Molecular Biology of Osteosarcoma

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.

miR-766-3p Targeting BCL9L Suppressed Tumorigenesis, Epithelial-Mesenchymal Transition, and Metastasis Through the β-Catenin Signaling Pathway in Osteosarcoma Cells

“…In the present study, miR-766-3p was lowly expressed in OS tissue specimens and cells, negatively related with OS malignancy, and might be used as a novel treating target for OS. Emerging research has demonstrated that the abnormal miRNA expression plays key regulatory role in OS progression (Czarnecka et al, 2020;Zhang H. et al, 2020), the potential mechanism of miR-766-3p has not been investigated. miR-766-3p has recently been recognized as a tumor suppressor through the β-catenin pathway in several tumors.…”

Use of Antiangiogenic Therapies in Pediatric Solid Tumors

“…Axitinib stabilized refractory osteosarcoma in two children [ 188 ], whereas pazopanib, despite good preclinical results [ 123 ], did not prevent progression [ 213 , 214 , 215 ]. Among MKIs, sorafenib stabilized the disease [ 213 , 216 ], maintaining a prolonged partial response during 51 months in a child with refractory osteosarcoma [ 217 ].…”

“…One of the best clinical responses obtained with antiangiogenics in osteosarcomas was using cabozantinib. The CABONE study, which included children and adults, showed that 37% of patients had a PFS at least 33% longer than when using other conventional therapies [ 215 ]. The only study published on imatinib showed no response, although it should be noted that the dose was lower than in other studies [ 141 , 167 ].…”

<p>Acacetin Induces Apoptosis in Human Osteosarcoma Cells by Modulation of ROS/JNK Activation</p>

“…1 The 5-year survival rate of OS has been greatly improved to approximately 60-70% due to the use of neoadjuvant chemotherapy in combination with surgery. 2 However, the long-term survival rate of patients has not been further improved in recent decades due to local relapse or early lung metastasis even after curative excision of the primary tumor and intensive chemotherapy. 3 Thus, novel pharmacological molecules or strategies for OS and the further elucidation of the underlying molecular mechanism are urgently needed to improve patient survival.…”