Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF^highneutrophils

Abstract

Bone marrow-derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients ( = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecF neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecF neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.

Understanding the tumor immune microenvironment (TIME) for effective therapy

“…87 ), can affect bone marrow myeloid progenitor expansion, thus leading to enhanced release of myeloid cells into circulation, and ultimately affect the number of circulating and tumor-infiltrating immunosuppressive myeloid cells and contribute to more severe disease and greater metastatic burden 74,88 . Tumor-induced systemic factors can affect the bone marrow and in turn promote tumor infiltration of cancer-promoting immune components, including neutrophils 89 , monocytes 90 and platelets 91 .…”

Cross-talk between lung cancer and bones results in neutrophils that promote tumor progression

“…A recent study showed that the newly formed osteoblasts derive from bone marrow endothelial cells when those are stimulated by metastatic cancer cells [63,64]. Engblom and colleagues introduce a new concept: osteoblasts can be remotely activated by tumor cells remotely even when those are not present in the bone [42]. Future studies will reveal what is the origin of newly formed osteoblasts activated by lung tumor, and whether they are also derived from endothelial cells.…”

“…Although neutrophils may present pro- or anti-tumoral activity, depending on specific tumor microenvironments [41], we are still far from fully understanding their function in the lung tumor microenvironment, and how this role can be regulated. Now, in an article in Science , Engblom and colleagues reveal the heterogeneity of neutrophils in the lung cancer microenvironment, and that only SiglecF high – expressing neutrophils promote tumor growth [42]. The authors investigated the systemic crosstalk between lung tumor and the bone that regulates the recruitment of pro-tumoral neutrophils by using elegant state-of-the-art techniques, including in vivo sophisticated Cre/loxP technologies in combination with several lung tumor models.…”

“…The authors investigated the systemic crosstalk between lung tumor and the bone that regulates the recruitment of pro-tumoral neutrophils by using elegant state-of-the-art techniques, including in vivo sophisticated Cre/loxP technologies in combination with several lung tumor models. Engblom and colleagues revealed, by using fluorescence-molecular tomography and Ocn-YFP mice, that lung tumors disrupt bone homeostatic activity, by increasing the number of osteocalcin (Ocn)-expressing osteoblasts through tumor-secreted factors [42]. Strikingly, these osteoblasts, in turn, promote lung tumor growth through the priming of pro-tumoral neutrophils (Figure 1).…”

“…Strikingly, these osteoblasts, in turn, promote lung tumor growth through the priming of pro-tumoral neutrophils (Figure 1). The authors demonstrated that genetic ablation of osteoblasts, by using Ocn-Cre/iDTR mice, abolished lung tumor progression, via the interruption of SiglecF high –expressing neutrophils supply to the tumor microenvironment [42]. Moreover, Engblom and colleagues showed that SiglecF high –expressing neutrophils expand tumor growth in vivo .…”