• 2018-07
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  • More recently primary tumor driven


    More recently, primary tumor driven generation of a bone pre-metastatic niche was observed in a mouse model of estrogen receptor-negative breast cancer metastasis. Specifically, lysyl oxidase (LOX) secreted into the circulation from hypoxic primary breast tumors disrupted bone homeostasis, thereby inducing osteolysis [8]. The osteolytic microdomains within the bone served as niches for subsequent metastatic tumor cells, and bisphosphonate administration in the pre-metastatic setting prevented development of metastatic disease. This work is the first reported observation of breast cancer induced osteolytic action-at-a-distance (breast cancers frequently induce osteolysis following their dissemination to bone, as we discuss later). These findings, if further supported, have important clinical implications and should prompt further investigation into systemic modulation of bone-specific pre-metastatic niches.
    Do primary tumors that impact the bone microenvironment also influence bone metastases? Interestingly, bone is a conduit during pre-metastatic niche formation in visceral tissues in nearly all reported studies to date [2]. In other words, pre-metastatic niche formation in extra-osseous organs involves mobilization, modification, and recruitment of bone marrow derived Lomustine (BMDCs) that help create the niche. Even before the discovery of pre-metastatic niches, investigation into the role of BMDCs in primary tumor progression and metastasis was an active area of research, as it still is today. Numerous studies have shown that tumor-derived systemically acting factors impact the bone microenvironment to expand and mobilize bone marrow cells (BMCs) into the circulation that are subsequently recruited to tumor sites where they instigate various processes that support tumor progression [9,10] (Table 1). For example, tumor-derived granulocyte colony-stimulating factor (G-CSF) and interleukin-1β (IL1β) mobilize tumor-supportive CD11b+/Gr1+ myeloid cells from the bone marrow into circulation, while vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF) release hemangiogenic BMCs (VEGFR1+ cells) from the bone marrow into circulation [9]. Breast cancer-associated fibroblasts (CAFs) have been Lomustine demonstrated to secrete CXCL12, which induces the release of pro-angiogenic hematopoietic progenitor cells into the circulation [11]. Tumor-derived microvesicles–membrane-bound particles released from a primary tumor that carry lipids, proteins, mRNAs and miRNAs–could also modulate cells in the bone microenvironment [12]. For example, melanoma exosomes were shown to ‘educate’ bone marrow progenitor cells toward a pro-metastatic phenotype [13]. More recently, OPN carried through the circulation by murine mammary carcinoma-derived microparticles in response to chemotherapy, was necessary for mobilizing pro-angiogenic cells from the bone marrow [14]. It is becoming increasingly apparent that tumor-derived factors can also alter certain BMCs by affecting their gene expression even prior to their mobilization into the circulation [12] (Table 1). Murine cancer models revealed that a subset of myeloid cells upregulated pro-angiogenic factors in response to tumor-derived G-CSF [15]. In studies of mouse xenograft models, tumor-derived soluble OPN, which functions as an inflammatory cytokine, rendered Sca1+/cKit-/CD45+ hematopoietic BMCs pro-tumorigenic by modulating gene expression prior to their mobilization into circulation [16].
    Do cancer-dependent systemic factors influence tumors that have disseminated to bone? Despite the frequency with which disseminated tumor cells (DTCs) are found in the bone marrow of cancer patients, the significance of these cells is unknown, as a considerable number of these patients never develop overt metastatic disease [4]. Such findings support the concepts of metastatic inefficiency and tumor dormancy [17] and suggest that while the bone microenvironment may be conducive to initial dissemination and survival of tumor cells, other processes are required to promote disease progression.