is often the limiting step in the survival to cancer, yet our understanding of how tumor cells escape the vascular system to initiate metastatic sites remains limited. Using an in vitro model of the human microvasculature, we assess here the importance of the tumor and vascular glycocalyces during tumor cell extravasation. Through selective manipulation of individual components of the glycocalyx, we reveal a novel mechanism whereby tumor cells prepare an adhesive vascular niche by depositing components of the glycocalyx along the endothelium. Accumulated hyaluronic acid shed by tumor cells subsequently mediates adhesion to the endothelium via the glycoprotein CD44. Transendothelial migration and invasion into the stroma occurs through binding of the isoform CD44v to components of the sub-endothelial extra-cellular matrix. Targeting of the hyaluronic acid-CD44 glycocalyx complex results in significant reduction in the extravasation of tumor cells. These studies provide evidence of tumor cells repurposing the glycocalyx to promote adhesive interactions leading to cancer progression. Such glycocalyx-mediated mechanisms may be therapeutically targeted to hinder metastasis and improve patient survival.

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“…Cancer cells nucleate primary tumors in part by releasing exosomes and other soluble factors that bias the local immune setting toward tolerance. These and other factors—such as the role of fibroblasts in the ECM—help establish a tumor‐supportive microenvironment known as the premetastatic niche (PMN); these sites have the stromal and cellular infrastructure to help a tumor develop . Excitingly, biomaterials have been used to create synthetic PMNs to sample tumor and immune cells.…”

Section: Biomaterials Enable Studies At the Interface Of Immune Cellsmentioning

confidence: 99%

“…These and other factors-such as the role of fibroblasts in the ECM-help establish a tumor-supportive microenvironment known as the premetastatic niche (PMN); these sites have the stromal and cellular infrastructure to help a tumor develop. [125] Excitingly, biomaterials have been used to create synthetic PMNs to sample tumor and immune cells. This has been accomplished using a microporous PLGA scaffold that can be implanted into mice.…”

Section: Biomaterials Can Be Used To Study How Altering Disease Micromentioning

confidence: 99%

Biomaterials as Tools to Decode Immunity

Eppler¹,

Jewell

2019

Advanced Materials

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The immune system has remarkable capabilities to combat disease with exquisite selectivity. This feature has enabled vaccines that provide protection for decades and, more recently, advances in immunotherapies that can cure some cancers. Greater control over how immune signals are presented, delivered, and processed will help drive even more powerful options that are also safe. Such advances will be underpinned by new tools that probe how immune signals are integrated by immune cells and tissues. Biomaterials are valuable resources to support this goal, offering robust, tunable properties. The growing role of biomaterials as tools to dissect immune function in fundamental and translational contexts is highlighted. These technologies can serve as tools to understand the immune system across molecular, cellular, and tissue length scales. A common theme is exploiting biomaterial features to rationally direct how specific immune cells or organs encounter a signal. This precision strategy, enabled by distinct material properties, allows isolation of immunological parameters or processes in a way that is challenging with conventional approaches. The utility of these capabilities is demonstrated through examples in vaccines for infectious disease and cancer immunotherapy, as well as settings of immune regulation that include autoimmunity and transplantation.

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Interactions in the (Pre)metastatic Niche Support Metastasis Formation

Cited by 116 publications

References 89 publications

Phase I dose‐escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer

Phase I dose‐escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Biomaterials as Tools to Decode Immunity

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