Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils

C Engblom, C Pfirschke, R Zilionis, J Da Silva Martins… - Science, 2017 - science.org
C Engblom, C Pfirschke, R Zilionis, J Da Silva Martins, SA Bos, G Courties, S Rickelt…
Science, 2017science.org
INTRODUCTION Myeloid cells have emerged as key regulators of cancer growth because of
their abundance in the tumor stroma in a broad range of cancers, their association with
clinical outcome, and their ability to modulate tumor progression. Most tumor-infiltrating
myeloid cells derive from circulating precursors, which are produced in distant tissues, and
some tumors amplify myeloid cell activity by skewing hematopoiesis toward the myeloid
lineage or increasing myeloid cell populations in the periphery. For example, patients across …
INTRODUCTION
Myeloid cells have emerged as key regulators of cancer growth because of their abundance in the tumor stroma in a broad range of cancers, their association with clinical outcome, and their ability to modulate tumor progression. Most tumor-infiltrating myeloid cells derive from circulating precursors, which are produced in distant tissues, and some tumors amplify myeloid cell activity by skewing hematopoiesis toward the myeloid lineage or increasing myeloid cell populations in the periphery. For example, patients across diverse cancer types can present with elevated levels of myeloid progenitor cells in peripheral blood. Additionally, increased numbers of circulating myeloid cells, such as neutrophils, often correlate with poorer clinical outcome. It is therefore important to consider host changes that occur away from the tumor stroma to more fully understand the biological processes underlying tumor growth.
RATIONALE
The bone marrow is a tissue of particular interest as it is the main production site for hematopoietic cells corresponding to all circulating blood lineages in the adult. The marrow contains resident cell components, such as osteoblasts, which not only participate in bone maintenance but also regulate hematopoiesis and immune cell fate. However, our understanding of bone dynamics in the context of cancer (growing at sites distant from the local bone microenvironment) and related immune responses remains limited. To address this knowledge gap, we explored whether a common solid cancer—lung adenocarcinoma—remotely affects bone tissue and how this might shape tumor-associated hematopoietic responses and tumor growth.
RESULTS
We show in different mouse models and in cancer patients (n = 70) that lung adenocarcinomas increase bone stromal activity even in the absence of local metastasis. Animal studies further reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn+) osteoblastic cells. Ocn+ cells affect distant tumor progression because experimentally reducing the number of these cells limits lung tumor growth. Also, Ocn+ cells are required for full-fledged tumor infiltration by a distinct subset of neutrophils that are defined by their high expression of the lectin SiglecF (sialic acid–binding immunoglobulin-like lectin F). Compared to other neutrophils, SiglecFhigh cells express genes associated with cancer-promoting processes, including angiogenesis, myeloid cell differentiation and recruitment, extracellular matrix remodeling, suppression of T cell responses, and tumor cell proliferation and growth. Additionally, SiglecFhigh neutrophils have increased reactive oxygen species production, promote macrophage differentiation, and boost tumor progression in vivo. We further report that the soluble receptor for advanced glycation end products (sRAGE) is up-regulated in the circulation of tumor-bearing mice and fosters osteoblastic activity and osteoblast-dependent neutrophil maturation in vitro.
CONCLUSION
This study identifies systemic cross-talk between lung tumors and bones: Lung tumors can remotely activate Ocn+ osteoblastic cells in bones even in the absence of local metastasis. In turn, these Ocn+ cells supply tumors with SiglecFhigh neutrophils, which foster cancer progression. The findings bear scientific and therapeutic importance because they reveal contributions of the host systemic environment to tumor growth and they position Ocn+ cells, SiglecFhigh neutrophils, and sRAGE as candidate clinical biomarkers and possible intervention points for anticancer therapy.
Systemic cross-talk between lung tumors and bones
Lung adenocarcinomas can …
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