Review of Osteosarcoma and Current Management

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Abstract

Osteosarcoma is the most common primary malignancy of bone in children and young adults. This tumor has a very heterogeneous genetic profile and lacks any consistent unifying event that leads to the pathogenesis of osteosarcoma. In this review, some of the important genetic events involved in osteosarcoma will be highlighted. Additionally, the clinical diagnosis of osteosarcoma will be discussed, as well as contemporary chemotherapeutic and surgical management of this tumor. Finally, the review will discuss some of the novel approaches to treating this disease.

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Most cited references 104

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Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS).

Beate Kempf-Bielack, Stefan S. Bielack, Heribert Jürgens … (2005)

To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma. Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients). After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy. Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.

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Src kinases as therapeutic targets for cancer.

Lori C Kim, Lanxi Song, Eric B. Haura (2009)

Src family kinases (SFKs) have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. SFKs comprise nine family members that share similar structure and function. Overexpression or high activation of SFKs occurs frequently in tumor tissues and they are central mediators in multiple signaling pathways that are important in oncogenesis. SFKs can interact with tyrosine kinase receptors, such as EGFR and the VEGF receptor. SFKs can affect cell proliferation via the Ras/ERK/MAPK pathway and can regulate gene expression via transcription factors such as STAT molecules. SFKs can also affect cell adhesion and migration via interaction with integrins, actins, GTPase-activating proteins, scaffold proteins, such as p130(CAS) and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs can regulate angiogenesis via gene expression of angiogenic growth factors, such as fibroblast growth factor, VEGF, and interleukin 8. On the basis of these important findings, small-molecule SFK inhibitors have been developed and are undergoing early phase clinical testing. In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers.

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Transcriptional regulation by p53.

Rachel Beckerman, Carol Prives (2010)

Inactivation of p53 is critical for the formation of most tumors. Illumination of the key function(s) of p53 protein in protecting cells from becoming cancerous is therefore a worthy goal. Arguably p53's most important function is to act as a transcription factor that directly regulates perhaps several hundred of the cell's RNA polymerase II (RNAP II)-transcribed genes, and indirectly regulates thousands of others. Indeed p53 is the most well studied mammalian transcription factor. The p53 tetramer binds to its response element where it can recruit diverse transcriptional coregulators such as histone modifying enzymes, chromatin remodeling factors, subunits of the mediator complex, and components of general transcription machinery and preinitiation complex (PIC) to modulate RNAPII activity at target loci (Laptenko and Prives 2006). The p53 transcriptional program is regulated in a stimulus-specific fashion (Murray-Zmijewski et al. 2008; Vousden and Prives 2009), whereby distinct subsets of p53 target genes are induced in response to different p53-activating agents, likely allowing cells to tailor their response to different types of stress. How p53 is able to discriminate between these different loci is the subject of intense research. Here, we describe key aspects of the fundamentals of p53-mediated transcriptional regulation and target gene promoter selectivity.

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Author and article information

Contributors

Hue H. Luu: hluu@bsd.uchicago.edu

Journal

Journal ID (nlm-ta): Rheumatol Ther

Journal ID (iso-abbrev): Rheumatol Ther

Title: Rheumatology and Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 2198-6576

ISSN (Electronic): 2198-6584

Publication date (Electronic): 19 October 2016

Publication date PMC-release: 19 October 2016

Publication date Collection: December 2016

Volume: 3

Issue: 2

Pages: 221-243

Affiliations

Department of Orthopaedic Surgery and Rehabilitation, University of Chicago, Chicago, IL USA

Article

Publisher ID: 46

DOI: 10.1007/s40744-016-0046-y

PMC ID: 5127970

PubMed ID: 27761754

SO-VID: 2f0fca7d-e221-4d41-bad2-8ed48a377eec

History

Date received : 5 August 2016

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Keywords: limb preservation surgery,osteosarcoma,review,targeted therapy

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Keywords: limb preservation surgery, osteosarcoma, review, targeted therapy

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Review of Osteosarcoma and Current Management

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Peer reviewer: gatekeeper or outdated?

Most cited references 104

Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS).

Src kinases as therapeutic targets for cancer.

Transcriptional regulation by p53.

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Cited by 158

Most referenced authors 1,460