Abstract
Breast cancer cells have a high predilection for skeletal homing, where they may either induce osteolytic bone destruction or enter a latency period in which they remain quiescent. Breast cancer cells produce and encounter autocrine and paracrine cytokine signals in the bone microenvironment, which can influence their behavior in multiple ways. For example, these signals can promote the survival and dormancy of bone-disseminated cancer cells or stimulate proliferation. The interleukin-6 (IL-6) cytokine family, defined by its use of the glycoprotein 130 (gp130) co-receptor, includes interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1), among others. These cytokines are known to have overlapping pleiotropic functions in different cell types and are important for cross-talk between bone-resident cells. IL-6 cytokines have also been implicated in the progression and metastasis of breast, prostate, lung, and cervical cancer, highlighting the importance of these cytokines in the tumor–bone microenvironment. This review will describe the role of these cytokines in skeletal remodeling and cancer progression both within and outside of the bone microenvironment.
Highlights
Upon dissemination into the bone marrow, breast cancer cells and other tumor types encounter a rigid [1], hypoxic [2] microenvironment containing bone-resident immune and stromal cell populations.It is hypothesized that disseminated tumor cells (DTCs) compete for the hematopoietic stem cell niche, and are maintained in a quiescent state by interactions with osteoblast lineage cells [3] for an indefinite period of time
These data suggest that the inhibition of STAT3 in the primary site is critical to reducing tumor cell growth, but in distant metastatic sites, such as the bone marrow, STAT3 inactivation could lead to the awakening of dormant tumor cells
Because leukemia inhibitory factor (LIF), oncostatin M (OSM), and ciliary neurotrophic factor (CNTF) are present in the bone marrow, bone-DTCs may receive these signals in the endosteal niche to remain in a dormant state; given that these cytokines can promote stemness, it will be important to determine whether LIF, OSM, and CNTF
Summary
Upon dissemination into the bone marrow, breast cancer cells and other tumor types encounter a rigid [1], hypoxic [2] microenvironment containing bone-resident immune and stromal cell populations. In the osteoblast lineage, it has been shown that OSM activates distinct signaling pathways, depending upon whether it complexes with OSMR or LIFR [25], suggesting that these cytokines and their specific receptor complexes may induce specific downstream signals in bone-resident cells. Despite the similar sequence homology, structure, and intron-exon and promoter elements between OSM and LIF [26], the individual IL-6 cytokines have differing roles in cancer and bone biology This may be partly due to tissue specificity for ligand and receptor expression or the activation of different downstream signals, which will be discussed . The knockout of Lif or Lifr resulted in an increase in large osteoclasts, with activity clustered near the growth plate in young mice [44,45] These cytokines orchestrate bone remodeling to maintain bone homeostasis; boneDTCs can hijack bone remodeling to alter the environment and make a more suitable environment. In this regard, understanding the role for gp130 cytokines in normal bone remodeling is essential to understanding the impact of gp130 cytokines and signaling in bone-DTCs
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