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PURPOSE OF REVIEW - The goal of this review is to summarize recent experimental and clinical evidence for metastatic latency and the molecular mechanisms that regulate tumor dormancy in the bone.
RECENT FINDINGS - Tumor dormancy contributes to the progression of metastasis and thus has significant clinical implications for prognosis and treatment. Tumor-intrinsic signaling and specialized bone marrow niches play a pivotal role in determining the dormancy status of bone disseminated tumor cells. Experimental models have provided significant insight into the effects of the bone microenvironment on tumor cells; however, these models remain limited in their ability to study dormancy. Despite recent advances in the mechanistic understanding of how tumor cells remain dormant in the bone for prolonged periods of time, the signals that trigger spontaneous dormancy escape remain unclear. This review highlights the need for further investigation of mechanisms underlying tumor dormancy using clinically relevant models.
The tumor-cell microenvironment is recognized as a dynamic place where critical cell interactions occur and play an important role in altering tumorigenesis. While many studies have investigated the effects of cellular cross-talk within distinct tumor microenvironments, these interactions have yet to be fully examined in bone. It is well-established that many common cancers metastasize to bone, resulting in the development of tumor-induced bone disease (TIBD), a multi-facetted illness that is driven by complex cell interactions within the bone marrow. Our group has previously published that myeloid progenitor cells expand in the presence of tumors in bone, aligning with the notion that myeloid cells can act as tumor promotors. Several groups, including ours, have established that transforming growth factor β (TGF-β), an abundant growth factor in bone, can regulate both TIBD and myeloid expansion. TGF-β inhibitors have been shown to increase bone volume, decrease bone destruction, and reduce but not eliminate tumor. Therefore, we hypothesize that inhibiting TGF-β will reduce myeloid expansion leading to a reduction of tumor burden in bone and osteoclast-mediated bone loss, causing to an overall reduction in TIBD. To address this hypothesis, two different mouse models of breast cancer bone colonization were pre-treated with the TGF-β neutralizing antibody, 1D11, prior to tumor inoculation (athymic: MDA-MB-231, BALB/c: 4T1) and continuously treated until sacrifice. Additionally, a genetically modified mouse model with a myeloid specific deletion of transforming growth factor beta receptor II (TGF-βRII) (TGF-βRII) was utilized in our studies. Systemic inhibition of TGF-β lead to fewer osteolytic lesions, and reduced tumor burden in bone as expected from previous studies. Additionally, early TGF-β inhibition affected expansion of distinct myeloid populations and shifted the cytokine profile of pro-tumorigenic factors in bone, 4T1 tumor cells, and bone-marrow derived macrophages. Similar observations were seen in tumor-bearing TGF-βRII mice, where these mice contained fewer bone lesions and significantly less tumor burden in bone, suggesting that TGF-β inhibition regulates myeloid expansion leading to a significant reduction in TIBD.
Published by Elsevier Inc.
Both the American Joint Committee on Cancer (AJCC) and Musculoskeletal Tumor Society (MSTS) staging systems for skeletal sarcomas have major weaknesses. A revised staging system for osteosarcoma (the Vanderbilt system) was developed based on exploratory analyses of the relative prognostic impacts of histologic grade, tumor size, local tumor extension, and specific anatomic sites of metastasis using case records from the National Cancer Database (N = 4,285). AJCC, MSTS, and Vanderbilt staging schemes were then compared using a separate, population-based cancer registry (the Surveillance, Epidemiology, and End Results database; N = 2,246) as a validation dataset. Predictive accuracy for 5-year sarcoma-specific survival was evaluated by comparing areas under receiver-operating characteristic curves generated from logistic regression. Three different concordance indices and Bayesian information criteria were also calculated for model comparisons. The Vanderbilt staging system showed comparable predictive accuracy for 5-year disease-specific survival (65%) compared to the AJCC (67%) and MSTS (67%) staging systems. Most cross-comparisons of model concordance were not significantly different either. Bayesian information criterion was lowest for the MSTS staging system. Substaging osteosarcoma by current anatomical criteria is ineffectual. A simplified staging system based only on histologic grade and the presence of distant metastasis to any anatomic site performs similarly to the current AJCC and MSTS staging systems by multiple statistical criteria and is proposed for clinical and pathological staging of osteosarcomas of the non-pelvic appendicular and non-spinal axial skeleton. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2802-2808, 2018.
© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
As the complexity of interactions between tumor and its microenvironment has become more evident, a critical need to engineer in vitro models that veritably recapitulate the 3D microenvironment and relevant cell populations has arisen. This need has caused many groups to move away from the traditional 2D, tissue culture plastic paradigms in favor of 3D models with materials that more closely replicate the in vivo milieu. Creating these 3D models remains a difficult endeavor for hard and soft tissues alike as the selection of materials, fabrication processes, and optimal conditions for supporting multiple cell populations makes model development a nontrivial task. Bone tissue in particular is uniquely difficult to model in part because of the limited availability of materials that can accurately capture bone rigidity and architecture, and also due to the dependence of both bone and tumor cell behavior on mechanical signaling. Additionally, the bone is a complex cellular microenvironment with multiple cell types present, including relatively immature, pluripotent cells in the bone marrow. This prospect will focus on the current 3D models in development to more accurately replicate the bone microenvironment, which will help facilitate improved understanding of bone turnover, tumor-bone interactions, and drug response. These studies have demonstrated the importance of accurately modelling the bone microenvironment in order to fully understand signaling and drug response, and the significant effects that model properties such as architecture, rigidity, and dynamic mechanical factors have on tumor and bone cell response.
© 2018 Wiley Periodicals, Inc.
Extent of response to neoadjuvant chemotherapy, tumor size, and patient age are important prognostic variables for patients with osteosarcoma, but applying information from these continuous variables in survival models is difficult. Dichotomization is usually inappropriate and alternative statistical techniques should be considered instead. Nonlinear multivariable regression methods (restricted cubic splines and fractional polynomials) were applied to data from the National Cancer Database to model continuous prognostic factors for overall survival from localized, high-grade osteosarcoma of the appendicular and nonspinal skeleton following neoadjuvant chemotherapy and surgical resection (N=2493). The assumption that log hazard ratios were linear in relation to these continuous prognostic factors was tested using likelihood ratio tests of model deviance and Wald tests of spline coefficients. Log hazard ratios for increasing patient age were linear over the range of 4 to 80 years, but showed evidence for variation in the coefficient over elapsed follow-up time. Tumor size also showed a linear relationship with log hazard over the range of 1 to 30 cm. Hazard ratios for chemotherapy effect profoundly deviated from log-linear (P<0.004), with significantly decreased hazard for death from baseline for patients with ≥90% tumor necrosis (hazard ratio, 0.32; 95% confidence interval, 0.20-0.52; P<0.0001). Important implications of these results include: (1) ≥90% tumor necrosis defines good chemotherapy response in a clinically useful manner; (2) staging osteosarcoma by dichotomizing tumor size is inappropriate; and (3) patient age can be modeled as a linear effect on the log hazard ratio in prognostic models with the caveat that risk may change over duration of the analysis.
Breast cancer bone metastasis develops as the result of a series of complex interactions between tumor cells, bone marrow cells, and resident bone cells. The net effect of these interactions are the disruption of normal bone homeostasis, often with significantly increased osteoclast and osteoblast activity, which has provided a rational target for controlling tumor progression, with little or no emphasis on tumor eradication. Indeed, the clinical course of metastatic breast cancer is relatively long, with patients likely to experience sequential skeletal-related events (SREs), often over lengthy periods of time, even up to decades. These SREs include bone pain, fractures, and spinal cord compression, all of which may profoundly impair a patient's quality-of-life. Our understanding of the contributions of the host bone and bone marrow cells to the control of tumor progression has grown over the years, yet the focus of virtually all available treatments remains on the control of resident bone cells, primarily osteoclasts. In this perspective, our focus is to move away from the current emphasis on the control of bone cells and focus our attention on the hallmarks of bone metastatic tumor cells and how these differ from primary tumor cells and normal host cells. In our opinion, there remains a largely unmet medical need to develop and utilize therapies that impede metastatic tumor cells while sparing normal host bone and bone marrow cells. This perspective examines the impact of metastatic tumor cells on the bone microenvironment and proposes potential new directions for uncovering the important mechanisms driving metastatic progression in bone based on the hallmarks of bone metastasis.
Differentiating osteoclast-rich lesions of bone (giant cell tumor of bone [GCTB], chondroblastoma [CBA], and aneurysmal bone cyst [ABC]) can be challenging, especially in small biopsies or fine-needle aspirations. Mutations affecting codons 34 and 36 of either H3 Histone Family Member 3A (H3F3A) and/or 3B (H3F3B) are characteristically seen in GCTB and CBAs. We devised a simple assay to identify these mutations and evaluated its applicability for routine clinical diagnosis. One hundred twenty-four tissue specimens from 108 patients (43 GCTBs, 38 CBAs and 27 ABCs) were collected from the archives of the Calgary Laboratory Services/University of Calgary and Vanderbilt University Medical Center. Histology was reviewed by an expert orthopedic pathologist. A single base extension assay (SNaPshot) is used to interrogate each nucleotide in codons 34 and 36 of H3F3A and codon 36 of H3F3B. Final diagnoses were generated after re-reviewing cases and incorporating molecular findings. Of 43 GCTBs, 38 (88%) had an H3F3A G34W mutation; 35 of 38 CBAs (92%) had a K36M mutation in either H3F3B (N = 31; 82%) or H3F3A (N = 4; 11%); none of 27 ABCs had a tested mutation. Molecular findings changed the histomorphologic diagnosis in 5 cases (3 GCTB changed to ABC, and 2 ABC changed to GCTB). These findings support the diagnostic utility of mutational analysis for this differential diagnosis in certain challenging cases when clinicoradiologic and histomorphologic features are not definitive, particularly for distinguishing cellular ABC versus GCTB with secondary ABC.
Copyright © 2017 Elsevier Inc. All rights reserved.
Advanced breast cancer is frequently associated with skeletal metastases and accelerated bone loss. Recombinant parathyroid hormone [teriparatide, PTH(1-34)] is the first anabolic agent approved in the US for treatment of osteoporosis. While signaling through the PTH receptor in the osteoblast lineage regulates bone marrow hematopoietic niches, the effects of anabolic PTH on the skeletal metastatic niche are unknown. Here, we demonstrate, using orthotopic and intratibial models of 4T1 murine and MDA-MB-231 human breast cancer tumors, that anabolic PTH decreases both tumor engraftment and the incidence of spontaneous skeletal metastasis in mice. Microcomputed tomography and histomorphometric analyses revealed that PTH increases bone volume and reduces tumor engraftment and volume. Transwell migration assays with murine and human breast cancer cells revealed that PTH alters the gene expression profile of the metastatic niche, in particular VCAM-1, to inhibit recruitment of cancer cells. While PTH did not affect growth or migration of the primary tumor, it elicited several changes in the tumor gene expression profile resulting in a less metastatic phenotype. In conclusion, PTH treatment in mice alters the bone microenvironment, resulting in decreased cancer cell engraftment, reduced incidence of metastases, preservation of bone microarchitecture and prolonged survival.
PURPOSE OF REVIEW - Bone is a structurally unique microenvironment that presents many challenges for the development of 3D models for studying bone physiology and diseases, including cancer. As researchers continue to investigate the interactions within the bone microenvironment, the development of 3D models of bone has become critical.
RECENT FINDINGS - 3D models have been developed that replicate some properties of bone, but have not fully reproduced the complex structural and cellular composition of the bone microenvironment. This review will discuss 3D models including polyurethane, silk, and collagen scaffolds that have been developed to study tumor-induced bone disease. In addition, we discuss 3D printing techniques used to better replicate the structure of bone. 3D models that better replicate the bone microenvironment will help researchers better understand the dynamic interactions between tumors and the bone microenvironment, ultimately leading to better models for testing therapeutics and predicting patient outcomes.
PURPOSE OF REVIEW - This review highlights our current knowledge of oxygen tensions in the bone marrow, and how low oxygen tensions (hypoxia) regulate tumor metastasis to and colonization of the bone marrow.
RECENT FINDINGS - The bone marrow is a relatively hypoxic microenvironment, but oxygen tensions fluctuate throughout the marrow cavity and across the endosteal and periosteal surfaces. Recent advances in imaging have made it possible to better characterize these fluctuations in bone oxygenation, but technical challenges remain. We have compiled evidence from multiple groups that suggests that hypoxia or hypoxia inducible factor (HIF) signaling may induce spontaneous metastasis to the bone and promote tumor colonization of bone, particularly in the case of breast cancer dissemination to the bone marrow. We are beginning to understand oxygenation patterns within the bone compartment and the role for hypoxia and HIF signaling in tumor cell dissemination to the bone marrow, but further studies are warranted.