Abstract
Osteosarcoma (OS) is the most frequent primary bone cancer in children and adolescents and the third most frequent in adults. Many inherited germline mutations are responsible for syndromes that predispose to osteosarcomas including Li Fraumeni syndrome, retinoblastoma syndrome, Werner syndrome, Bloom syndrome or Diamond–Blackfan anemia. TP53 is the most frequently altered gene in osteosarcoma. Among other genes mutated in more than 10% of OS cases, c-Myc plays a role in OS development and promotes cell invasion by activating MEK–ERK pathways. Several genomic studies showed frequent alterations in the RB gene in pediatric OS patients. Osteosarcoma driver mutations have been reported in NOTCH1, FOS, NF2, WIF1, BRCA2, APC, PTCH1 and PRKAR1A genes. Some miRNAs such as miR-21, -34a, -143, -148a, -195a, -199a-3p and -382 regulate the pathogenic activity of MAPK and PI3K/Akt-signaling pathways in osteosarcoma. CD133+ osteosarcoma cells have been shown to exhibit stem-like gene expression and can be tumor-initiating cells and play a role in metastasis and development of drug resistance. Although currently osteosarcoma treatment is based on adriamycin chemoregimens and surgery, there are several potential targeted therapies in development. First of all, activity and safety of cabozantinib in osteosarcoma were studied, as well as sorafenib and pazopanib. Finally, novel bifunctional molecules, of potential imaging and osteosarcoma targeting applications may be used in the future.
Highlights
Primary bone cancers are a group of rare neoplasms responsible for 3–5% of pediatric cancers and nearly 0.2% of all malignant neoplasms [1]
Children and adolescents suffering from genetic syndromes such as Li–Fraumeni, hereditary retinoblastoma, Rothmund–Thomson, Bloom or Werner syndrome are more prone to developing OS [4,6]
A number of inherited germline mutations are responsible for syndromes that predispose to some neoplasms, including osteosarcomas
Summary
Primary bone cancers are a group of rare neoplasms responsible for 3–5% of pediatric cancers and nearly 0.2% of all malignant neoplasms [1]. The second peak of osteosarcoma in older patients is related to higher risk of Paget’s disease of bone (PDB) and increased bone resorption by osteoclasts. OS is a primary malignant neoplasm of the skeleton, affecting mostly the long bones, where sarcoma cells form immature bone or osteoid tissue. It can be divided into subtypes depending on the tumor’s features and predominant stromal differentiation (osteoblastic, fibroblastic, chondroblastic, small-cell, telangiectatic high-grade surface and extraskeletal). Despite numerous attempts with different chemotherapy regimens for the past 20 years, survival rates remain essentially unchanged and no successful targeted therapies have been developed for osteosarcoma so far [11,14,15]. As a neoplasm with numerous chromosomal abnormalities and mutations, OS appears to be a tumor that could potentially respond to immunotherapy
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