scholarly journals Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Baotong Zhang ◽  
Yixiang Li ◽  
Qiao Wu ◽  
Lin Xie ◽  
Benjamin Barwick ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factor ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Advanced Prostate Cancer ◽  
Paracrine Signaling ◽  
Mesenchymal Phenotype ◽  
Cxcr4 Signaling ◽  
Metastatic Lesions ◽  
Underlying Mechanisms

AbstractAdvanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-β induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.

scholarly journals Recent Advances in Nanomedicine for the Diagnosis and Treatment of Prostate Cancer Bone Metastasis

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 384
Author(s):  
Daniel E. Hagaman ◽  
Jossana A. Damasco ◽  
Joy Vanessa D. Perez ◽  
Raniv D. Rojo ◽  
Marites P. Melancon
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Advanced Prostate Cancer ◽  
Bone Fractures ◽  
Diagnosis And Treatment ◽  
Survival Times ◽  
Preclinical Research ◽  
Relieve Pain ◽  
Translational Models

Patients with advanced prostate cancer can develop painful and debilitating bone metastases. Currently available interventions for prostate cancer bone metastases, including chemotherapy, bisphosphonates, and radiopharmaceuticals, are only palliative. They can relieve pain, reduce complications (e.g., bone fractures), and improve quality of life, but they do not significantly improve survival times. Therefore, additional strategies to enhance the diagnosis and treatment of prostate cancer bone metastases are needed. Nanotechnology is a versatile platform that has been used to increase the specificity and therapeutic efficacy of various treatments for prostate cancer bone metastases. In this review, we summarize preclinical research that utilizes nanotechnology to develop novel diagnostic imaging tools, translational models, and therapies to combat prostate cancer bone metastases.

scholarly journals In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer

2021 ◽  
Vol 7 (27) ◽  
pp. eabg2564
Author(s):  
Nathalie Bock ◽  
Thomas Kryza ◽  
Ali Shokoohmand ◽  
Joan Röhl ◽  
Akhilandeshwari Ravichandran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Advanced Prostate Cancer ◽  
Adaptive Responses ◽  
Metastatic Tissue ◽  
Metastatic Lesions ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

While androgen-targeted therapies are routinely used in advanced prostate cancer (PCa), their effect is poorly understood in treating bone metastatic lesions and ultimately results in the development of metastatic castrate resistant prostate cancer (mCRPC). Here, we used an all-human microtissue-engineered model of mineralized metastatic tissue combining human osteoprogenitor cells, 3D printing and prostate cancer cells, to assess the effects of the antiandrogens, bicalutamide, and enzalutamide in this microenvironment. We demonstrate that cancer/bone stroma interactions and antiandrogens drive cancer progression in a mineralized microenvironment. Probing the bone microenvironment with enzalutamide led to stronger cancer cell adaptive responses and osteomimicry than bicalutamide. Enzalutamide presented with better treatment response, in line with enzalutamide delaying time to bone-related events and enzalutamide extending survival in mCRPC. The all-human microtissue-engineered model of mineralized metastatic tissue presented here represents a substantial advance to dissect the role of the bone tumor microenvironment and responses to therapies for mCPRC.

scholarly journals Tumor- and Osteoblast-Derived Periostin in Prostate Cancer bone Metastases

2022 ◽  
Vol 11 ◽  
Author(s):  
Chuan-Yu Sun ◽  
Yuan-Yuan Mi ◽  
Sheng-Yang Ge ◽  
Qing-Feng Hu ◽  
Ke Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Integrin Αvβ3 ◽  
Integrin Receptors ◽  
Secreted Expression ◽  
Metastatic Lesions ◽  
Promising Therapeutic Target ◽  
Pet Ct

Exploring the biological function of periostin (POSTN) in prostate cancer (PCa) bone metastasis is of importance. It was observed that the expression of POSTN was high in PCa, especially highest in PCa metastasized to bone. In this study, we found that inhibiting POSTN in PCa cells could significantly alleviate PCa bone metastasis in vivo, suggesting POSTN is a promising therapeutic target. Since, due to the secreted expression of POSTN in osteoblasts and PCa, we hypothesized the positive feedback loop between osteoblasts and PCa mediated by POSTN in PCa bone metastasis. The in vitro experiments demonstrated that osteoblast-derived POSTN promoted PCa cell proliferation and invasion and PCa cell-derived POSTN promotes proliferation of osteoblasts. Furthermore, we found that POSTN regulated PCa and osteoblast function through integrin receptors. Finally, 18F-Alfatide II was used as the molecule probe of integrin αvβ3 in PET-CT, revealing high intake in metastatic lesions. Our findings together indicate that targeting POSTN in PCa cells as well as in the osteoblastic may be an effective treatment for PCa bone metastasis.

scholarly journals National survey of radiation oncologists’ practice patterns regarding hormone-naïve prostate cancer with bone metastases

2020 ◽  
Vol 50 (10) ◽  
pp. 1188-1194
Author(s):  
Katsumasa Nakamura ◽  
Hitoshi Ishikawa ◽  
Tetsuo Akimoto ◽  
Manabu Aoki ◽  
Shinji Kariya ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Practice Patterns ◽  
Primary Treatment ◽  
Dose Fractionation ◽  
Radiation Oncologists ◽  
Multiple Bone Metastases ◽  
Single Bone ◽  
Radiotherapy Dose

Abstract Objective To explore radiation oncologists’ attitudes and practice patterns of radiotherapy for hormone-naïve prostate cancer with bone metastases in Japan. Methods An internet-based survey was distributed to board-certified radiation oncologists of the Japanese Society of Radiation Oncology. Three hypothetical cases were assumed: hormone-naïve prostate cancer with single, three or multiple non-symptomatic bone metastases. The respondents described their attitude regarding such cases, treatment methods and the radiotherapy dose fractionation that they would recommend. Results Among the 1013 board-certified radiation oncologists in Japan, 373 (36.8%) responded to the questionnaire. Most of the respondents (85.0%) believed that radiotherapy may be applicable as a primary treatment for hormone-naïve prostate cancer with bone metastases in some circumstances. For Case 1 (single bone metastasis), 55.0% of the respondents recommended radiotherapy for the prostate and bone metastasis. For Case 2 (three bone metastases), only 24.4% recommended radiotherapy for all lesions, and 31.4% recommended radiotherapy for the prostate only. For Case 3 (multiple bone metastases), 49.1% of the respondents stated that there was no indication for radiotherapy. However, 34% of the respondents still preferred to administer radiotherapy for the prostate. The radiotherapy techniques and dose fractionations varied widely among the respondents. Conclusion Most of the respondent radiation oncologists believed that radiotherapy may be beneficial for hormone-naïve prostate cancer with bone metastases.

scholarly journals The Mode-of-Action of Targeted Alpha Therapy Radium-223 as an Enabler for Novel Combinations to Treat Patients with Bone Metastasis

2019 ◽  
Vol 20 (16) ◽  
pp. 3899 ◽  
Author(s):  
Mari I. Suominen ◽  
Timothy Wilson ◽  
Sanna-Maria Käkönen ◽  
Arne Scholz
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Cancer Cells ◽  
Bone Cells ◽  
Metastatic Cancer ◽  
Signal Molecules ◽  
Targeted Alpha Therapy ◽  
Radium 223 ◽  
Alpha Therapy

Bone metastasis is a common clinical complication in several cancer types, and it causes a severe reduction in quality of life as well as lowering survival time. Bone metastases proceed through a vicious self-reinforcing cycle that can be osteolytic or osteoblastic in nature. The vicious cycle is characterized by cancer cells residing in bone releasing signal molecules that promote the differentiation of osteoclasts and osteoblasts either directly or indirectly. The increased activity of osteoclasts and osteoblasts then increases bone turnover, which releases growth factors that benefit metastatic cancer cells. In order to improve the prognosis of patients with bone metastases this cycle must be broken. Radium-223 dichloride (radium-223), the first targeted alpha therapy (TAT) approved, is an osteomimetic radionuclide that is incorporated into bone metastases where its high-linear energy transfer alpha radiation disrupts both the activity of bone cells and cancer cells. Therefore, radium-223 treatment has been shown preclinically to directly affect cancer cells in both osteolytic breast cancer and osteoblastic prostate cancer bone metastases as well as to inhibit the differentiation of osteoblasts and osteoclasts. Clinical studies have demonstrated an increase in survival in patients with metastatic castration-resistant prostate cancer. Due to the effectiveness and low toxicity of radium-223, several novel combination treatment strategies are currently eliciting considerable research interest.

scholarly journals Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Rachel Eyre ◽  
Denis G. Alférez ◽  
Angélica Santiago-Gómez ◽  
Kath Spence ◽  
James C. McConnell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Colony Formation ◽  
Breast Cancer Cells ◽  
Wnt Signalling ◽  
Early Event ◽  
Metastatic Lesions ◽  
Breast Cancer Bone Metastasis

Abstract Dissemination of tumour cells to the bone marrow is an early event in breast cancer, however cells may lie dormant for many years before bone metastases develop. Treatment for bone metastases is not curative, therefore new adjuvant therapies which prevent the colonisation of disseminated cells into metastatic lesions are required. There is evidence that cancer stem cells (CSCs) within breast tumours are capable of metastasis, but the mechanism by which these colonise bone is unknown. Here, we establish that bone marrow-derived IL1β stimulates breast cancer cell colonisation in the bone by inducing intracellular NFkB and CREB signalling in breast cancer cells, leading to autocrine Wnt signalling and CSC colony formation. Importantly, we show that inhibition of this pathway prevents both CSC colony formation in the bone environment, and bone metastasis. These findings establish that targeting IL1β-NFKB/CREB-Wnt signalling should be considered for adjuvant therapy to prevent breast cancer bone metastasis.

615 Long-term efficacy and safety of zoledronic acid in men with advanced prostate cancer and bone metastases

2004 ◽  
Vol 3 (2) ◽  
pp. 156 ◽  
Author(s):  
F. Saad ◽  
D. Gleason ◽  
R. Murray ◽  
P. Venner ◽  
S. Tchekmedyian ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Advanced Prostate Cancer ◽  
Efficacy And Safety ◽  
Term Efficacy

A pilot study on the clinical value of 18F-sodium fluoride PET/CT in advanced prostate cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10589-10589
Author(s):  
Joseph W. Kim ◽  
Maria Liza Lindenberg ◽  
William L. Dahut ◽  
James L. Gulley ◽  
Ravi A. Madan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Sodium Fluoride ◽  
Advanced Prostate Cancer ◽  
Bone Scan ◽  
Malignant Lesion ◽  
Benign Lesions ◽  
Pet Ct ◽  
Medicine Physician ◽  
Malignant Lesions

10589 Background: We evaluated the clinical utility of 18F-sodium fluoride PET/CT bone scan (18F-NaF) in the detection of bone metastases in patients (pts) with prostate cancer in comparison with Technetium-99m MDP bone scan (TcBS). Methods: In a prospective study, from October 2010-December 2011, 30 prostate cancer pts (ages 51-79), 21 with known bone metastases and 9 without known bone metastases, had18F-NaF and a TcBS performed. Abnormal foci of uptake on both TcBS and 18F-NaFwere classified as benign, malignant or indeterminate. Benign lesions included uptake in the joints and linear uptake at the endplates of the vertebral bodies consistent with degenerative changes. Malignant uptake on 18F-NaF scans was confirmed by characteristic osteoblastic features on CT. All TcBS and 18F-NaF were reviewed by an experienced nuclear medicine physician. For the patient-based analysis, scan results were categorized as positive (POS) = any malignant lesion; indeterminate (IND) = not distinctly malignant or benign; negative (NEG) = benign lesions only. Results: In the lesion-based analysis, 21 of 30 (70%) pts had more malignant lesions identified on 18F-NaF than on TcBS. The mean number of additional malignant lesions per patient on 18F-NaF vs TcBS was 4. Eight of the 30 pts had same number of malignant lesions identified in both studies. One of 30 pts had one less malignant lesion identified on 18F-NaF than on TcBS. CT correlation by 18F-NaF PET/CT of this particular lesion did not confirm osteoblastic feature. Malignant lesion distribution on 18F-NaF included: spine (28%), thorax (26%), pelvis (24%), long bones (13%) and skull (10%). In the patient-based analysis, 24 pts (80%) were POS by 18F-NaF, of whom 14 pts were POS, 8 were IND, and 2 were NEG by corresponding TcBS; in the 4 pts with NEG 18F-NaF, zero were POS, 2 were IND and 2 were NEG by corresponding TcBS. Conclusions: 18F-NaF identified more malignant lesions than TcBS. 18F-NaF may also add useful information in the management of advanced prostate cancer pts with and without known bone metastases.

Evaluation of bone metastasis of castration-resistant prostate cancer after enzalutamide and abiraterone using Bone Scan Index on bone scintigraphy.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. e596-e596
Author(s):  
Suguru Kadomoto ◽  
Kouji Izumi ◽  
Takahiro Nohara ◽  
Konaka Hiroyuki ◽  
Yoshifumi Kadono ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Bone Scintigraphy ◽  
Bone Scan ◽  
Average Rate ◽  
Castration Resistant Prostate Cancer ◽  
Bone Scan Index ◽  
Castration Resistant ◽  
Better Than

e596 Background: It was ambiguous till now to evaluate the change of bone metastasis by various treatments. To quantify the change of bone metastases by enzalutamide, abiraterone, and docetaxel for the castration-resistant prostate cancer (CRPC) with bone metastases (bmCRPC), we employed Bone Scan Index (BSI) on bone scintigraphy. Methods: We retrospectively evaluated the change of PSA and bone metastases of CRPC patients who were treated with enzalutamide (Enz), abiraterone (Abi) and/or docetaxel (DOC) in our hospital. All patients underwent Tc-99m MDP bone scintigraphy. The degree of bone metastases was analyzed using BSI, which was calculated by BONENAVI (FUJIFILM RI Pharma, Japan; EXINIbone, EXINI Diagnostics, Sweden). 19 patients were treated with enzalutamide (8 cases: pre-docetaxel, 11 cases: post-docetaxel). The median PSA of patients treated with Enz was 12.64 ng/ml (1.63-199 ng/ml). And 11 patients were treated with abiraterone (5 cases: pre-docetaxel, 6 cases: post-docetaxel). The median PSA of patients treated with Abi was 26.37 ng/ml (2.29-199 ng/ml). Results: We observed decline of PSA in 18/30 cases (9 cases: pre-DOC, 9 cases: post-DOC). Decline of PSA to 50% or more was observed in 14 cases. In contrast, decline of BSI was observed in 53.3% (16/30) cases and decline of PSA to 25% or more was observed in only 6 cases. BSI decreased in 84.6% (11/13) of pre-DOC setting and in 29.4% (5/17) of post-DOC setting indicating that change of BSI was poor in post-DOC setting. However, DOC had already decreased BSI in 91.7% (11/12) before Abi or Enz treatment. Moreover, the average rate of BSI decline in the patients that BSI decreased by DOC was better than the patients that BSI decreased by Abi/Enz (-48.46% vs -28.56%). Finally, although the rate of BSI change by Enz was weakly correlated with the rate of PSA decline (y = 0.3906x + 25.35, R2 = 0.3423), BSI continued to increase in four cases in spite of PSA decline. Conclusions: BSI using BONENAVI on bone scintigraphy was helpful for evaluating the effectiveness of treatment and following-up of bmCRPC.

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