The work included in this thesis is aimed at developing novel tools to advance our understanding of prostate cancer. The clinical problem of prostate cancer is presented and discussed in the wider... Show moreThe work included in this thesis is aimed at developing novel tools to advance our understanding of prostate cancer. The clinical problem of prostate cancer is presented and discussed in the wider context of the current clinical knowledge, highlighting the genetic mechanisms at its base. A dedicated chapter focuses on bone metastases, highly morbid feature of advanced prostate cancer, discussing the known mechanisms and the available models to study it in translational research. Then, moving from the molecular analysis of clinical specimens of bone metastasis, a biochemical pathway is identified and further studied in vitro, ex vivo and in vivo, validating the initial findings. A novel, early-stage prostate cancer patient-derived xenograft is presented and extensively characterized and implemented in a drug screening. This allowed to screen the effect of over 70 known drugs on prostate cancer models, using three-dimensional cultures and a semi-automated platform. As all research builds on previously established findings, a bibliometric analysis tool is presented, to assist in the generation of a knowledge network arranged by topic and impact of research. All these aspects and findings are then discussed in the context of the current direction of prostate cancer research, its emerging tools and its long-known challenges. Show less
Ataei, A.; Eggermont, F.; Baars, M.; Linden, Y. van der; Rooy, J. de; Verdonschot, N.; Tanck, E. 2021
Purpose Accurate identification of metastatic lesions is important for improvement in biomechanical models that calculate the fracture risk of metastatic bones. The aim of this study was therefore... Show morePurpose Accurate identification of metastatic lesions is important for improvement in biomechanical models that calculate the fracture risk of metastatic bones. The aim of this study was therefore to assess the inter- and intra-operator reliability of manual segmentation of femoral metastatic lesions. Methods CT scans of 54 metastatic femurs (19 osteolytic, 17 osteoblastic, and 18 mixed) were segmented two times by two operators. Dice coefficients (DCs) were calculated adopting the quantification that a DC>0.7 indicates good reliability. Results Generally, rather poor inter- and intra-operator reliability of lesion segmentation were found. Inter-operator DCs were 0.54 (+/- 0.28) and 0.50 (+/- 0.32) for the first and second segmentations, respectively, whereas intra-operator DCs were 0.56 (+/- 0.28) for operator I and 0.71 (+/- 0.23) for operator II. Larger lesions scored significantly higher DCs in comparison with smaller lesions. Of the femurs with larger mean segmentation volumes, 83% and 93% were segmented with good inter- and intra-operator DCs (> 0.7), respectively. There was no difference between the mean DCs of osteolytic, osteoblastic, and mixed lesions. Conclusion Manual segmentation of femoral bone metastases is very challenging and resulted in unsatisfactory mean reliability values. There is a need for development of a segmentation protocol to reduce the inter- and intra-operator segmentation variation as the first step and use of computer-assisted segmentation tools as a second step as this study shows that manual segmentation of femoral metastatic lesions is highly challenging. Show less
Todd, G.M.; Gao, Z.C.; Hyvonen, M.; Brazil, D.P.; Dijke, P. ten 2020
Bone morphogenetic proteins (BMPs) are multifunctional secreted cytokines that act in a highly context-dependent manner. BMP action extends beyond the induction of cartilage and bone formation, to... Show moreBone morphogenetic proteins (BMPs) are multifunctional secreted cytokines that act in a highly context-dependent manner. BMP action extends beyond the induction of cartilage and bone formation, to encompass pivotal roles in controlling tissue and organ homeostasis during development and adulthood. BMPs signal via plasma membrane type I and type II serine/threonine kinase receptors and intracellular SMAD transcriptional effectors. Exquisite temporospatial control of BMP/SMAD signalling and crosstalk with other cellular cues is achieved by a series of positive and negative regulators at each step in the BMP/SMAD pathway. The interaction of BMP ligand with its receptors is carefully controlled by a diverse set of secreted antagonists that bind BMPs and block their interaction with their cognate BMP receptors. Perturbations in this BMP/BMP antagonist balance are implicated in a range of developmental disorders and diseases, including cancer. Here, we provide an overview of the structure and function of secreted BMP antagonists, and summarize recent novel insights into their role in cancer progression and bone metastasis. Gremlin1 (GREM1) is a highly studied BMP antagonist, and we will focus on this molecule in particular and its role in cancer. The therapeutic potential of pharmacological inhibitors for secreted BMP antagonists for cancer and other human diseases will also be discussed. Show less
Bone metastases of the long bones can cause pain and pathologic fractures. Local treatment consists of radiotherapy or surgical stabilisation. The most appropriate treatment depends on many factors... Show moreBone metastases of the long bones can cause pain and pathologic fractures. Local treatment consists of radiotherapy or surgical stabilisation. The most appropriate treatment depends on many factors, including the symptoms, the location and extent of the lesion, the wishes and expectations of the patient, and the expected remaining survival. Survival estimation of patients with symptomatic long bone metastases is crucial to prevent over- and undertreatment. This thesis aimed to develop a prognostic model for estimating survival in patients with cancer and symptomatic metastases of the long bones, evaluate current (surgical) treatment modalities and trends, and provide rationale for future prospective randomized trials. As a result, the OPTIModel was developed: an easy-to-use prognostic model that categorises patients into four clinically relevant survival categories based on only three variables (tumour type, Karnofsky Performance Score, visceral/brain metastases). To enable easy use of the model, an app was created (OPTIModel). Futhermore, this thesis shows that almost all treatments of pathologic fractures are based on expert opinion and small, retrospective cohorts, as opposed to large, prospective (randomized) trials, which is interesting in an era of evidence based medicine. This confirms the need of a prospective, multicenter cohort, which was designed and implemented accordingly. Show less
Willeumier, J.J.; Linden, Y.M. van der; Dijkstra, P.D.S. 2016
In the past decade it became increasingly clear that tumor heterogeneity represents one of the major problems for cancer treatment, also in prostate cancer. The identification of the molecular... Show moreIn the past decade it became increasingly clear that tumor heterogeneity represents one of the major problems for cancer treatment, also in prostate cancer. The identification of the molecular properties of highly aggressive cells (Cancer Stem Cells, CSCs) dispersed within the tumor represents a challenge for the identification of new efficient therapies. In most of the cases, current treatments are indeed successful in eradicating the primary tumor. However, the clinical evidence of relapse and the occurrence of therapy resistance, suggest the presence of subpopulation of cells within the tumor, that can survive such treatments and can perpetuate the cancer. In this thesis we investigated the molecular properties of selected highly aggressive CSCs and indentified novel modulators responsible for the maintenance of their aggressive behavior. Collectively, the studies described in this thesis have increased our insights into the molecular properties of highly metastatic and tumorigenic prostate cancer stem-like cells and provided new targets for possible diagnostic and therapeutic applications. Show less
Groenen, K.H.J.; Pouw, M.H.; Hannink, G.; Hosman, A.J.F.; Linden, Y.M. van der; Verdonschot, N.; Tanck, E. 2016
Once prostate cancer has spread to the skeleton, patients cannot be cured from their disease. Identification of the cell(s) of origin of prostate cancer as well as the neoplastic cell(s) involved... Show moreOnce prostate cancer has spread to the skeleton, patients cannot be cured from their disease. Identification of the cell(s) of origin of prostate cancer as well as the neoplastic cell(s) involved in the formation of distant metastases is, therefore, fundamental to understanding of carcinogenesis and metastasis. The functional identification of metastasis-initiating cells is a prerequisite for properly targeted therapy of metastatic disease in advanced prostate cancer. In chapter 2 of this thesis, the possible use of aldehyde dehydrogenase (ALDH) as marker for the identification and isolation of tumor-initiating and metastasis-initiating cells in prostate cancer is studied. In chapter 3, the functional role of a single ALDH isoform (ALDH7A1) in metastatic prostate cancer is investigated by knockdown studies in vitro and in vivo. In chapter 4, the functional involvement of _v integrins in the formation of a metastatic stem/progenitor prostate cancer phenotype is studied. Subsequently, in chapter 5, the targeting of integrins by a novel non-peptide integrin antagonist is evaluated in vitro and in preclinical models of prostate cancer progression and metastasis. Finally, general conclusions and discussions are described in chapter 6. Show less
Hoogen, C. van den; Horst, G. van der; Cheung, H.; Buijs, J.T.; Pelger, R.C.M.; Pluijm, G. van der 2011
The skeleton is one of the most common organs to be affected by metastatic disease. However, only a restricted number of solid cancers, especially those of the breast and prostate, are responsible... Show moreThe skeleton is one of the most common organs to be affected by metastatic disease. However, only a restricted number of solid cancers, especially those of the breast and prostate, are responsible for the majority of the bone metastases. Bone metastases are a major cause of morbidity, characterized by severe pain and high incidence of fractures, spinal cord compression and bone marrow aplasia requiring hospitalization. Despite the high frequency of skeletal metastases, the molecular mechanisms underlying the predisposition for tumors to colonize bone are poorly understood and treatment options are often unsatisfactory. The focus of this thesis was to better understand the processes that contribute to the formation of distant metastasis (chapter 2), particularly to bone (chapter 4__7), as well as to explore new treatment strategies with conventional (chapter 4 and 5) and novel therapeutic molecules (chapter 6 and 7) using optical imaging to sensitively monitor growth, dissemination and metastasis in mouse models (chapter 3__7). Show less
