Journal Article

Platelets guide the formation of early metastatic niches

Labelle, Myriam, Begum, Shahinoor, Hynes, Richard O.

2014

Overview

Specialized microenvironments (or “niches”) are essential for metastasis, but how cancer cells and host cells contribute to their establishment remains poorly understood. Our study reveals that platelets and granulocytes are sequentially recruited to disseminated tumor cells to form “early metastatic niches” that promote metastatic progression. Importantly, the recruitment of granulocytes is not primarily due to tumor cell-derived signals but rather relies on platelet-derived CXCL5/7 chemokines. Prevention of granulocyte recruitment via inhibition of the CXCL5/7 receptor CXCR2, or depletion of either platelets or granulocytes inhibits metastasis, thereby uncovering a key role for platelet-to-granulocyte signaling in the establishment of metastases. Specific inhibition of platelet-to-granulocyte interactions may thus represent a valuable antimetastatic therapy in addition to cancer cell-centered treatments. 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Biological Sciences / Blood platelets / Blood Platelets - metabolism / Blood Platelets - pathology / Cell Line, Tumor / Cells / chemokine CXCL5 / Chemokine CXCL5 - genetics / Chemokine CXCL5 - metabolism / chemokine CXCL7 / Chemokines / Chemokines, CXC - genetics / Chemokines, CXC - metabolism / CHO Cells / Cricetinae / Cricetulus / CXCR2 receptor / granulocytes / Granulocytes - metabolism / Granulocytes - pathology / Metastasis / Mice / Mice, Inbred NOD / Mice, Knockout / Mice, SCID / Microenvironments / neoplasm cells / Neoplasm Metastasis / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Neoplasms, Experimental - genetics / Neoplasms, Experimental - metabolism / Neoplasms, Experimental - pathology / niches / PNAS Plus / PNAS PLUS: Significance Statements / Receptors, Interleukin-8B - genetics / Receptors, Interleukin-8B - metabolism / secretion / sowing / Tumor Microenvironment / Tumors