There is some evidence to suggest that treatment of the primary tumour can reduce tumour progression elsewhere metastatic disease. Over 2, men were recruited, which is exceptional. Prostate radiotherapy did not improve overall survival in men with newly diagnosed metastatic disease. However, radiotherapy did improve survival in men with low metastatic burden. This is prostate cancer that has spread either to lymph glands or to the bones in the pelvis and spine but has not spread to other organs. Given the survival advantage, prostate radiotherapy in men with low metastatic burden should now be the new standard of care.
Treating the primary once the cancer has metastasised has conventionally thought to be futile. This has been challenged by finding that in low metastatic burden prostate cancer, radiotherapy to the primary significantly improves survival and should become standard of care. This study raises the issue whether this would apply to other cancers and interesting biological questions as to the mechanism. Is it an effect of debulking the primary? Is it immunological?
Is it due to reducing secondary spread of aggressive clones? It seems we have underestimated in prostate cancer, the impact of local control in the setting of metastatic disease. Professor Huddart works in the same department as the study chief investigator and has been a local investigator on the study.
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Share your views on the research. Why was this study needed? What did this study do? What did it find? After three years: There was no difference in overall survival between men who had radiotherapy with standard care compared with those who just had standard care hazard ratio [HR] 0. What does current guidance say on this issue? There is no recommendation regarding radiotherapy in men with metastatic prostate cancer.
What are the implications? Background Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy. Methods We did a randomised controlled phase 3 trial at hospitals in Switzerland and the UK.
Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a ratio to standard of care control group or standard of care and radiotherapy radiotherapy group.
Managing Bone Metastases and Pain | Prostate Cancer Foundation
Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use from December, , and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, Men allocated radiotherapy received either a daily 55 Gy in 20 fractions over 4 weeks or weekly 36 Gy in six fractions over 6 weeks schedule that was nominated before randomisation.
Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors.
The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. Findings Between Jan 22, , and Sept 2, , men underwent randomisation, were allocated the control and radiotherapy. LNCaP showed a significant adaptive response under androgen deprivation in the microtissues, with the notable appearance of neuroendocrine transdifferentiation features and increased expression of related markers dopa decarboxylase, enolase 2.
Androgen deprivation affected the biology of the metastatic microenvironment with stronger upregulation of androgen receptor, alkaline phosphatase, and dopa decarboxylase, as seen in the transition towards resistance. The unique microtissues engineered here represent a substantial asset to determine the involvement of the human bone microenvironment in prostate cancer progression and response to a therapeutic context in this microenvironment.
With androgen signaling being key in prostate cancer, the use of androgen deprivation therapy ADT is the treatment of choice for patients with recurrent disease.
In the bone, androgen deprivation can indeed alter both osteoblastogenesis and osteoclastogenesis, negatively affecting the bone tumor microenvironment. In the last two decades, the unmet need for better in vitro cancer models has drawn tissue-engineering technologies into the arena of cancer research. The ability to dissociate biological processes is equally important to gain insight into specific interactions between targeted cell populations. In the context of prostate cancer, where lesions are mostly osteoblast-driven, fundamental advances will be gained by separating the bone formation process from the bone resorption process, and opting for an osteoclast-free approach, as successfully justified previously.
In this work, we present for the first time a tissue-engineered model that comprises both osteoblastic cells, osteocytic cells, and appropriate expression of osteoblast and osteocyte-derived proteins and mineral content. This model, viable long-term, can represent some of the key cellular and microenvironmental interactions between osteoblasts, their produces and prostate cancer for a more accurate study of osteoblastic bone metastases. The model is validated here by co-culture studies with metastatic prostate cancer cell lines, testing the hypothesis that the in vitro osteoblastic tumor microenvironment could reproduce some of the cellular alterations seen in vivo with androgen deprivation.
Additive manufacturing and tissue-engineering technologies were combined to establish an in vitro osteoblast-derived microtissue model to study prostate cancer osteoblastic bone metastases. Scaffolds were 3D printed via melt electrowriting Fig. S1b, c , with high viability Fig. Histological analysis showed a 3D tissue arrangement composed of connective tissue and homogeneous cellular distribution with cells surrounded by lacunae, as seen in vivo for osteocytic cells Fig.
Bioengineering of a human osteoblast-derived microtissue and characterization. Adapted with copyright from Farrugia et al. The culture of the cellular construct for at least 7 weeks leads to a human osteoblast-derived mineralized microtissue hOBMT containing live osteoblastic hOB and osteocytic cells hOS , bone extracellular matrix ECM and hydroxyapatite HA mineralized nodules. At the protein level, typical bone ECM collagen-I , osteoblast mineralization osteocalcin , as well as osteocyte sclerostin markers were expressed, as demonstrated by immunohistochemistry IHC, Fig.
S1f and immunofluorescence IF, Fig.
How metastatic cancer affects bone
Combined, this data illustrates the importance of using 3D platforms to obtain a more relevant and mature osteoblast-derived tissue microenvironment. The calcium to phosphorus Ca:P ratios of the microtissues were similar to that measured in the native bone from which the primary cells were isolated Fig. No mineralization was observed on empty control CaP-coated scaffolds cultured in the same conditions Fig. S2c , in line with osteoblast bio-mineralization, as seen previously, 19 and as opposed to material-related physicochemical nucleation.
Open arrows show fibers and arrow heads show deposited HA nodules. Both c and d show increased mineralization over time. The analysis of mRNA levels over time showed that hOBMT reached osteoblast maturation and osteocyte differentiation earlier than 2D cultures, as seen by a decrease in osteoblastic, ECM and mineralization markers and increase in osteocytic and bone remodeling genes Fig.
Altogether, hOBMT are viable long-term, highly mineralized, and able to partly display, contrary to 2D, the marker profile of osteocytogenesis. After 10 weeks osteogenic differentiation, the hOBMT were cultured in prostate cancer PCa -cell media for 3 weeks, to study the effects of androgen regulation on osteoblasts. Without osteogenic supplements Fig. Metabolic activity was similar across all media conditions Fig. As seen in Fig. Again, this decrease is expected as ALP is a by-product of osteoblastic activity, highly expressed in pre-osteoblasts and osteoblasts but not expressed by transitional cells and osteocytes.
P- values are compared to PCa-Norm. M shows the P- values for overall effect of Medium. Fold changes are normalized to PCa-Norm for each dimension. At the protein level Fig. Overall, the data demonstrates that the hOBMT platform allows for long-term co-culture experiments up to 28 days in PCa cell-based media in contrast to 2D co-culture experiments, which fail on many levels after 3—4 days.
Once attached, cells keep proliferating to form micro-aggregates at the surface of the hOBMT, up to 3 weeks post seeding. Shape factor values range from 1 round to 0 fully elongated. Over significance is shown for Cell type and Medium. Attachment rates Fig. CB under androgen deprivation also attached at similar rates as PC3, suggesting the acquisition of androgen-independent features upon androgen deprivation.
The morphometric features of cancer cells can inform on cell plasticity and malignancy 26 and be used to evaluate adaptive phenotype. Such distinct morphological features increased cellular volume, decreased shape factor are hallmarks of transition to resistance and hence represent a useful tool for quantification. The results disclosed that PC3 had the highest cellular volume Fig. S5b, c , and were indeed not affected by androgen deprivation. Yet, reduced volume and decreased shape factor Fig. LNCaP had the smallest shape factor across all cell lines with the smallest value under androgen deprivation 0.
Cancer cell migration and proliferation are important components of metastasis progression.
Treating Prostate Cancer Spread to Bones
Although reduced in trend, no statistical differences in proliferation were observed for any cell line under androgen-deprived conditions Fig. PC3 migrated the most [ Remarkably, while CB were affected by androgen deprivation, there was no significant impact of androgen deprivation on LNCaP. For instance MSD was 8. On the other hand, the more aggressive CB cells migrated more [ Since LNCaP would be affected by androgen deprivation in a mono-culture setting, these results clearly highlight the possible contribution of the osteoblast-derived microenvironment to androgen-responsive LNCaP survival.
Over long-term co-culture, single cancer cells aggregated within the first week of co-culture Fig.
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S6 a, b and Fig. S7a , forming prostate cancer aggregates on the surface of the hOBMT. CB aggregates did not display morphological differences under androgen deprivation when compared to PCa-Norm Fig. S6c , and remained compact. The asterisks show the hOBMT and the arrows show the cancer cells. The open arrow shows a scaffold fiber, the arrow heads show the hOBMT and the full arrows show the cancer cells. To our knowledge, we are the first to establish a model that allows to study the adaptive features of androgen-responsive LNCaP cells under androgen deprivation in an osteoblast-derived microenvironment.
Gene analysis Fig. DDC , a neuroendocrine marker of prostate cancer linked to progression to castrate resistance 33 was also upregulated in both co-cultures. While PSA was significantly lower Figs. S8 a and S9 in prostate cancer cells and co-cultures, genes associated with progression to aggressive disease and resistance to therapy 9 , 29 were upregulated in both co-culture types: AR , DDC , and ENO2.
Conversely, epithelial-to-mesenchymal transition-relevant genes Slug , Snail , Zeb-1 were found unaltered under androgen deprivation in the co-cultures not shown. AR , known to amplify during androgen deprivation to facilitate tumor cell growth in low androgen concentrations 33 , 34 was expressed significantly higher in all settings at both gene and protein levels. PTH1R , a key regulator in tumor—bone interactions, was upregulated under androgen deprivation in prostate cancer mono-culture and co-cultures. PSA was highly downregulated by androgen deprivation, as expected Fig.
S8b , demonstrating the contribution of the bone microenvironment in maintaining PSA expression. This is in line with increased ALP serum levels in patients under androgen deprivation therapy. Finally, we used quantitative IHC to confirm protein expression levels Fig.
Clinical trials with agents such as zolenodrate or denosumab, which inhibit osteoclast activity, showed that osteoclast-targeting agents could reverse bone loss from hormonal therapies, yet did not slow down the progression of bone metastases, 3 demonstrating that osteoblasts remain one of the key drivers in prostate cancer bone metastasis.
Androgen deprivation therapy is inevitable for patients with recurrent disease, and is maintained throughout disease progression, despite inducing resistance at the metastatic sites 38 and higher mortality. Importantly, at the early stage of androgen deprivation therapy, whether or not prostate cancer has progressed to bone yet, the systemic suppression of androgens has severe implications for the bone organ, with loss of mineral density, high remodeling rates, and a higher risk of fractures.
Emphasis needs to be given to models that can reproduce androgen deprivation and demonstrate similarities to the clinical scenario, where bone metastases are found in patients already under ADT. Three-dimensional 3D in vitro models of bone metastases have become increasingly recognized to enhance the current knowledge, which is built on 2D culture models and in vivo animal models of skeletal metastasis.
Advanced prostate cancer
Specifically in the context of prostate cancer bone metastasis, which is mostly driven by osteoblasts, many responsible factors have still not been identified 3 and hence an approach that is osteoclast-free has a stronger rationale. One strength of this model is rooted in its capability to perform long-term studies and osteoblast-derived microtissues displaying the morphological features of a highly mineralized mature tissue.
The presence of osteocytic cells enabled the expression of mature bone markers, which is often not seen in 2D, and not well-designed 3D, models. Direct-contact 3D cancer assays are critical to assess cell-to-cell and cell-to-matrix interactions. Biophysical, as much as biochemical, interactions indeed promote cancer transition towards resistance, with explicit adaptive phenotype.
Importantly, DDC upregulation was already occurring in androgen-replete conditions, as a result of co-culture, validating the bone contribution in initiating adaptive response mechanisms prior to androgen deprivation. We further presented evidence that the osteoblast-derived microenvironment was supportive of the AR-positive and dependent LNCaP cells by reducing only slightly cancer cell proliferation and migration, but not significantly, as would have been expected at the start of ADT.
The cells still reached similar proliferative, migratory, and morphometric properties as CB under androgen deprivation. Higher migratory properties seen for CB in androgen-replete conditions corroborated the fact that CB are past the transition to castrate resistance and derived from bone metastases formed by LNCaP, hence are used to growing in this microenvironment. Importantly, a vast majority of castration-resistant cases are not truly depleted of androgens and still use androgens to maintain cell proliferation and tumor growth, 38 hence the effects observed here on CB.
The osteoblast-derived microenvironment showed active participation to the adaptive transition of cancer cells. This process contributes to maintaining LNCaP proliferation and migration in the bone microenvironment by a mechanism that partially relies on AR. As SOST is expressed by some prostate cancer cells, circulating sclerostin levels are usually significantly increased in prostate cancer patients and particularly in those receiving ADT, 48 as androgens are key regulators of bone metabolism in this population.
Consistent with these findings, SOST expression, provided here by the osteocytic population from hOBMT was heightened by androgen deprivation, 25 , 48 also explaining the reduced migration observed for CB under androgen deprivation. This is the demonstration of a clear adaptive response from the bone tumor microenvironment to aid metastasis progression. In future, it will also be important to investigate other metastatic cell lines, such as VCaP, DuCaP, or C, to further unravel the effects of androgen deprivation for those metastatic variants in the osteoblast-derived microenvironment.
Finally, the use of patient-derived tissues xenografts, prostatectomy samples in co-culture with the microtissues would be warranted in the future as a predictive platform for the testing of current and novel therapeutics for individual patients. Technical challenges remain, as direct-contact models provide a complex milieu, which challenges downstream analyses, 42 with difficulties including the recovery of mRNA and proteins. Importantly, the proposed model focused on prostate cancer interactions with osteoblasts, osteocytes, and their respective ECM, due to the pathological relevance of osteoblastic lesions, yet some prostate cancer types present with mixed osteoblastic and osteolytic lesions.
Hence it will be valuable to have a complementary model that includes osteoclasts in the future. In conclusion, although every in vitro model is imperfect by definition, 14 this study represents a significant advancement in the field, as it addresses some of the key challenges in engineering osteoblast-derived metastatic microenvironments.
Isolation of human osteoprogenitor cells from donor bone tissue was in accordance with QUT ethics approval number Osteogenic potential was validated by alizarin red staining Fig. Isolated cells were seeded at passage 4—5 on sterilized scaffolds 0. The bioengineered constructs are referred to as human osteoblast-derived microtissues hOBMT.
For specific details, see the Methods Supplement. See the Methods Supplement. Cells from passages 18—35 were used. Cancer cell volume and shape factor were obtained from Imaris imaging analysis software version 9. Algorithm details are found in the Methods Supplement. After attachment, the co-culture microtissues were placed in a new well-plate and secured down using Teflon ring inserts Prestige Manufacturing Pty Ltd. Fluorescent signal from prostate cancer cells was used to track movement on the hOBMT. The list of primers is found in Table 1. Similar experimental design was used as for the RT-qPCR co-culture experiments On day 10, conditioned media and cell protein lysates were collected and analyzed.
Protein arrays and westerns blots WB on conditioned media and WB on protein lysates were performed as detailed in the Methods Supplement. Details are found in the Methods Supplement. Body, J. Targeting bone metastases in prostate cancer: improving clinical outcome.
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