The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease.

Multiple myeloma (MM) is an osteolytic malignancy that is incurable due to the emergence of treatment resistant disease. Defining how, when and where myeloma cell intrinsic and extrinsic bone microenvironmental mechanisms cause relapse is challenging with current biological approaches. Here, we report a biology-driven spatiotemporal hybrid agent-based model of the MM-bone microenvironment. Results indicate MM intrinsic mechanisms drive the evolution of treatment resistant disease but that the protective effects of bone microenvironment mediated drug resistance (EMDR) significantly enhances the probability and heterogeneity of resistant clones arising under treatment. Further, the model predicts that targeting of EMDR deepens therapy response by eliminating sensitive clones proximal to stroma and bone, a finding supported by in vivo studies. Altogether, our model allows for the study of MM clonal evolution over time in the bone microenvironment and will be beneficial for optimizing treatment efficacy so as to significantly delay disease relapse.

How circulating tumor cluster biology contributes to the metastatic cascade: from invasion to dissemination and dormancy.

Circulating tumor cells (CTCs) are known to be prognostic for metastatic relapse and are detected in patients as solitary cells or cell clusters. Circulating tumor cell clusters (CTC clusters) have been observed clinically for decades and are of significantly higher metastatic potential compared to solitary CTCs. Recent studies suggest distinct differences in CTC cluster biology regarding invasion and survival in circulation. However, differences regarding dissemination, dormancy, and reawakening require more investigations compared to solitary CTCs. Here, we review the current state of CTC cluster research and consider their clinical significance. In addition, we discuss the concept of collective invasion by CTC clusters and molecular evidence as to how cluster survival in circulation compares to that of solitary CTCs. Molecular differences between solitary and clustered CTCs during dormancy and reawakening programs will also be discussed. We also highlight future directions to advance our current understanding of CTC cluster biology.

γδ-Enriched CAR-T cell therapy for bone metastatic castrate-resistant prostate cancer.

Immune checkpoint blockade has been largely unsuccessful for the treatment of bone metastatic castrate-resistant prostate cancer (mCRPC). Here, we report a combinatorial strategy to treat mCRPC using γδ-enriched chimeric antigen receptor (CAR) T cells and zoledronate (ZOL). In a preclinical murine model of bone mCRPC, γδ CAR-T cells targeting prostate stem cell antigen (PSCA) induced a rapid and significant regression of established tumors, combined with increased survival and reduced cancer-associated bone disease. Pretreatment with ZOL, a U.S. Food and Drug Administration-approved bisphosphonate prescribed to mitigate pathological fracture in mCRPC patients, resulted in CAR-independent activation of γδ CAR-T cells, increased cytokine secretion, and enhanced antitumor efficacy. These data show that the activity of the endogenous Vγ9Vδ2 T cell receptor is preserved in CAR-T cells, allowing for dual-receptor recognition of tumor cells. Collectively, our findings support the use of γδ CAR-T cell therapy for mCRPC treatment.

Integrated computational and in vivo models reveal Key Insights into macrophage behavior during bone healing.

Myeloid-derived monocyte and macrophages are key cells in the bone that contribute to remodeling and injury repair. However, their temporal polarization status and control of bone-resorbing osteoclasts and bone-forming osteoblasts responses is largely unknown. In this study, we focused on two aspects of monocyte/macrophage dynamics and polarization states over time: 1) the injury-triggered pro- and anti-inflammatory monocytes/macrophages temporal profiles, 2) the contributions of pro- versus anti-inflammatory monocytes/macrophages in coordinating healing response. Bone healing is a complex multicellular dynamic process. While traditional in vitro and in vivo experimentation may capture the behavior of select populations with high resolution, they cannot simultaneously track the behavior of multiple populations. To address this, we have used an integrated coupled ordinary differential equations (ODEs)-based framework describing multiple cellular species to in vivo bone injury data in order to identify and test various hypotheses regarding bone cell populations dynamics. Our approach allowed us to infer several biological insights including, but not limited to,: 1) anti-inflammatory macrophages are key for early osteoclast inhibition and pro-inflammatory macrophage suppression, 2) pro-inflammatory macrophages are involved in osteoclast bone resorptive activity, whereas osteoblasts promote osteoclast differentiation, 3) Pro-inflammatory monocytes/macrophages rise during two expansion waves, which can be explained by the anti-inflammatory macrophages-mediated inhibition phase between the two waves. In addition, we further tested the robustness of the mathematical model by comparing simulation results to an independent experimental dataset. Taken together, this novel comprehensive mathematical framework allowed us to identify biological mechanisms that best recapitulate bone injury data and that explain the coupled cellular population dynamics involved in the process. Furthermore, our hypothesis testing methodology could be used in other contexts to decipher mechanisms in complex multicellular processes.

EphA2 Is a Clinically Relevant Target for Breast Cancer Bone Metastatic Disease.

EphA2 receptor tyrosine kinase (RTK) is highly expressed in breast tumor cells across multiple molecular subtypes and correlates with poor patient prognosis. In this study, the potential role of EphA2 in this clinically relevant phenomenon is investigated as metastasis of breast cancer to bone is a major cause of morbidity and mortality in patients. It was found that the EphA2 function in breast cancer cells promotes osteoclast activation and the development of osteolytic bone disease. Blocking EphA2 function molecularly and pharmacologically in breast tumors reduced the number and size of bone lesions and the degree of osteolytic disease in intratibial and intracardiac mouse models, which correlated with a significant decrease in the number of osteoclasts at the tumor-bone interface. EphA2 loss of function in tumor cells impaired osteoclast progenitor differentiation in coculture, which is mediated, at least in part, by reduced expression of IL-6. EPHA2 transcript levels are enriched in human breast cancer bone metastatic lesions relative to visceral metastatic sites; EphA2 protein expression was detected in breast tumor cells in bone metastases in patient samples, supporting the clinical relevance of the study's findings. These data provide a strong rationale for the development and application of molecularly targeted therapies against EphA2 for the treatment of breast cancer bone metastatic disease. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Computational modeling reveals a key role for polarized myeloid cells in controlling osteoclast activity during bone injury repair.

Bone-forming osteoblasts and -resorbing osteoclasts control bone injury repair, and myeloid-derived cells such as monocytes and macrophages are known to influence their behavior. However, precisely how these multiple cell types coordinate and regulate each other over time within the bone marrow to restore bone is difficult to dissect using biological approaches. Conversely, mathematical modeling lends itself well to this challenge. Therefore, we generated an ordinary differential equation (ODE) model powered by experimental data (osteoblast, osteoclast, bone volume, pro- and anti-inflammatory myeloid cells) obtained from intra-tibially injured mice. Initial ODE results using only osteoblast/osteoclast populations demonstrated that bone homeostasis could not be recovered after injury, but this issue was resolved upon integration of pro- and anti-inflammatory myeloid population dynamics. Surprisingly, the ODE revealed temporal disconnects between the peak of total bone mineralization/resorption, and osteoblast/osteoclast numbers. Specifically, the model indicated that osteoclast activity must vary greatly (> 17-fold) to return the bone volume to baseline after injury and suggest that osteoblast/osteoclast number alone is insufficient to predict bone the trajectory of bone repair. Importantly, the values of osteoclast activity fall within those published previously. These data underscore the value of mathematical modeling approaches to understand and reveal new insights into complex biological processes.

Host-Derived Matrix Metalloproteinase-13 Activity Promotes Multiple Myeloma-Induced Osteolysis and Reduces Overall Survival.

Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type I collagen-rich bone matrix by activated osteoclasts results in the release of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP13 largely localizes to the stromal compartment compared with CD138+ myeloma cells. In this study, we further identified that multiple myeloma induces MMP13 expression in bone stromal cells. Because of its ability to degrade type I collagen, we examined whether bone stromal-derived MMP13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild-type or MMP13-null mice. In independent in vivo studies, MMP13-null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared with wild-type controls. Unexpectedly, no differences in type I collagen processing between the groups were observed. Ex vivo stromal coculture assays showed reduced formation and activity in MMP13-null osteoclasts. Analysis of soluble factors from wild-type and MMP13-null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP13 catalytic activity in multiple myeloma progression, we demonstrate the in vivo efficacy of a novel and highly selective MMP13 inhibitor that provides a translational opportunity for the treatment of this incurable disease. SIGNIFICANCE: Genetic and pharmacologic approaches show that bone stromal-derived MMP13 catalytic activity is critical for osteoclastogenesis, bone destruction, and disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2415/F1.large.jpg.

Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer.

Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.

Quantification and Optimization of Standard-of-Care Therapy to Delay the Emergence of Resistant Bone Metastatic Prostate Cancer.

BACKGROUND: Bone metastatic prostate cancer (BMPCa), despite the initial responsiveness to androgen deprivation therapy (ADT), inevitably becomes resistant. Recent clinical trials with upfront treatment of ADT combined with chemotherapy or novel hormonal therapies (NHTs) have extended overall patient survival. These results indicate that there is significant potential for the optimization of standard-of-care therapies to delay the emergence of progressive metastatic disease. METHODS: Here, we used data extracted from human bone metastatic biopsies pre- and post-abiraterone acetate/prednisone to generate a mathematical model of bone metastatic prostate cancer that can unravel the treatment impact on disease progression. Intra-tumor heterogeneity in regard to ADT and chemotherapy resistance was derived from biopsy data at a cellular level, permitting the model to track the dynamics of resistant phenotypes in response to treatment from biological first-principles without relying on data fitting. These cellular data were mathematically correlated with a clinical proxy for tumor burden, utilizing prostate-specific antigen (PSA) production as an example. RESULTS: Using this correlation, our model recapitulated the individual patient response to applied treatments in a separate and independent cohort of patients (n = 24), and was able to estimate the initial resistance to the ADT of each patient. Combined with an intervention-decision algorithm informed by patient-specific prediction of initial resistance, we propose to optimize the sequence of treatments for each patient with the goal of delaying the evolution of resistant disease and limit cancer cell growth, offering evidence for an improvement against retrospective data. CONCLUSIONS: Our results show how minimal but widely available patient information can be used to model and track the progression of BMPCa in real time, offering a clinically relevant insight into the patient-specific evolutionary dynamics of the disease and suggesting new therapeutic options for intervention. TRIAL REGISTRATION: NCT # 01953640. FUNDING: Funded by an NCI U01 (NCI) U01CA202958-01 and a Moffitt Team Science Award. CCL and DB were partly funded by an NCI PSON U01 (U01CA244101). AA was partly funded by a Department of Defense Prostate Cancer Research Program (W81XWH-15-1-0184) fellowship. LC was partly funded by a postdoctoral fellowship (PF-13-175-01-CSM) from the American Cancer Society.

Prostate cancer-derived MMP-3 controls intrinsic cell growth and extrinsic angiogenesis.

Bone metastatic prostate cancer significantly impacts patient quality of life and overall survival, and despite available therapies, it is presently incurable with an unmet need for improved treatment options. As mediators of tumor progression, matrix metalloproteinases (MMPs) can degrade extracellular matrix components and regulate growth factor and cytokine bioactivity. Depending on tissue context, MMPs can either promote or inhibit tumorigenesis. Therefore, it is essential to study individual MMPs in specific cancer contexts and microenvironments to support the design and application of selective MMP inhibitors. Here we report that tumor-derived MMP-3 contributes to bone metastatic prostate cancer progression via intrinsic and extrinsic routes. MMP-3 ablation in prostate cancer cell lines significantly reduced in vitro growth combined with lowered AKT and ERK phosphorylation and total VEGFR1 and FGFR3 protein levels. In vivo, MMP-3 ablated tumors grew at a slower rate and were significantly less vascularized. Quantitative PCR analyses of wild type and MMP-3 silenced prostate cancer cells also demonstrate downregulation of a wide array of angiogenic factors. The extrinsic role for MMP-3 in angiogenesis was supported by in vitro endothelial tube formation assays where the lack of MMP-3 in prostate cancer conditioned media resulted in slower rates of tube formation. Taken together, our results suggest that tumor-derived MMP-3 contributes to prostate cancer growth in bone. These data indicate that selective inhibition of MMP-3 and/or targeting MMP generated products could be efficacious for the treatment of prostate to bone metastases.

Modeling Osteocyte Network Formation: Healthy and Cancerous Environments.

Advanced cancers, such as prostate and breast cancers, commonly metastasize to bone. In the bone matrix, dendritic osteocytes form a spatial network allowing communication between osteocytes and the osteoblasts located on the bone surface. This communication network facilitates coordinated bone remodeling. In the presence of a cancerous microenvironment, the topology of this network changes. In those situations, osteocytes often appear to be either overdifferentiated (i.e., there are more dendrites than healthy bone) or underdeveloped (i.e., dendrites do not fully form). In addition to structural changes, histological sections from metastatic breast cancer xenografted mice show that number of osteocytes per unit area is different between healthy bone and cancerous bone. We present a stochastic agent-based model for bone formation incorporating osteoblasts and osteocytes that allows us to probe both network structure and density of osteocytes in bone. Our model both allows for the simulation of our spatial network model and analysis of mean-field equations in the form of integro-partial differential equations. We considered variations of our model to study specific physiological hypotheses related to osteoblast differentiation; for example predicting how changing biological parameters, such as rates of bone secretion, rates of cancer formation, and rates of osteoblast differentiation can allow for qualitatively different network topologies. We then used our model to explore how commonly applied therapies such as bisphosphonates (e.g., zoledronic acid) impact osteocyte network formation.

Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma.

Overall survival rates for patients with advanced osteosarcoma have remained static for over three decades. An in vitro analysis of osteosarcoma cell lines for sensitivity to an array of approved cancer therapies revealed that panobinostat, a broad spectrum histone deacetalyase (HDAC) inhibitor, is highly effective at triggering osteosarcoma cell death. Using in vivo models of orthotopic and metastatic osteosarcoma, here we report that panobinostat impairs the growth of primary osteosarcoma in bone and spontaneous metastasis to the lung, the most common site of metastasis for this disease. Further, pretreatment of mice with panobinostat prior to tail vein inoculation of osteosarcoma prevents the seeding and growth of lung metastases. Additionally, panobinostat impaired the growth of established lung metastases and improved overall survival, and these effects were also manifest in the lung metastatic SAOS2-LM7 model. Mechanistically, the efficacy of panobinostat was linked to high expression of HDAC1 and HDAC2 in osteosarcoma, and silencing of HDAC1 and 2 greatly reduced osteosarcoma growth in vitro. In accordance with these findings, treatment with the HDAC1/2 selective inhibitor romidepsin compromised the growth of osteosarcoma in vitro and in vivo. Analysis of patient-derived xenograft osteosarcoma cell lines further demonstrated the sensitivity of the disease to panobinostat or romidepsin. Collectively, these studies provide rationale for clinical trials in osteosarcoma patients using the approved therapies panobinostat or romidepsin.

CAR-T Engineering: Optimizing Signal Transduction and Effector Mechanisms.

The adoptive transfer of genetically engineered T cells expressing a chimeric antigen receptor (CAR) has shown remarkable results against B cell malignancies. This immunotherapeutic approach has advanced and expanded rapidly from preclinical models to the recent approval of CAR-T cells to treat lymphomas and leukemia by the Food and Drug Administration (FDA). Ongoing research efforts are focused on employing CAR-T cells as a therapy for other cancers, and enhancing their efficacy and safety by optimizing their design. Here we summarize modifications in the intracellular domain of the CAR that gave rise to first-, second-, third- and next-generation CAR-T cells, together with the impact that these different designs have on CAR-T cell biology and function. Further, we describe how the structure of the antigen-sensing ectodomain can be enhanced, leading to superior CAR-T cell signaling and/or function. Finally we discuss how tissue-specific factors may impact the clinical efficacy of CAR-T cells for bone and the central nervous system, as examples of specific indications that may require further CAR signaling optimization to perform in such inhospitable microenvironments.

Betaglycan drives the mesenchymal stromal cell osteogenic program and prostate cancer-induced osteogenesis.

Bone metastatic prostate cancer provokes extensive osteogenesis by driving the recruitment and osteoblastic differentiation of mesenchymal stromal cells (MSCs). The resulting lesions greatly contribute to patient morbidity and mortality, underscoring the need for defining how prostate metastases subvert the MSC-osteoblast differentiation program. To gain insights into this process we profiled the effects of co-culture of primary MSCs with validated bone metastatic prostate cancer cell line models. These analyses revealed a cast of shared differentially induced genes in MSC, including betaglycan, a co-receptor for TGFß. Betaglycan has not been studied in the context of bone metastatic disease previously. Here we report that loss of betaglycan in MSC is sufficient to augment TGFß signaling, proliferation and migration, and completely blocks the MSC-osteoblast differentiation program. Further, betaglycan was revealed as necessary for prostate cancer-induced osteogenesis in vivo. Mechanistically, gene expression analysis revealed betaglycan controls the expression of a large repertoire of genes in MSCs, and that betaglycan loss provokes >60-fold increase in the expression of Wnt5a that plays important roles in stemness. In accord with the increased Wnt5a levels, there was a marked induction of canonical Wnt signaling in betaglycan ablated MSCs, and the addition of recombinant Wnt5a to MSCs was sufficient to impair osteogenic differentiation. Finally, the addition of Wnt5a neutralizing antibody was sufficient to induce the expression of osteogenic genes in betaglycan-ablated MSCs. Collectively, these findings suggest a betaglycan-Wnt5a circuit represents an attractive vulnerability to ameliorate prostate cancer-induced osteogenesis.

Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) recurs after androgen deprivation therapy (ADT) and is incurable. Reactivation of androgen receptor (AR) signaling in the low androgen environment of ADT drives CRPC. This AR activity occurs through a variety of mechanisms, including up-regulation of AR coactivators such as VAV3 and expression of constitutively active AR variants such as the clinically relevant AR-V7. AR-V7 lacks a ligand-binding domain and is linked to poor prognosis. We previously showed that VAV3 enhances AR-V7 activity to drive CRPC progression. Gene expression profiling after depletion of either VAV3 or AR-V7 in CRPC cells revealed arginine vasopressin receptor 1a (AVPR1A) as the most commonly down-regulated gene, indicating that this G protein-coupled receptor may be critical for CRPC. Analysis of publicly available human PC datasets showed that AVPR1A has a higher copy number and increased amounts of mRNA in advanced PC. Depletion of AVPR1A in CRPC cells resulted in decreased cell proliferation and reduced cyclin A. In contrast, androgen-dependent PC, AR-negative PC, or nontumorigenic prostate epithelial cells, which have undetectable AVPR1A mRNA, were minimally affected by AVPR1A depletion. Ectopic expression of AVPR1A in androgen-dependent PC cells conferred castration resistance in vitro and in vivo. Furthermore, treatment of CRPC cells with the AVPR1A ligand, arginine vasopressin (AVP), activated ERK and CREB, known promoters of PC progression. A clinically safe and selective AVPR1A antagonist, relcovaptan, prevented CRPC emergence and decreased CRPC orthotopic and bone metastatic growth in mouse models. Based on these preclinical findings, repurposing AVPR1A antagonists is a promising therapeutic approach for CRPC.

Proteolytic Regulation of Parathyroid Hormone-Related Protein: Functional Implications for Skeletal Malignancy.

Parathyroid hormone-related protein (PTHrP), with isoforms ranging from 139 to 173 amino acids, has long been implicated in the development and regulation of multiple tissues, including that of the skeleton, via paracrine and autocrine signaling. PTHrP is also known as a potent mediator of cancer-induced bone disease, contributing to a vicious cycle between tumor cells and the bone microenvironment that drives the formation and progression of metastatic lesions. The abundance of roles ascribed to PTHrP have largely been attributed to the N-terminal 1-36 amino acid region, however, activities for mid-region and C-terminal products as well as additional shorter N-terminal species have also been described. Studies of the protein sequence have indicated that PTHrP is susceptible to post-translational proteolytic cleavage by multiple classes of proteases with emerging evidence pointing to novel functional roles for these PTHrP products in regulating cell behavior in homeostatic and pathological contexts. As a consequence, PTHrP products are also being explored as potential biomarkers of disease. Taken together, our enhanced understanding of the post-translational regulation of PTHrP bioactivity could assist in developing new therapeutic approaches that can effectively treat skeletal malignancies.

Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell Alloreactivity Yet Spares Donor Anti-tumor Immunity.

Acute graft- vs. -host disease (GVHD) is an important cause of morbidity and death after allogeneic hematopoietic cell transplantation (HCT). We identify a new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) alloactivation of T cells, yet preserves graft- vs.-leukemia (GVL). Exceeding endoplasmic reticulum (ER) capacity results in a spliced form of X-box binding protein-1 (XBP-1s). XBP-1s mediates ER stress and inflammatory responses. We demonstrate that siRNA targeting XBP-1 in moDCs abrogates their stimulation of allogeneic T cells. B-I09, an inositol-requiring enzyme-1α (IRE1α) inhibitor that prevents XBP-1 splicing, reduces human moDC migration, allo-stimulatory potency, and curtails moDC IL-1ß, TGFß, and p40 cytokines, suppressing Th1 and Th17 cell priming. B-I09-treated moDCs reduce responder T cell activation via calcium flux without interfering with regulatory T cell (Treg) function or GVL effects by cytotoxic T lymphocytes (CTL) and NK cells. In a human T cell mediated xenogeneic GVHD model, B-I09 inhibition of XBP-1s reduced target-organ damage and pathogenic Th1 and Th17 cells without impacting donor Tregs or anti-tumor CTL. DC XBP-1s inhibition provides an innovative strategy to prevent GVHD and retain GVL.

Multifaceted Roles for Macrophages in Prostate Cancer Skeletal Metastasis.

Bone-metastatic prostate cancer is common in men with recurrent castrate-resistant disease. To date, therapeutic focus has largely revolved around androgen deprivation therapy (ADT) and chemotherapy. While second-generation ADTs and combination ADT/chemotherapy approaches have been successful in extending overall survival, the disease remains incurable. It is clear that molecular and cellular components of the cancer-bone microenvironment contribute to the disease progression and potentially to the emergence of therapy resistance. In bone, metastatic prostate cancer cells manipulate bone-forming osteoblasts and bone-resorbing osteoclasts to produce growth and survival factors. While osteoclast-targeted therapies such as bisphosphonates have improved quality of life, emerging data have defined important roles for additional cells of the bone microenvironment, including macrophages and T cells. Disappointingly, early clinical trials with checkpoint blockade inhibitors geared at promoting cytotoxic T cell response have not proved as promising for prostate cancer compared to other solid malignancies. Macrophages, including bone-resident osteomacs, are a major component of the bone marrow and play key roles in coordinating normal bone remodeling and injury repair. The role for anti-inflammatory macrophages in the progression of primary prostate cancer is well established yet relatively little is known about macrophages in the context of bone-metastatic prostate cancer. The focus of the current review is to summarize our knowledge of macrophage contribution to normal bone remodeling and prostate-to-bone metastasis, while also considering the impact of standard of care and targeted therapies on macrophage behavior in the tumor-bone microenvironment.

Cutting to the Chase: How Matrix Metalloproteinase-2 Activity Controls Breast-Cancer-to-Bone Metastasis.

Bone metastatic breast cancer is currently incurable and will be evident in more than 70% of patients that succumb to the disease. Understanding the factors that contribute to the progression and metastasis of breast cancer can reveal therapeutic opportunities. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes whose role in cancer has been widely documented. They are capable of contributing to every step of the metastatic cascade, but enthusiasm for the use of MMP inhibition as a therapeutic approach has been dampened by the disappointing results of clinical trials conducted more than 20 years ago. Since the trials, our knowledge of MMP biology has expanded greatly. Combined with advances in the selective targeting of individual MMPs and the specific delivery of therapeutics to the tumor microenvironment, we may be on the verge of finally realizing the promise of MMP inhibition as a treatment strategy. Here, as a case in point, we focus specifically on MMP-2 as an example to show how it can contribute to each stage of breast-cancer-to-bone metastasis and also discuss novel approaches for the selective targeting of MMP-2 in the setting of the bone-cancer microenvironment.

Size Matters: Metastatic Cluster Size and Stromal Recruitment in the Establishment of Successful Prostate Cancer to Bone Metastases.

Prostate cancer (PCa) impacts over 180,000 men every year in the USA alone, with 26,000 patients expected to succumb to the disease ( cancer.gov ). The primary cause of death is metastasis, with secondary lesions most commonly occurring in the skeleton. Prostate cancer to bone metastasis is an important, yet poorly understood, process that is difficult to explore with experimental techniques alone. To this end we have utilized a hybrid (discrete-continuum) cellular automaton model of normal bone matrix homeostasis that allowed us to investigate how metastatic PCa can disrupt the bone microenvironment. Our previously published results showed that PCa cells can recruit mesenchymal stem cells (MSCs) that give rise to bone-building osteoblasts. MSCs are also thought to be complicit in the establishment of successful bone metastases (Lu, in Mol Cancer Res 4(4):221-233, 2006). Here we have explored the aspects of early metastatic colonization and shown that the size of PCa clusters needs to be within a specific range to become successfully established: sufficiently large to maximize success, but not too large to risk failure through competition among cancer and stromal cells for scarce resources. Furthermore, we show that MSC recruitment can promote the establishment of a metastasis and compensate for relatively low numbers of PCa cells seeding the bone microenvironment. Combined, our results highlight the utility of biologically driven computational models that capture the complex and dynamic dialogue between cells during the initiation of active metastases.