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The use of oncolytic viruses forms an appealing approach for cancer treatment. On the one hand the viruses replicate in, and kill, tumor cells, leading to their intra-tumoral amplification. On the other hand the viral infection will activate virus-directed immune responses, and may trigger immune responses directed against tumor cells and tumor antigens. To date, a wide variety of oncolytic viruses is being developed for use in cancer treatment. While the development of oncolytic viruses has often been initiated by researchers in academia and other public institutions, a large majority of the final product development and the testing of these products in clinical trials is industry led. As a consequence relatively few pre-clinical and clinical studies evaluated different oncolytic viruses in competitive side-by-side preclinical or clinical studies. In this review we will summarize the steps and considerations essential in the development and characterization of oncolytic viruses, and describe our multidisciplinary academic consortium, which involves a dozen departments in three different Dutch universities, collaborating in the development of oncolytic viruses. This consortium has the ambition to develop a small series of oncolytic viruses and to evaluate these in various cancers., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Bladder cancer is the fifth most common malignancy in the Western world and the second most frequently diagnosed genitourinary tumor. In the majority of cases, death from bladder cancer results from metastatic disease. Understanding the multistep process of carcinogenesis and metastasis in urothelial cancers is pivotal to the development of new therapeutic strategies. Molecular imaging of cancer growth and metastasis in preclinical models provides the essential link between cell-based experiments and clinical translation., Objective: Develop preclinical models for sensitive bladder cancer cell tracking during tumor progression and metastasis., Design, Setting, and Participants: A human transitional cell carcinoma UM-UC-3 cell line was generated that stably expresses luciferase 2 (UM-UC-3luc2), a mammalian codon-optimized firefly luciferase with superior expression. Preclinical models were developed with human UM-UC-3luc2 cells xenografted into the bladder (orthotopic model with metastases) or inoculated into the left cardiac ventricle (bone metastasis model) of immunocompromised mice., Measurements: Noninvasive, sensitive bioluminescent imaging of human firefly luciferase 2-positive bladder cancer in mice using the IVIS100 imaging system., Results and Limitations: In the orthotopic model (intravesical inoculation), tumor growth could be followed directly after inoculation of UM-UC-3luc2 cells. Importantly, micrometastatic lesions originating from orthotopically implanted cancer cells could be detected in the locoregional lymph nodes and in distant organs. In addition, the superior bioluminescent indicator firefly luciferase 2 allows the detection and monitoring of micrometastatic lesions in real time after intracardiac inoculation of human bladder cancer cells in mice. The main disadvantage is the lack of T-cell immunity in the preclinical models., Conclusions: The new bioluminescence-based preclinical bladder cancer models enable superior, noninvasive, and real-time tracking of cancer cells, tumor progression, and micrometastasis. Because of the significant improvement in detection of small cell numbers, the presented models are ideally suited for functional studies dealing with minimal residual disease as well as real-time imaging of drug response., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Bone morphogenetic protein 7 (BMP7) is a member of the transforming growth factor-β (TGF-β) superfamily of growth factors. In recent years, it has become clear that BMP7 is a very pleiotropic growth factor. As described in this review, it plays a pivotal role in the development of bone and kidney, and has only recently been demonstrated to also be crucially involved in differentiation of brown adipose tissue. Because BMP7 thus controls the development and maintenance of many physiological processes in the human body, aberrant expression of BMP7 is associated with a variety of diseases. This review gives a broad overview on the involvement of BMP7 in several pathological conditions, such as incomplete fracture healing, osteoarthritis, the development of bone metastases, renal fibrosis and obesity. Furthermore, the therapeutic potential of BMP7 in these disease states is discussed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Acquisition of an invasive phenotype of cancer cells in primary tumors is an absolute requirement for bone metastasis. The majority of bone metastases is derived from epithelial cancers, particularly those of the breast and prostate. Accumulating evidence suggest that transformed epithelial cells can activate embryonic programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype also referred to as epithelial-to-mesenchymal transition (EMT). Induction of EMT can, therefore, lead to invasion of surrounding stroma, intravasation, dissemination and colonization of distant sites. In bone/bone marrow disseminated tumor cells can partially regain their original epithelial characteristics via a mesenchymal-to-epithelial transition (MET) as glandular structures in bone metastasis are frequently observed. To date, the importance of epithelial plasticity in cancer cells disseminated to the bone/bone marrow microenvironment has remained largely elusive. Interestingly, a number of growth factors that play a prominent role in EMT induction in the primary tumor have been identified as important stimulators of skeletal metastasis formation. Recent studies have demonstrated that EMT may render cancer cells with properties of stem cells, which in turn can lead to escape from immune surveillance, increased resistance to apoptosis, diminished senescence and, last-but-not least, therapy resistance. This review will discuss current concepts regarding the role of epithelial plasticity in the multistep processes of bone metastasis, the issue of minimal residual disease, cancer stem cells and the importance of EMT in the development of novel targeted drug therapy., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Breast cancer frequently metastasizes to bone, where tumor cells induce osteoclasts to locally destroy bone. During bone resorption, growth factors are locally released that may support bone metastatic growth. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates and osteoprotegerin (OPG), are available for bone. We examined the hypothesis that inhibition of bone resorption by two different mechanisms may also affect the growth of cancer cells in bone. For this, we tested the effects of high doses of OPG and zoledronic acid (ZOL) on progression of MDA-231-B/Luc+ breast cancer cells in the bone microenvironment using whole body bioluminescent reporter imaging (BLI). Both treatments significantly inhibited the development of radiographically detectable osteolytic lesions. Histologic examination corroborated the radiographic findings, showing that both treatments preserved the integrity of bone trabeculae and prevented bone destruction (significantly higher trabecular bone volumes vs. vehicle). However, whereas practically no TRAcP-positive osteoclasts were observed in tibiae preparations of animals treated with Fc-OPG, TRAcP-positive osteoclasts were still present in the animals treated with ZOL. Intra-bone tumor burden was reduced with ZOL and Fc-OPG treatment. Although there appeared to be a trend for less overall total tumor burden upon treatment with both compounds, this was not significant as assessed by BLI and histomorphometric analysis due to the extramedullary growth of cancer cells which was not affected by these treatments. Collectively, anti-resorptive agents with different mechanisms of action - ZOL and OPG - significantly reduced cancer-induced osteolysis and intra-osseous tumor burden, but failed to restrain local tumor growth. However, interference with the bone micro-environmental growth support could still be of therapeutic relevance when given to patients early in the course of bone metastatic disease.