Bone Formation Deregulations Are the Oncogenesis Keys in Osteosarcomas
11 Apr 2012-
TL;DR: No significant improvement in prognosis for patients with OS was observed since the advent of multiagent chemotherapy, increasing the long term outcome, and molecular research was developed to find new prognostic biomarkers and to define new therapeutic targets.
Abstract: The reciprocal osteoblast-osteoclast interactions are essential in the coordinated healthy bone formation and resorption. These communications in the bone microenvironment are highly complex events and need precise regulated molecular processes to ensure constant healthy bone remodeling. (Matsuo and Irie, 2008). Malignant bone tumors seem to be mainly linked to deregulation of this osteoblast-osteoclast cooperation processes. The major malignant bone tumor in pediatrics (5% of pediatric cancers) is high-grade osteosarcoma (OS). Usually, this bone cancer is diagnosed during adolescence and represent the second most common cancer after lymphoma in this period of age. A second peak observed in life is after 50 years. During adolescence, the kids are having their puberty development and the long bones are growing then particularly fast, with a rapid cell turnover in and around the growth plate (Mathew et al., 2011; Marina et al., 2004). Then, in a not surprising way, the most common locations of OS are the long bones (frequently, distal femur, proximal tibia and humerus) and especially in these metaphyseal regions around growth plates. Furthermore, no significant improvement in prognosis for patients with OS was observed since the advent of multiagent chemotherapy, increasing the long term outcome. Even this therapeutic progress, the overall survival of the patients is now at a plateau of 70% (Le Deley et al., 2007; Mirabello et al., 2009). After increasing the patient survival, new challenges regarding chemoresistances are now appearing and are involved in the recurrence of the disease despite a successful local resection. 15 to 20% of diagnosed patients will have radiographically detectable pulmonary metastases whereas 80% will already presenting undetectable micrometastases (Bruland et al., 2009). The lack of prognostic marker at diagnosis is another key point in this cancer. The only prognostic marker is the Huvos histological grading on tumor resection after neo-adjuvant chemotherapy (Juergens et al., 1981). It is classifying patients into good responders to chemotherapy and poor responders but after 4-month-chemotherapy already done. All these epidemiologic and therapeutic characteristics initially led to develop molecular research to find new prognostic biomarkers and to define new therapeutic targets. In this context, the research focused on several genetic predisposition genes implicated in OS development even most OS tumors are sporadic cases without familial patterns. Rapidly thereafter, the OS molecular research was taking into account the worldwide well-known OS histological features, which are the presence of malignant osteoid matrix produced by the proliferating malignant osteoblastic cells. This definition underlie the fact that OS may be considered as a disease of osteoblast
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01 Jul 2000
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TL;DR: Osteosarcoma, which is the most common primary bone tumor, occurs most frequently in adolescents, but there is a second incidence peak among individuals aged >60 years, and direct comparisons among patients of all ages and ethnicities are not available.
Abstract: Background
Osteosarcoma, the most common primary bone tumor, occurs most frequently in adolescents, but a second incidence peak among individuals over age 60 exists. Most osteosarcoma epidemiology studies have been embedded in large analyses of all bone tumors, or focused on cases occurring in adolescence. Detailed descriptions of osteosarcoma incidence and survival specifically, with direct comparisons among subjects of all ages and ethnicities, are not available.
1,723 citations
"Bone Formation Deregulations Are th..." refers background in this paper
...Even this therapeutic progress, the overall survival of the patients is now at a plateau of 70% (Le Deley et al., 2007; Mirabello et al., 2009)....
[...]
TL;DR: Rules of tissue architecture elucidated in bone morphogenesis may provide insights into tissue engineering and be universally applicable for all organs/tissues, including bones and joints.
Abstract: Morphogenesis is the developmental cascade of pattern formation and body plan establishment, culminating in the adult form. It has formed the basis for the emerging discipline of tissue engineering, which uses principles of molecular developmental biology and morphogenesis gleaned through studies on inductive signals, responding stem cells, and the extracellular matrix to design and construct spare parts that restore function to the human body. Among the many organs in the body, bone has considerable powers for regeneration and is a prototype model for tissue engineering. Implantation of demineralized bone matrix into subcutaneous sites results in local bone induction. This model mimics sequential limb morphogenesis and has permitted the isolation of bone morphogens, such as bone morphogenetic proteins (BMPs), from demineralized adult bone matrix. BMPs initiate, promote, and maintain chondrogenesis and osteogenesis, but are also involved in the morphogenesis of organs other than bone. The symbiosis of the mechanisms underlying bone induction and differentiation is critical for tissue engineering and is governed by both biomechanics (physical forces) and context (microenvironment/extracellular matrix), which can be duplicated by biomimetic biomaterials such as collagens, hydroxyapatite, proteoglycans, and cell adhesion glycoproteins, including fibronectins and laminin. Rules of tissue architecture elucidated in bone morphogenesis may provide insights into tissue engineering and be universally applicable for all organs/tissues, including bones and joints.
830 citations
Additional excerpts
...The osteogenic BMPs include 2, 4, 6, 7 and 9 (Deng et al., 2008; Tang et al., 2008; Reddi, 1998)....
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TL;DR: Molecular communication between osteoclasts and osteoblasts at distinct phases of bone remodeling are described and bidirectional signaling generated by interaction between ephrinB2 on osteoclast and EphB4 on osteoblast precursors facilitates the transition.
668 citations
Additional excerpts
...(Matsuo and Irie, 2008)....
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TL;DR: The authors review the state of the art management for patients with osteosarcoma in North America and Europe including the use of limb-salvage procedures and reconstruction as well as discuss the etiologic and biologic factors associated with tumor development.
Abstract: Osteosarcoma is the most common malignant bone tumor in children and adolescents. Survival for these patients was poor with the use of surgery and/or radiotherapy. The introduction of multi-agent chemotherapy dramatically improved the outcome for these patients and the majority of modern series report 3-year disease-free survival of 60%-70%. This paper describes current strategies for treating patients with osteosarcoma as well as review of the clinical features, radiologic and diagnostic work-up, and pathology. The authors review the state of the art management for patients with osteosarcoma in North America and Europe including the use of limb-salvage procedures and reconstruction as well as discuss the etiologic and biologic factors associated with tumor development. Therapy-related sequelae and future directions in the biology and therapy for these patients are also discussed.
631 citations
"Bone Formation Deregulations Are th..." refers background in this paper
...During adolescence, the kids are having their puberty development and the long bones are growing then particularly fast, with a rapid cell turnover in and around the growth plate (Mathew et al., 2011; Marina et al., 2004)....
[...]
TL;DR: The structure, function, and inhibition of chemokines are discussed, which results in, among other functions, the migration of inflammatory and noninflammatory cells to the appropriate tissues or compartments within tissues.
Abstract: Chemokines are the largest family of cytokines in human immunophysiology. These proteins are defined by four invariant cysteines and are categorized based on the sequence around the first two cysteines, which leads to two major and two minor subfamilies. Chemokines function by activating specific G protein–coupled receptors, which results in, among other functions, the migration of inflammatory and noninflammatory cells to the appropriate tissues or compartments within tissues. Some of these proteins and receptors have been implicated or shown to be involved in inflammation, autoimmune diseases, and infection by HIV-1. The three-dimensional structure of each monomer is virtually identical, but the quaternary structure of chemokines is different for each subfamily. Structure-function studies reveal several regions of chemokines to be involved in function, with the N-terminal region playing a dominant role. A number of proteins and small-molecule antagonists have been identified that inhibit chemokine activ...
611 citations