scholarly journals Hybrid Discrete-Continuum Cellular Automaton (HCA) model of Prostate to Bone Metastasis

2016 ◽  
Author(s):  
Arturo Araujo ◽  
David Basanta
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Molecular Mechanisms ◽  
Bone Matrix ◽  
Cellular Interactions ◽  
Vicious Cycle ◽  
Bone Microenvironment ◽  
Basic Multicellular Unit ◽  
Bone Degradation ◽  
The Impact

AbstractProstate to bone metastases induce a “vicious cycle” by promoting excessive osteoclast and osteoblast mediated bone degradation and formation that in turn yields factors that drive cancer growth. Recent advances defining the molecular mechanisms that control the vicious cycle have revealed new therapeutic targeting opportunities. However, given the complex temporal and simultaneous cellular interactions occurring in the bone microenvironment, assessing the impact of putative therapies is challenging. To this end, we have integrated biological and computational approaches to generate an accurate model of normal bone matrix homeostasis and the prostate cancer-bone microenvironment. The model faithfully reproduces the basic multicellular unit (BMU) bone coupling process and introduction of a single prostate cancer cell yields a vicious cycle that is similar in cellular composition and pathophysiology to models of prostate to bone metastasis.

scholarly journals Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Navatha Shree Polavaram ◽  
Samikshan Dutta ◽  
Ridwan Islam ◽  
Arup K. Bag ◽  
Sohini Roy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Potential Effect ◽  
Tumor Burden ◽  
Bone Lesions ◽  
Prostate Cancer Cells

AbstractUnderstanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

Radium 223 treatment in metastatic castrate-resistant prostate cancer: Impact of sequencing on survival—Real-world outcomes from a single United Kingdom center.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 223-223 ◽  
Author(s):  
Xue Yan Jiang ◽  
Sarah Atkinson ◽  
Sam Cuming ◽  
Alexander Burns ◽  
Rachel Anne Pearson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Systemic Treatment ◽  
Survival Outcomes ◽  
Prior Chemotherapy ◽  
Radium 223 ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Impact

223 Background: Radium 223 (Ra-223) is a FDA and EMA approved alpha particle radiopharmaceutical used to treat men with metastatic castrate resistant prostate cancer (mCRPC) with symptomatic bone metastasis. In view of emerging systemic options, new EMA 2018 licence indication is for 3rd line onwards. We aim to evaluate the impact of systemic therapy sequencing on survival outcomes from a heterogeneous cohort of 228 patients treated with Ra-223 in a single UK centre. Methods: We prospectively collected data from 228 men underwent Ra-223 therapy for mCRPC between April 2014 and August 2018. Survival outcomes in relation to sequence of systemic treatment used prior to Ra-223 were analysed. Results: Medium age = 72 (51-87) years. Most patients (n = 142, 69%) received at least one systemic agent prior to Ra-223: docetaxel and/or cabaxitaxel chemotherapy (n = 60, 29%), abiraterone (n = 62, 30.1%) and enzalutamide (n = 67, 32.5%) in various sequences. No patients received concurrent Ra-223 /systemic treatment other than LHRH analogue. Key findings are summarized in table below. Conclusions: Our data demonstrated better survival trend in patients who received Ra-223 early. Patients who received prior chemotherapy have worse survival compared with those who were chemo-naïve likely due to bone marrow depletion. Ra-223 should not be offered to patients who have already had both cabaxitaxel and docetaxel as their medium survival is too poor to justify a treatment which takes 6 months to complete.[Table: see text]

scholarly journals The Osteoblastic and Osteoclastic Interactions in Spinal Metastases Secondary to Prostate Cancer

2013 ◽  
Vol 6 ◽  
pp. CGM.S12769 ◽  
Author(s):  
Sathana Dushyanthen ◽  
Davina A.F. Cossigny ◽  
Gerald M.Y. Quan
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Molecular Mechanisms ◽  
Spinal Metastases ◽  
Bone Destruction ◽  
Cord Compression ◽  
Intractable Pain ◽  
Critical Pathway ◽  
Functional Roles ◽  
High Propensity

Prostate cancer (PC) is one of the most common cancers arising in men and has a high propensity for bone metastasis, particularly to the spine. At this stage, it often causes severe morbidity due to pathological fracture and/or metastatic epidural spinal cord compression which, if untreated, inevitably leads to intractable pain, neurological deficit, and paralysis. Unfortunately, the underlying molecular mechanisms driving growth of secondary PC in the bony vertebral column remain largely unknown. Further investigation is warranted in order to identify therapeutic targets in the future. This review summarizes the current understanding of PC bone metastasis in the spine, highlighting interactions between key tumor and bone-derived factors which influence tumor progression, especially the functional roles of osteoblasts and osteoclasts in the bone microenvironment through their interactions with metastatic PC cells and the critical pathway RANK/RANKL/OPG in bone destruction.

scholarly journals Second-generation hormonotherapy in prostate cancer and bone microenvironment

2021 ◽  
Author(s):  
Wafa Bouleftour ◽  
Karima Boussoualim ◽  
Sandrine Sotton ◽  
Cecile Vassal ◽  
Thierry Thomas ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Hormone Therapy ◽  
Independent Living ◽  
Second Generation ◽  
Health Management ◽  
Bone Microenvironment ◽  
Mineral Density ◽  
Aged Patients ◽  
Androgen Synthesis ◽  
The Impact

Prostate cancer (Pca) is the most commonly diagnosed cancer affecting men in France. Before the age of 75 years old, 1 in 8 French men will have Pca. Androgen deprivation therapies (ADT) remain the standard of care. Such therapies induces significant bone loss. Bone-remodelling cycle depends on the androgen synthesis signalling pathways. Furthermore, age-specific hormonal decline plays a key role in the decrease in bone mass. As a result, the older the patients, the more likely they are to have osteoporosis if they are treated with hormone therapy. Their risk of osteoporotic fracture has an impact on their quality of live and their capacity of independent living. In recent years, newer hormone therapies (acetate abiraterone, enzalutamide, apalutamide and darolutamide) have proved efficient in metastatic castration-resistant Pca (mCRPC) patients as well as in hormone naïve patients, and actually in non-metastatic diagnosis. The combination of these treatments with ADT highly inhibit androgen production pathways. They are prescribed to aged patients undergoing bone density loss after first generation anti-androgen treatment. Specific recommendations for bone health management in Pca patients are currently lacking. To date, bone mineral density in patients treated with second-generation hormone therapy has never been assessed in a prospective study. This review aims at reviewing what is known about the impact of second-generation hormonotherapy on bone microenvironment.

Effects of ALK1Fc treatment on prostate cancer cells interacting with bone and bone cells in bone metastasis models.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16576-e16576
Author(s):  
Marianna Kruithof-de Julio ◽  
Letizia Astrologo ◽  
Eugenio Zoni ◽  
Sofia Karkampouna ◽  
Peter C Gray ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Bone Cells ◽  
Critical Role ◽  
Prostate Cancer Cells ◽  
Primary Prostate Cancer ◽  
The Impact

e16576 Background: Prostate cancer is the second most common cancer in men worldwide. Lethality is normally associated with the consequences of metastasis rather than the primary tumor. In particular, bone is the most frequent site of metastasis and once prostate tumor cells are engrafted in the skeleton, curative therapy is no longer possible. Bone morphogenetic proteins (BMPs) play a critical role in bone physiology and pathology. However, little is known about the role of BMP9 and its signaling receptors, ALK1 and ALK2, in prostate cancer and bone metastasis. In this context, we investigate the impact of BMP9 on primary prostate cancer and derived bone metastasis. Methods: The human ALK1 extracellular domain (ECD) binds BMP9 and BMP10 with high affinity. In order to study the effect of BMP9 in vitro and in vivo we use a soluble chimeric protein, consisting of ALK1 ECD fused to human Fc (ALK1Fc), for preventing the activation of endogenous signaling. ALK1Fc sequesters BMP9 and BMP10, preserving the activation of ALK1 through other ligands. Results: We show that ALK1Fc reduces BMP9-mediated signaling and decreases proliferation of highly metastatic and tumor initiating human prostate cancer cells in vitro. In line with these observations, we demonstrate that ALK1Fc reduces tumor growth in vivo in an orthotopic transplantation model. The propensity of the primary prostate cancer to metastasize to the bone is also investigated. In particular, we report how the ALK1Fc influences the prostate cancer cells in vitro and in vivo when these are probed in different bone settings (co-culture with bone cells and intraosseous transplantation in mice). Conclusions: Our study provides the first demonstration that ALK1Fc inhibits prostate cancer cells growth identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. All together, these findings justify the ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity.

Prostate cancer promotes a vicious cycle of bone metastasis progression through inducing osteocytes to secrete GDF15 that stimulates prostate cancer growth and invasion

Oncogene ◽  
2019 ◽  
Vol 38 (23) ◽  
pp. 4540-4559 ◽  
Author(s):  
Wenchu Wang ◽  
Xin Yang ◽  
Jinlu Dai ◽  
Yi Lu ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Growth ◽  
Vicious Cycle
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