scispace - formally typeset
Search or ask a question
Author

Matthew L. Broadhead

Bio: Matthew L. Broadhead is an academic researcher from St. Vincent's Health System. The author has contributed to research in topics: Osteosarcoma & PEDF. The author has an hindex of 11, co-authored 26 publications receiving 604 citations. Previous affiliations of Matthew L. Broadhead include University of New South Wales & John Hunter Hospital.

Papers
More filters
Journal ArticleDOI
13 Apr 2011-Sarcoma
TL;DR: The pathogenic mechanisms of osteosarcoma oncogenesis and progression are outlined and some of the more frontline translational studies performed to date in search of novel, safer, and more targeted drugs for disease management are discussed.
Abstract: 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.

311 citations

Journal ArticleDOI
TL;DR: This review seeks to present the underlying molecular mechanisms of osteoclast differentiation and activity as a basis for understanding the current treatment of osteoporosis and malignant tumors in bone.
Abstract: 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 potent...

44 citations

Journal ArticleDOI
TL;DR: PEDF has great potential as a focused anti-neoplastic therapy against a variety of tumor types and is referred closely to experimental methodology whilst still highlighting the clinical significance of PEDF in cancer.
Abstract: 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 PEDF's 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.

44 citations

Journal ArticleDOI
TL;DR: 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.

37 citations

Journal ArticleDOI
TL;DR: Systemically delivered PEDF is effective in suppressing the size of primary and secondary tumours in an orthotopic murine model of osteosarcoma and caused a reduction in both primary tumour volume and burden of pulmonary metastases.
Abstract: Osteosarcoma is an aggressive primary bone cancer that predominately affects adolescents and young adults. Neo-adjuvant chemotherapy, adjuvant chemotherapy and surgical resection are the mainstays of treatment for osteosarcoma. Advances in diagnostic imaging have provided a more complete evaluation of tumour anatomy and have allowed the treating surgeon to consider a variety of limb salvage techniques. Despite these advances, however, patient prognosis has not improved significantly since the 1970s when multiagent chemotherapy regimes were introduced (Guise et al, 2009). The 5-year survival rate for osteosarcoma remains steady at 60–70% (Kumar et al, 2005). Novel approaches are desperately needed to improve the treatment of patients with osteosarcoma, particularly for those with chemoresistant or recurrent disease. With this challenge in mind, research has focused on characterising the genetic basis of osteosarcoma. The molecular pathways that underlie tumourigenesis, proliferation, invasion and metastasis are being identified as targets for novel treatment agents (Broadhead et al, 2010). Targeting the deranged molecular signalling of osteosarcoma should enhance the effectiveness of conventional chemotherapeutics and possibly reduce patient morbidity. Pigment epithelium-derived factor (PEDF) is a multifunctional molecule with a potential role as a therapeutic agent for osteosarcoma. Pigment epithelium-derived factor is an endogenous 50-kDa glycoprotein that was first shown to be capable of inducing differentiation of Y-79 retinoblastoma cells (Tombran-Tink and Johnson, 1989). Pigment epithelium-derived factor is expressed in a wide range of tissues including the eye, brain, spinal cord, plasma, bone, cartilage, heart, lung, prostate and pancreas (Broadhead et al, 2009). Pigment epithelium-derived factor has diverse roles in these tissues; however, it has attracted attention foremost as a potent anti-angiogenic agent. Pigment epithelium-derived factor is twice as potent as angiostatin and seven times as potent as endostatin (Dawson et al, 1999). It was the anti-angiogenic properties of PEDF that lead to the study of its potential as an anti-tumour agent for various cancers (Broadhead et al, 2009). Anti-angiogenic agents such as bevacizumab have already been adopted as adjunctive treatments for cancers, including metastatic colon carcinoma, breast carcinoma, renal cell carcinoma, non-small-cell lung carcinoma and glioblastoma multiforme. Previous studies have provided proof of principle for PEDF as an anti-osteosarcoma agent. Quan et al (2002) first examined the role of cartilage-derived anti-angiogenic factors at the growth plate of long bones. Using immunohistochemistry and in situ hybridisation, PEDF expression was shown to be largely restricted to the avascular resting, proliferative and upper hypertrophic layers of the growth plate. These are the regions that are consistently resistant to osteosarcoma invasion from the adjacent metaphysis. Ek et al (2007a) and Takenaka et al (2005) later showed that PEDF restricted osteosarcoma growth in vitro through both the induction of apoptosis and the inhibition of cell cycling. Pigment epithelium-derived factor also restricted the metastatic capacity of osteosarcoma cells by improving cellular adhesion and restricting invasion. Pigment epithelium-derived factor has been tested in a number of compelling in vivo animal studies for osteosarcoma. Ek et al (2007a) applied PEDF to a spontaneously metastasising orthotopic model of osteosarcoma. SaOS-2 human osteosarcoma cells were first treated with PEDF and primary osteosarcoma was induced by intra-tibial injection of treated cells in Balb/c nude mice. Pigment epithelium-derived factor restricted the growth of primary tumours and the occurrence of pulmonary metastases. Ek et al (2007b) also showed that PEDF overexpression in an orthotopic model reduced microvessel density and osteolysis. Pigment epithelium-derived factor gene delivery in this model resulted in reduced tumour growth, both when used alone and in combination with doxorubicin therapy (Ta et al, 2009a). All of these previous in vivo studies with PEDF have utilised a clinically relevant orthotopic model that allows an evaluation of both primary and secondary tumour progression. However, while showing proof of principle, the results of treating osteosarcoma cells with PEDF prior to inoculation (Ek et al, 2007a), and the use of a PEDF-expressing plasmid (Ek et al, 2007b; Ta et al, 2009a), are difficult to extrapolate for human use. In order to truly evaluate the therapeutic efficacy of PEDF in a clinically relevant model of disease, treatment with PEDF should be delayed until after the establishment of primary tumours, and preferably be performed with systemic recombinant protein. This would more accurately replicate the human condition where patients most commonly present for treatment with an established tumour. In this study we aimed to evaluate systemically administered PEDF in a model optimised for clinical relevance. Using an orthotopic murine model of spontaneously metastasising osteosarcoma, we show for the first time that systemic delivery of PEDF is capable of restricting the size of established primary and secondary osteosarcoma.

35 citations


Cited by
More filters
Journal ArticleDOI
TL;DR: This review focuses on diabetic wound healing, paying special attention to the aberrations that have been described in the proliferative, remodeling, and maturation phases of wound angiogenesis and considers therapeutics that may offer promise to better wound healing outcomes.
Abstract: Diabetes Mellitus Type II (DM2) is a growing international health concern with no end in sight. Complications of DM2 involve a myriad of comorbidities including the serious complications of poor wound healing, chronic ulceration, and resultant limb amputation. In skin wound healing, which has definite, orderly phases, diabetes leads to improper function at all stages. While the etiology of chronic, non-healing diabetic wounds is multi-faceted, the progression to a non-healing phenotype is closely linked to poor vascular networks. This review focuses on diabetic wound healing, paying special attention to the aberrations that have been described in the proliferative, remodeling, and maturation phases of wound angiogenesis. Additionally, this review considers therapeutics that may offer promise to better wound healing outcomes.

484 citations

Journal ArticleDOI
TL;DR: The intrachromosomal X-chromosome fusion described here represents a new subtype of bone Sarcoma caused by a newly identified gene fusion mechanism and it is shown that CCNB3 immunohistochemistry is a powerful diagnostic marker for this subgroup of sarcoma.
Abstract: The identification of subtype-specific translocations has revolutionized the diagnostics of sarcoma and has provided new insight into oncogenesis. We used RNA-seq to investigate samples from individuals diagnosed with small round cell tumors of bone, possibly Ewing sarcoma, but which lacked the canonical EWSR1-ETS translocation. A new fusion was observed between BCOR (encoding the BCL6 co-repressor) and CCNB3 (encoding the testis-specific cyclin B3) on the X chromosome. RNA-seq results were confirmed by RT-PCR and through cloning of the tumor-specific genomic translocation breakpoints. In total, 24 BCOR-CCNB3-positive tumors were identified among a series of 594 sarcoma cases. Gene profiling experiments indicated that BCOR-CCNB3-positive cases are biologically distinct from other sarcomas, particularly Ewing sarcoma. Finally, we show that CCNB3 immunohistochemistry is a powerful diagnostic marker for this subgroup of sarcoma and that overexpression of BCOR-CCNB3 or of truncated CCNB3 activates S phase in NIH3T3 cells. Thus, the intrachromosomal X-chromosome fusion described here represents a new subtype of bone sarcoma caused by a newly identified gene fusion mechanism.

386 citations

Journal ArticleDOI
TL;DR: Next-generation sequencing is applied to analyze the exome of a single individual who has a severe form of OI and whose parents are second cousins to provide genetic evidence for PEDF involvement in human bone homeostasis.
Abstract: Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis.

330 citations

Journal ArticleDOI
13 Apr 2011-Sarcoma
TL;DR: The pathogenic mechanisms of osteosarcoma oncogenesis and progression are outlined and some of the more frontline translational studies performed to date in search of novel, safer, and more targeted drugs for disease management are discussed.
Abstract: 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.

311 citations