Platelets guide the formation of early metastatic niches

Abstract

During metastasis, host cells are recruited to disseminated tumor cells to form specialized microenvironments ("niches") that promote metastatic progression, but the mechanisms guiding the assembly of these niches are largely unknown. Tumor cells may autonomously recruit host cells or, alternatively, host cell-to-host cell interactions may guide the formation of these prometastatic microenvironments. Here, we show that platelet-derived rather than tumor cell-derived signals are required for the rapid recruitment of granulocytes to tumor cells to form "early metastatic niches." Granulocyte recruitment relies on the secretion of CXCL5 and CXCL7 chemokines by platelets upon contact with tumor cells. Blockade of the CXCL5/7 receptor CXCR2, or transient depletion of either platelets or granulocytes prevents the formation of early metastatic niches and significantly reduces metastatic seeding and progression. Thus, platelets recruit granulocytes and guide the formation of early metastatic niches, which are crucial for metastasis. Interactions between host cells and tumor cells both at the primary and metastatic sites are crucial for efficient metastasis (1-3). At the site of metastasis, host cell-tumor cell cross talk contributes to the formation of a metastatic niche, a specialized microenvironment necessary for disease progression. Leukocytes, in particular monocytes and macrophages, have been shown to be recruited to metastatic niches and to support metastasis (4-10). Mechanistically, macrophages secrete VEGFA that facilitates tumor cell extravasation (4). In addition, interaction of monocytes/ macrophages with tumor cells via VCAM1 can prevent tumor cell apoptosis and allow reinitiation of growth at the metastatic site (8, 9). Granulocytes have also been reported to interact with tumor cells and facilitate metastatic seeding possibly by enhancing tumor cell arrest and extravasation (11-13). However, granulocytes exposed to specific environmental stimuli can kill metastatic tumor cells, suggesting that their role in metastasis is highly context dependent (14, 15).Platelets, which interact with tumor cells during their transit through the circulation, also enhance metastasis via multiple mechanisms (3, 16). Metastatic tumor cells can express high levels of tissue factor (TF) and adhesion molecules, such as P-selectin ligands, through which they bind to and activate platelets (16). These interactions result in the formation by platelets of a physical shield around tumor cells, which prevents attacks from natural killer (NK) cells and promotes tumor cell adhesion to the endothelium (17-19). In addition, platelets also promote tumor cell extravasation by increasing endothelial permeability and by directly signaling to tumor cells to enhance their invasive and metastatic potential (20,21). In particular, direct contact between platelets and tumor cells triggers the TGFβ1 and NF-κB signaling pathways in tumor cells, which induce an epithelial-mesenchymal transition and promote metastasis (20). Given their important signa...

The platelet-to-lymphocyte ratio as a predictor of patient outcomes in ovarian cancer: a meta-analysis

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Tumor-Induced NETosis as a Risk Factor for Metastasis and Organ Failure

“…Although not identified as NETs, platelet-granulocyte complexes with tumor cells were recently demonstrated to form early metastatic niches, crucial for later metastatic progression (28). In this context, granulocyte recruitment was initiated by secretion of CXCL5 and CXCL7 by platelets upon contact with tumor cells (28).…”

FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

“…The clinical observation that thrombocytosis is frequently associated with cancer was made more than 100 years ago (17,18). Recent studies indicate that platelets are integral elements of the tumor microenvironment; platelets were shown to be crucial for tumor growth (19), chemoresistance (20), and metastasis (21,22). Additionally, patients with ovarian cancer with an increased number of platelets at the time of initial diagnosis have significantly worse overall and progressionfree survival (20,23).…”

“…We and others have shown that platelets enhance tumor growth (19,23,26), chemoresistance (20), and metastasis (21,22). Although platelet number and function can be altered by hypoxia (27)(28)(29), the functional effects of hypoxia in the tumor microenvironment on platelets are unknown.…”