Browsing by Subject "bone metastases"

Now showing 1 - 5 of 5
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    Alkaline phosphatase in metastatic castration-resistant prostate cancer: reassessment of an older biomarker
    (Future Medicine, 2018-06-21) Heinrich, Daniel; Bruland, Øyvind; Guise, Theresa A; Suzuki, Hiroyoshi; Sartor, Oliver; Medicine, School of Medicine
    Since most patients with metastatic castration-resistant prostate cancer (mCRPC) have bone metastases, it is important to understand the potential impact of therapies on prognostic biomarkers, such as ALP. Clinical studies involving mCRPC life-prolonging agents (i.e., sipuleucel-T, abiraterone, enzalutamide, docetaxel, cabazitaxel, and radium-223) have shown that baseline ALP level is prognostic for overall survival, and may be a better prognostic marker for overall survival than prostate-specific antigen in patients with bone-dominant mCRPC. Mechanism of action differences between therapies may partly explain ALP dynamics during treatment. ALP changes can be interpreted within the context of other parameters while monitoring disease activity to better understand the underlying pathology. This review evaluates the current role of ALP in mCRPC.
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    Halofuginone inhibits TGF-β/BMP signaling and in combination with zoledronic acid enhances inhibition of breast cancer bone metastasis
    (Impact Journals, 2017-09-23) Juárez, Patricia; Fournier, Pierrick G.J.; Mohammad, Khalid S.; McKenna, Ryan C.; Davis, Holly W.; Peng, Xiang H.; Niewolna, Maria; Mauviel, Alain; Chirgwin, John M.; Guise, Theresa A.; Medicine, School of Medicine
    More efficient therapies that target multiple molecular mechanisms are needed for the treatment of incurable bone metastases. Halofuginone is a plant alkaloid-derivative with antiangiogenic and antiproliferative effects. Here we demonstrate that halofuginone is an effective therapy for the treatment of bone metastases, through multiple actions that include inhibition of TGFβ and BMP-signaling., Halofuginone blocked TGF-β-signaling in MDA-MB-231 and PC3 cells showed by inhibition of TGF-β–induced Smad-reporter, phosphorylation of Smad-proteins, and expression of TGF-β-regulated metastatic genes. Halofuginone increased inhibitory Smad7-mRNA and reduced TGF-β-receptor II protein. Proline supplementation but not Smad7-knockdown reversed halofuginone-inhibition of TGF-β-signaling. Halofuginone also decreased BMP-signaling. Treatment of MDA-MB-231 and PC3 cells with halofuginone reduced the BMP-Smad-reporter (BRE)4, Smad1/5/8-phosphorylation and mRNA of the BMP-regulated gene Id-1. Halofuginone decreased immunostaining of phospho-Smad2/3 and phospho-Smad1/5/8 in cancer cells in vivo., Furthermore, halofuginone decreased tumor-take and growth of orthotopic-tumors. Mice with breast or prostate bone metastases treated with halofuginone had significantly less osteolysis than control mice. Combined treatment with halofuginone and zoledronic-acid significantly reduced osteolytic area more than either treatment alone. Thus, halofuginone reduces breast and prostate cancer bone metastases in mice and combined with treatment currently approved by the FDA is an effective treatment for this devastating complication of breast and prostate-cancer.
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    Halofuginone inhibits the establishment and progression of melanoma bone metastases
    (American Association for Cancer Research, 2012-12-01) Juárez, Patricia; Mohammad, Khalid S.; Yin, Juan Juan; Fournier, Pierrick G. J.; McKenna, Ryan C.; Davis, Holly W.; Peng, Xiang H.; Niewolna, Maria; Javelaud, Delphine; Chirgwin, John M.; Mauviel, Alain; Guise, Theresa A.; Department of Medicine, IU School of Medicine
    Transforming growth factor (TGF-β) derived from bone fuels melanoma bone metastases by inducing tumor secretion of pro-metastatic factors that act on bone cells to change the skeletal microenvironment. Halofuginone is a plant alkaloid derivative that blocks TGF-β signaling with antiangiogenic and antiproliferative properties. Here, we demonstrate for the first time that halofuginone therapy decreases development and progression of bone metastasis caused by melanoma cells through inhibition of TGF-β signaling. Halofuginone treatment of human melanoma cells inhibited cell proliferation, phosphorylation of SMAD proteins in response to TGF-β, and TGF-β-induced SMAD-driven transcription. In addition, halofuginone reduced expression of TGF-β target genes that enhance bone metastases, including PTHrP, CTGF, CXCR4, and IL11. Also, cell apoptosis was increased in response to halofuginone. In nude mice inoculated with 1205Lu melanoma cells, a preventive protocol with halofuginone inhibited bone metastasis. The beneficial effects of halofuginone treatment were comparable to those observed with other anti-TGF-β strategies, including systemic administration of SD208, a small molecule inhibitor of TGF-β receptor I kinase, or forced overexpression of Smad7, a negative regulator of TGF-β signaling. Furthermore, mice with established bone metastases treated with halofuginone had significantly less osteolysis than mice receiving placebo assessed by radiographys. Thus, halofuginone is also effective in reducing the progression of melanoma bone metastases. Moreover, halofuginone treatment reduced melanoma metastasis to the brain, showing the potential of this novel treatment against cancer metastasis.
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    In vitro model of predicting metastatic ability using tumor derived extracellular vesicles; beyond seed soil hypothesis
    (Springer, 2022-11-24) Bhadresha, Kinjal; Upadhyay, Vinal; Brahmbhatt, Jpan; Mughal, Muhammad Jameel; Jain, Nayan; Rawal, Rakesh; Medicine, School of Medicine
    Lung cancer progression is often driven by metastasis, which has resulted in a considerable increase in lung cancer-related deaths. Cell-derived extracellular vesicles (EVs), particularly exosomes, serve key roles in cellular signal transmission via microenvironment, however, their biological relevance in cancer development and metastasis still needs to be clear. Here, we demonstrate that extracellular vesicles (EVs) derived from lung cancer bone metastatic patients exhibited a great capacity to promote the progression of lung cancer cells. We carried out a comprehensive meta-analysis to identify the gene expression profile of bone metastases using publicly available microarray datasets. Furthermore, mRNA expression of six identified genes was quantified by real time PCR in lung cancer with and without bone metastasis and healthy individual derived EVs. In addition, we utilized a very novel approach by to study how lung cancer cells uptake EVs by co-culturing EVs with lung cells. We observed that EVs obtained from bone metastases patients were efficiently ingested by lung cancer cells. Morevore, integration and uptake of these EVs lead to increased lung cancer cell proliferation, migration, invasion, and sphere formation. We discovered that EV uptake increase the expression of SPP1, CD44, and POSTN genes in lung cancer cells. The data obtained from this study, support to the possibility that circulating EVs play a significant role in the formation of the pre-metastatic niche, eventually leading to metastasis.
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    Influence of Breast Cancer and Metastases on Incidence of Diabete
    (Research Square, 2021) Ballinger, Tarah; Liu, Ziyue; El-Azab, Sarah A.; Broyles, Andrea; Guise, Theresa; Imel, Erik A.; Medicine, School of Medicine
    Purpose: Diabetes increases the risk of subsequent breast cancer. However, the inverse relationship of breast cancer to incident diabetes development is unclear. In preclinical models increased bone turnover due to bone metastases or endocrine therapies impacts insulin secretion. This analysis was conducted to estimate the incidence of diabetes after breast cancer and the influence of metastases and therapeutic agents. Methods: This retrospective case-control study combined data from a large electronic health data exchange and the Indiana State Cancer Registry on breast cancer patients and controls between 2007 and 2017. Primary exposure was presence of breast cancer and bone or non-bone metastases. The primary outcome was frequency of incident diabetes detected by ICD codes, medication use, or laboratory results, compared between breast cancer cases and controls using conditional or ordinary logistic regressions. Results: 36,083 cases and 36,083 matched controls were detected. Incident diabetes was higher in early stage breast cancer (OR 1.17, 95%CI 1.11-1.23, p<0.0001) and metastatic breast cancer (OR 1.62, 95% CI 1.25-2.09, p=0.0002), compared to controls. Bone metastases conferred higher odds of both pre-existing (OR 1.20, 95% CI 1.03-1.63, p=0.0272) and incident diabetes (OR 1.64, 95% CI 1.19-2.25, p=0.0021). Endocrine therapy was associated with reduced diabetes (OR 0.86, 95% CI 0.79-0.83, p=0.002). Anti-resorptives reduced incident diabetes in those with bone metastases (OR 0.44, 95% CI 0.25-0.78, p=0.005). Conclusion: Breast cancer, especially with metastases, increases subsequent risk of diabetes. As patients with breast cancer live longer, identifying and managing diabetes may impact treatment delivery, cost, survival, and quality of life.