Matthew L. Broadhead

The molecular pathogenesis of osteosarcoma: a review.

Osteosarcoma is the most common primary malignancy of bone. It arises in bone during periods of rapid growth and primarily affects adolescents and young adults. The 5-year survival rate for osteosarcoma is 60%–70%, with no significant improvements in prognosis since the advent of multiagent chemotherapy. Diagnosis, staging, and surgical management of osteosarcoma remain focused on our anatomical understanding of the disease. As our knowledge of the molecular pathogenesis of osteosarcoma expands, potential therapeutic targets are being identified. A comprehensive understanding of these mechanisms is essential if we are to improve the prognosis of patients with osteosarcoma through tumour-targeted therapies. This paper will outline the pathogenic mechanisms of osteosarcoma oncogenesis and progression and will discuss some of the more frontline translational studies performed to date in search of novel, safer, and more targeted drugs for disease management.

In vitro and in vivo biological activity of PEDF against a range of tumors.

Background: Pigment epithelium-derived factor (PEDF) is an emerging anti-cancer agent that targets both tumor tissue and its supporting vasculature. These direct and indirect effects of PEDF have been examined in vitro and in vivo for a range of malignancies. Objective: This review seeks to present PEDF as a potential anti-cancer agent with applications across multiple malignancies. We refer closely to experimental methodology whilst still highlighting the clinical significance of PEDF in cancer, drawing on biological findings in vitro and in vivo. Methods: A Pubmed database search was performed limiting the scope of this discussion paper mainly to PEDFs biological role in cancer, specifically lung, breast, prostatic, ovarian and pancreatic carcinomas, melanoma, glioma and osteosarcoma. Conclusions: The biological roles of PEDF are diverse and multidimensional. As an anti-cancer agent, PEDF has great potential as a focused anti-neoplastic therapy against a variety of tumor types.

Therapeutic targeting of osteoclast function and pathways

Introduction: Osteoclasts are responsible for bone resorption and underlie a number of pathological states in which osteolysis is a feature. Over recent decades our molecular understanding of osteoclast differentiation and activation has expanded significantly, and this has allowed for the development of a number of osteoclast-targeted therapies. Areas covered: This review seeks to present the underlying molecular mechanisms of osteoclast differentiation and activity as a basis for understanding our current treatment of osteoporosis and malignant tumors in bone. Osteoclast-targeted therapies are also being evaluated for the treatment of rheumatoid arthritis, osteosarcoma and giant cell tumor of bone. Expert opinion: With concurrent advances in the fields of molecular biology, pathology and advanced imaging, osteoclast-targeted therapies show great potential for treating conditions in which excess resorption of bone is a key pathological process. Targeting of osteoclast control mechanisms offers the potential of combining ‘molecular imaging’ with therapeutic intervention and longitudinal monitoring of disease processes.

Cancer cell apoptotic pathways mediated by PEDF: prospects for therapy

Pigment epithelium-derived factor (PEDF) has roles in antiangiogenesis and antitumourigenesis that are intimately entwined and is showing promise as a potential anticancer agent. However, the function of PEDF in the deregulated apoptotic pathways of malignant cells must first be fully characterized. Here, we review the currently known apoptotic pathways that are relevant to PEDF and cancer. Recently, a pathway that includes the PEDF receptor, PPARgamma and p53 has emerged. It is hoped that further characterization of this and other pathways involved in cancer will bring to light potential new therapeutic targets and approaches, which due to their specificity might be free of the morbidity associated with conventional chemotherapy.

The applied biochemistry of PEDF and implications for tissue homeostasis.

Pigment epithelium-derived factor (PEDF) is an endogenously produced glycoprotein with a spectrum of biological roles across diverse pathologies. Recent research has focused on the biochemical properties of PEDF and its associated receptors. This review discusses the recent developments in PEDF biochemistry and how this new knowledge will help progress our understanding of PEDF as a molecular mediator for anti-angiogenesis and -tumorigenesis. Additionally, pathophysiological roles for PEDF in healing and tissue homeostasis are being revealed and our enhanced understanding of the interactions between PEDF and its receptors may yet prove useful in propelling PEDF towards clinical application.

The pathophysiological role of PEDF in bone diseases.

First discovered in 1991 as a factor secreted by retinal pigment epithelial cells, the potency of pigment epithelium derived factor (PEDF) as an anti-angiogenic has led to examination of its role in active bone growth, repair and remodelling. In the musculoskeletal system, PEDF expression occurs particularly at sites of active bone formation. Expression has been noted in osteoblasts and to a lesser degree osteoclasts, the major classes of bone cells. In fact, PEDF is capable of inducing differentiation of precursor cells into mature osteoblasts. Expression and localisation are closely linked with that of vascular endothelial growth factor (VEGF). Studies at the epiphyseal plate have revealed that PEDF expression plays a key role in endochondral ossification, and beyond this may account for the epiphyseal plates innate ability to resist neoplastic cell invasion. Collagen-1, the major protein in bone, is avidly bound by PEDF, implicating an important role played by this protein on PEDF function, possibly through MMP-2 and -9 activity. Surprisingly, the role of PEDF has not been evaluated more widely in bone disorders, so the challenge ahead lies in a more diverse evaluation of PEDF in various osteologic pathologies including osteoarthritis and fracture healing.

Systemically administered PEDF against primary and secondary tumours in a clinically relevant osteosarcoma model

Background:Pigment epithelium-derived factor (PEDF) is an endogenous glycoprotein with a potential role as a therapeutic for osteosarcoma. Animal studies have demonstrated the biological effects of PEDF on osteosarcoma; however, these results are difficult to extrapolate for human use due to the chosen study design and drug delivery methods.Methods:In this study we have attempted to replicate the human presentation and treatment of osteosarcoma using a murine orthotopic model of osteosarcoma. The effects of PEDF on osteosarcoma cell lines were evaluated in vitro prior to animal experimentation. Orthotopic tumours were induced by intra-tibial injection of SaOS-2 osteosarcoma cells. Treatment with PEDF was delayed until after the macroscopic appearance of primary tumours. Pigment epithelium-derived factor was administered systemically via an implanted intraperitoneal micro-osmotic pump.Results:In vitro, PEDF inhibited proliferation, induced apoptosis and inhibited cell cycling of osteosarcoma cells. Pigment epithelium-derived factor promoted adhesion to Collagen I and inhibited invasion through Collagen I. In vivo, treatment with PEDF caused a reduction in both primary tumour volume and burden of pulmonary metastases. Systemic administration of PEDF did not cause toxic effects on normal tissues.Conclusion:Systemically delivered PEDF is effective in suppressing the size of primary and secondary tumours in an orthotopic murine model of osteosarcoma.

An interesting diagnosis for a presacral mass: case report.

A presacral mass can present a diagnostic dilemma for the surgical oncologist. Differential diagnoses include congenital causes such as teratoma or chordoma, neurological causes such as neurilemoma or neurofibroma or other malignancies such as lymphoma or sarcoma. Diagnosis usually requires imaging such as CT and MRI and tissue biopsy. We present an unusual cause of a presacral mass being extramedullary haematopoiesis, found incidentally in a 71 year old female. Extramedullary haematopoiesis is defined as the production of myeloid and erythroid elements outside of the bone-marrow. This diagnosis is extremely rare in the presacral area especially in a patient with no haematological abnormalities. A review of the literature is presented.

Outcomes of Total Knee Arthroplasty in English-Versus Non–English-Speaking Patients

Purpose. To compare outcomes of total knee arthroplasty (TKA) in English- versus non–English-speaking patients. Methods. 193 women and 85 men (mean age, 72 years) underwent 117 left and 161 right primary TKAs. 237 and 41 patients were English and non–English speaking, respectively. Interpretation was provided. Pre- and post-operative functional outcomes were measured using the International Knee Society (IKS) score. Results. Most non–English-speaking patients were female (38 vs 3 of 41, p<0.001). The mean body mass index of non–English-speaking patients was significantly higher (34 vs 31 kg/m2, p=0.003). 14 foreign languages were spoken among the 41 non–English-speaking patients, of which Greek and Italian were the most common. Non–English-speaking patients had significantly worse IKS scores both preoperatively and at the 12-month follow-up. The proportions of poor postoperative IKS scores were significantly higher in non–English-speaking patients (58% vs 27%, p<0.001), in whom pain was also significantly worse (p=0.017). In a multiple logistic regression analysis, being non–English speaking was the only predictor of poor functional outcome at the 12-month follow-up (odds ratio=2.77, confidence interval=1.25–6.14, p=0.012). Conclusion. The non–English-speaking background of a patient is a predictor of less favourable functional outcome after TKA.

Efficacy of Continuously Administered PEDF-Derived Synthetic Peptides against Osteosarcoma Growth and Metastasis

The potent antiangiogenic pigment epithelium-derived factor (PEDF) has shown promise against osteosarcoma, a tumour that originates in the bone and metastasises to the lungs. Neurotrophic, antiangiogenic, antiproliferative, and antimetastatic properties of PEDF have been attributed to a number of functional epitopes on the PEDF glycoprotein. StVOrth-2 (residues 78–102) and StVOrth-3 (residues 90–114) are two PEDF-derived peptides based on these functional epitopes. StVOrth-2 has previously been shown to inhibit osteosarcoma cell proliferation, while StVOrth-3 increased osteosarcoma cell adhesion to collagen I in vitro. In this paper, we have evaluated systemically and continuously delivered StVOrth-2 and StVOrth-3 using a clinically relevant murine model of osteosarcoma with spontaneous metastasis. Treatment with StVOrth-2 or StVOrth-3 with microosmotic pumps was initiated after primary osteosarcoma was established in the tibia. While treatment with StVOrth-2 and StVOrth-3 did not appear to affect local tumour invasion, tumour necrosis or apoptosis, StVOrth-2 predominantly restricted the growth of primary tumours, while StVOrth-3 restricted the burden of pulmonary metastatic disease. No peptide caused gross toxicity in mouse tissues as assessed by measuring weight of animals, serum biochemistry, and gross tissue observation. The differential effects exhibited by StVOrth-2 and StVOrth-3 in this orthotopic model of osteosarcoma may be related to the functional epitopes on the PEDF glycoprotein that they represent.