IU Indianapolis ScholarWorks :: Browsing by Subject "Bone metastasis"

Browsing by Subject "Bone metastasis"

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Attraction and Compaction of Migratory Breast Cancer Cells by Bone Matrix Proteins through Tumor-Osteocyte Interactions
(Nature Publishing Group, 2018-04-03) Chen, Andy; Wang, Luqi; Liu, Shengzhi; Wang, Yue; Liu, Yunlong; Wang, Mu; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
Bone is a frequent site of metastasis from breast cancer. To understand the potential role of osteocytes in bone metastasis, we investigated tumor-osteocyte interactions using two cell lines derived from the MDA-MB-231 breast cancer cells, primary breast cancer cells, and MLO-A5/MLO-Y4 osteocyte cells. When three-dimensional (3D) tumor spheroids were grown with osteocyte spheroids, tumor spheroids fused with osteocyte spheroids and shrank. This size reduction was also observed when tumor spheroids were exposed to conditioned medium isolated from osteocyte cells. Mass spectrometry-based analysis predicted that several bone matrix proteins (e.g., collagen, biglycan) in conditioned medium could be responsible for tumor shrinkage. The osteocyte-driven shrinkage was mimicked by type I collagen, the most abundant organic component in bone, but not by hydroxyapatite, a major inorganic component in bone. RNA and protein expression analysis revealed that tumor-osteocyte interactions downregulated Snail, a transcription factor involved in epithelial-to-mesenchymal transition (EMT). An agarose bead assay showed that bone matrix proteins act as a tumor attractant. Collectively, the study herein demonstrates that osteocytes attract and compact migratory breast cancer cells through bone matrix proteins, suppress tumor migration, by Snail downregulation, and promote subsequent metastatic colonization.
The Biology of Bone Metastasis
(Cold Spring Harbor Laboratory Press, 2018-06-01) Esposito, Mark; Guise, Theresa; Kang, Yibin; Medicine, School of Medicine
Bone metastasis, or the development of secondary tumors within the bone of cancer patients, is a debilitating and incurable disease. Despite its morbidity, the biology of bone metastasis represents one of the most complex and intriguing of all oncogenic processes. This complexity derives from the intricately organized bone microenvironment in which the various stages of hematopoiesis, osteogenesis, and osteolysis are jointly regulated but spatially restricted. Disseminated tumor cells (DTCs) from various common malignancies such as breast, prostate, lung, and kidney cancers or myeloma are uniquely primed to subvert these endogenous bone stromal elements to grow into pathological osteolytic or osteoblastic lesions. This colonization process can be separated into three key steps: seeding, dormancy, and outgrowth. Targeting the processes of dormancy and initial outgrowth offers the most therapeutic promise. Here, we discuss the concepts of the bone metastasis niche, from controlling tumor-cell survival to growth into clinically detectable disease.
Bone Microenvironment-Suppressed T Cells Increase Osteoclast Formation and Osteolytic Bone Metastases in Mice
(Wiley, 2022) Arellano, Danna L.; Juárez, Patricia; Verdugo-Meza, Andrea; Almeida-Luna, Paloma S.; Corral-Avila, Juan A.; Drescher, Florian; Olvera, Felipe; Jiménez, Samanta; Elzey, Bennett D.; Guise, Theresa A.; Fournier, Pierrick G.J.; Medicine, School of Medicine
Immunotherapies use components of the immune system, such as T cells, to fight cancer cells, and are changing cancer treatment, causing durable responses in some patients. Bone metastases are a debilitating complication in advanced breast and prostate cancer patients. Approved treatments fail to cure bone metastases or increase patient survival and it remains unclear whether immunotherapy could benefit patients. The bone microenvironment combines various immunosuppressive factors, and combined with T cell products could increase bone resorption fueling the vicious cycle of bone metastases. Using syngeneic mouse models, our study revealed that bone metastases from 4T1 breast cancer contain tumor-infiltrating lymphocyte (TILs) and their development is increased in normal mice compared to immunodeficient and T-cell depleted mice. This effect seemed caused by the TILs specifically in bone, because T-cell depletion increased 4T1 orthotopic tumors and did not affect bone metastases from RM-1 prostate cancer cells, which lack TILs. T cells increased osteoclast formation ex vivo and in vivo contributing to bone metastasis vicious cycle. This pro-osteoclastic effect is specific to unactivated T cells, because activated T cells, secreting interferon γ (IFNγ) and interleukin 4 (IL-4), actually suppressed osteoclastogenesis, which could benefit patients. However, non-activated T cells from bone metastases could not be activated in ex vivo cultures. 4T1 bone metastases were associated with an increase of functional polymorphonuclear and monocytic myeloid-derived suppressor cells (MDSCs), potent T-cell suppressors. Although effective in other models, sildenafil and zoledronic acid did not affect MDSCs in bone metastases. Seeking other therapeutic targets, we found that monocytic MDSCs are more potent suppressors than polymorphonuclear MDSCs, expressing programmed cell death receptor-1 ligand (PD-L1)+ in bone, which could trigger T-cell suppression because 70% express its receptor, programmed cell death receptor-1 (PD-1). Collectively, our findings identified a new mechanism by which suppressed T cells increase osteoclastogenesis and bone metastases. Our results also provide a rationale for using immunotherapy because T-cell activation would increase their anti-cancer and their anti-osteoclastic properties.
Bone Pain and Muscle Weakness in Cancer Patients
(Springer, 2017-04) Milgrom, Daniel P.; Lad, Neha L.; Koniaris, Leonidas G.; Zimmers, Teresa A.; Surgery, School of Medicine
PURPOSE OF REVIEW: In this article, we will discuss the current understanding of bone pain and muscle weakness in cancer patients. We will describe the underlying physiology and mechanisms of cancer-induced bone pain (CIBP) and cancer-induced muscle wasting (CIMW), as well as current methods of diagnosis and treatment. We will discuss future therapies and research directions to help patients with these problems. RECENT FINDINGS: There are several pharmacologic therapies that are currently in preclinical and clinical testing that appear to be promising adjuncts to current CIBP and CIMW therapies. Such therapies include resiniferitoxin, which is a targeted inhibitor of noceciptive nerve fibers, and selective androgen receptor modulators, which show promise in increasing lean mass. CIBP and CIMW are significant causes of morbidity in affected patients. Current management is mostly palliative; however, targeted therapies are poised to revolutionize how these problems are treated.
Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain
(Elsevier, 2015-10) Yoneda, Toshiyuki; Hiasa, Masahiro; Nagata, Yuki; Okui, Tatsuo; White, Fletcher; Department of Medicine, IU School of Medicine
Solid and hematologic cancer colonized bone produces a number of pathologies. One of the most common complications is bone pain. Cancer-associated bone pain (CABP) is a major cause of increased morbidity and diminishes the quality of life and affects survival. Current treatments do not satisfactorily control CABP and can elicit adverse effects. Thus, new therapeutic interventions are needed to manage CABP. However, the mechanisms responsible for CABP are poorly understood. The observation that specific osteoclast inhibitors can reduce CABP in patients indicates a critical role of osteoclasts in the pathophysiology of CABP. Osteoclasts create an acidic extracellular microenvironment by secretion of protons via vacuolar proton pumps during bone resorption. In addition, bone-colonized cancer cells also release protons and lactate via plasma membrane pH regulators to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Since acidosis is algogenic for sensory neurons and bone is densely innervated by sensory neurons that express acid-sensing nociceptors, the acidic bone microenvironments can evoke CABP. Understanding of the mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and the expression and function of the acid-sensing nociceptors are regulated should facilitate the development of novel approaches for management of CABP. Here, the contribution of the acidic microenvironment created in cancer-colonized bone to elicitation of CABP and potential therapeutic implications of blocking the development and recognition of acidic microenvironment will be described. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells
(MDPI, 2021-11-09) Li, Ke-Xin; Sun, Xun; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.
Finite Element Analysis of the Mouse Distal Femur with Tumor Burden in Response to Knee Loading
(Medip Academy, 2018) Jiang, Feifei; Liu, Shengzhi; Chen, Andy; Li, Bai-Yan; Robling, Alexander G.; Chen, Jie; Yokota, Hiroki; Mechanical and Energy Engineering, School of Engineering and Technology
Breast cancer-associated bone metastasis induces bone loss, followed by an increased risk of bone fracture. To develop a strategy for preventing tumor growth and protecting bone, an understanding of the mechanical properties of bone under tumor burden is indispensable. Using a mouse model of mammary tumor, we conducted finite element analysis (FEA) of two bone samples from the distal femur. One sample was from a placebo-treated mouse, and the other was from a mouse treated with the investigational drug candidate, PD407824, an inhibitor of checkpoint kinases. Mechanical testing and microCT images revealed that bone strength is improved by administration of PD407824. In response to loading to the knee, FEA predicted that the peaks of von Mises stress, an indicator of fracture yielding, as well as the third principal compressive stress, were higher in the placebo-treated femur than the drug-treated femur. Higher peak stresses in trabecular segments were observed in the lateral condyle, a critical region for integrity of the knee joint. Collectively, this FE study supports the notion that mechanical weakening of the femur was observed in the tumor-invaded trabecular bone, and chemical agents such as PD407824 may potentially assist in preventing bone loss and bone fracture.
An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer
(American Association for Cancer Research, 2018-07-15) Lu, Xin; Pan, Xiaolu; Wu, Chang-Jiun; Zhao, Di; Feng, Shan; Zang, Yong; Lee, Rumi; Khadka, Sunada; Amin, Samirkumar B.; Jin, Eun-Jung; Shang, Xiaoying; Deng, Pingna; Luo, Yanting; Morgenlander, William R.; Weinrich, Jacqueline; Lu, Xuemin; Jiang, Shan; Chang, Qing; Navone, Nora M.; Troncoso, Patricia; DePinho, Ronald A.; Wang, Y. Alan; Biostatistics, IU School of Medicine
Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/β-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer.Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis. Cancer Res; 78(14); 3823-33. ©2018 AACR.
Opposing roles of TGFβ and BMP signaling in prostate cancer development
(Cold Spring Harbor Laboratory Press, 2017-12-01) Lu, Xin; Jin, Eun-Jung; Cheng, Xi; Feng, Shan; Shang, Xiaoying; Deng, Pingna; Jiang, Shan; Chang, Qing; Rahmy, Sharif; Chaudhary, Seema; Lu, Xuemin; Zhao, Ren; Wang, Y. Alan; DePinho, Ronald A.; Medicine, School of Medicine
SMAD4 constrains progression of Pten-null prostate cancer and serves as a common downstream node of transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) pathways. Here, we dissected the roles of TGFβ receptor II (TGFBR2) and BMP receptor II (BMPR2) using a Pten-null prostate cancer model. These studies demonstrated that the molecular actions of TGFBR2 result in both SMAD4-dependent constraint of proliferation and SMAD4-independent activation of apoptosis. In contrast, BMPR2 deletion extended survival relative to Pten deletion alone, establishing its promoting role in BMP6-driven prostate cancer progression. These analyses reveal the complexity of TGFβ-BMP signaling and illuminate potential therapeutic targets for prostate cancer.
Osteocyte-Driven Downregulation of Snail Restrains Effects of Drd2 Inhibitors on Mammary Tumor Cells
(American Association for Cancer Research, 2018-07-15) Liu, Shengzhi; Fan, Yao; Chen, Andy; Jalali, Aydin; Minami, Kazumasa; Ogawa, Kazuhiko; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
While bone is a frequent target of breast cancer-associated metastasis, little is known about the effects of tumor-bone interactions on the efficacy of tumor-suppressing agents. Here we examined the effect of two FDA-approved dopamine modulators, fluphenazine and trifluoperazine, on mammary tumor cells, osteoclasts, osteoblasts, and osteocytes. These agents suppressed proliferation and migration of mammary tumor cells chiefly by antagonizing dopamine receptor D2 and reduced bone resorption by downregulating nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1). Three-dimensional spheroid formation assays revealed that tumor cells have high affinity to osteocytes and type I collagen, and interactions with osteocytes as well as administration of fluphenazine and trifluoperazine downregulated Snail and suppressed migratory behaviors. Unlike the inhibitory action of fluphenazine and trifluoperazine on tumor growth, tumor-osteocyte interactions stimulated tumor proliferation by upregulating NFκB and Akt. In the bone microenvironment, osteocytes downregulated Snail and acted as an attractant as well as a stimulant to mammary tumor cells. These results demonstrate that tumor-osteocyte interactions strengthen dopamine receptor-mediated suppression of tumor migration but weaken its inhibition of tumor proliferation in the osteocyte-rich bone microenvironment.Significance: These findings provide novel insight into the cellular cross-talk in the bone microevironment and the effects of dopamine modulators on mammary tumor cells and osteocytes. Cancer Res; 78(14); 3865-76. ©2018 AACR.

Browsing by Subject "Bone metastasis"

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