Certainly dynamic interactions between DTCs and stromal
Certainly, dynamic interactions between DTCs and stromal orexin a within the bone microenvironment disrupt bone homeostasis, which is normally tightly controlled, to fuel metastatic progression  (Table 1). For example, it is well established that osteolytic breast cancer DTC-derived factors, such as matrix metalloproteinases, cause the release of latent TGF-β from the bone microenvironment. This, in turn, induces DTC production of a variety of cytokines, most notably parathyroid hormone-related protein (PTHrP), which either promotes osteoclast maturation or stimulates osteoblast secretion of IL-6 and RANKL thus propagating a vicious cycle of tumor outgrowth and osteolytic bone breakdown . Tumor cells can also directly secrete interleukins (specifically IL-6, IL-8, and IL-11) to increase osteoclastogenesis, and thus fuel the vicious cycle of tumor progression . Likewise, osteoblastic DTCs, such as those that metastasize from prostate cancers, initiate paracrine interactions within the bone microenvironment that serve to promote their growth .
The fact that many of the same tumor-supportive cytokines that are secreted by DTCs within the bone microenvironment are also secreted by the primary tumors that spawned them begs the question of how much influence the primary tumor has on DTCs in the bone. The answer may have clinical relevance, considering that patients who develop metastatic disease after surgery and treatment of their primary cancer clearly had DTCs in the periphery at the time of their initial diagnosis. Indeed, pre-clinical models of the early phases of metastatic disease, when patients harbor indolent DTCs at a time when their primary tumor is present, have provided important insights into systemic cross talk between distantly located tumors. For example, early studies of chemically-induced cancers revealed that some tumors establish an immune-permissive environment for the outgrowth of otherwise immunogenic tumors at distant sites . In a process that was termed “systemic instigation”, certain primary tumors promote the outgrowth of otherwise indolent lung metastases by secreting factors that cause mobilization and recruitment of BMDCs that aid metastatic outgrowth . In the case of systemic instigation by triple-negative breast cancer, primary tumors secrete OPN into the circulation, which is necessary for rendering BMCs pro-tumorigenic. In systemic instigation models of luminal breast cancer, tumor-derived cytokines and growth factors are taken up by circulating platelets that cooperate with BMDCs to promote angiogenesis in the distant tumors. In addition to tumor cells, cells in the primary tumor microenvironment can impact distant metastasis. For example, cancer activated fibroblasts secrete growth/differentiation factor 15 (GDF15, also known as macrophage inhibitory cytokine-1, MIC-1, a member of the TGF-β family of growth factors) to promote metastatic outgrowth in the lung .
Conclusions and questions The past decade has seen a significant expansion in our knowledge about the intimate, yet long-distance relationship between various cancers and the bone microenvironment (Fig. 1). Nevertheless, surprisingly little is known about whether or how such systemic endocrinal interactions impact bone metastases. Development of better pre-clinical models of bone metastasis, with validation in clinical studies, should help guide interventions aimed at inhibiting underlying systemic signaling cascades, if they exist, and could offer clinical benefit for cancer patients. Hence, some critical questions in this active area of research remain unanswered:
Acknowledgement This work was supported in part by the Department of Defense BCMRP Era of Hope Scholar AwardW81XWH-14-1-0191 (SSM).
ECM determines cell behaviour Given the importance of the ECM in directing almost all cellular behaviour, it is not too surprising that altered ECM deposition, synthesis and post-translational modification leads to a disorganised mesh with differing properties and results in diseases such as organ fibrosis and cancer. For more detailed reviews on how increased stiffness translate into regulation of cellular processes such as motility, proliferation and survival please see Cox and Erler 2014  and Pickup et al. 2015 ).