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Liposarcoma (LS) represents the single most common type of soft tissue neoplasm, representing an estimated 17–25% of all sarcomas. LPSs are classified according to World Health Organization into five types, 1) Atypical lipomatous tumors (ALT)/Well differentiated LPS (WDLPS); 2) De-differentiated LPS (DDLPS); 3) Myxoid LPS (MLPS); 4) Pleomorphic LPS (PLPS) and 5) Mixed-type LPS. Among these, WDLPS and DDLPS are the most frequent types occurring in 40-50% of all LPS cases and are characterized by the presence of supernumerary ring and/or giant marker chromosomes. Histologically, all subtypes simulate normal adipose tissue to some extent and have in common the presence of the malignant ‘‘lipoblast.’’ This is a primitive, neoplastic cell which is thought to arise from a stem cell progenitor. The major subtypes are not only histologically distinct but also they are each associated with slightly different patient prognosis and treatment regimen. Moreover, the most common subtypes of LS have a distinctive cytogenetic and molecular signature.
A characteristic feature of WD/DDLPS is the presence of giant rod chromosomes and/or supernumerary ring. These chromosomes contain amplified segments from the 12q13–15 region that can be identified with fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). Intensive research has identified several oncogenes residing in this region including CDK4, MDM2, HMGA2, CHOP, TSPAN31, OS1, OS9 and GLI1. The most compelling evidence to date demonstrates an oncogenic role in WD/DDLPS for CDK4, MDM2, HMGA2 and TSPAN31. Additional amplification events may also play a role in liposarcoma genesis, for instance, c-Jun in the de-differentiation process. MDM2 amplification is a crucial feature of WD/DDLPS and is amplified and overexpressed in many other cancers, highlighting its importance in tumorigenesis.
Furthermore, researchers analyzed LPS genomic landscape by SNP arrays, whole exome sequencing and targeted exome sequencing to uncover the genomic information for development of specific anti-cancer targets. SNP array analysis indicated known amplified genes (CDK4, MDM2, HMGA2) and important novel genes (UAP1, MIR557, LAMA4, CPM, IGF2, ERBB3, IGF1R). Carboxypeptidase M (CPM), recurrently amplified gene in well-differentiated/de-differentiated LPS was noted as a putative oncogene involved in the EGFR pathway. Significantly and recurrently mutated genes included PLEC, MXRA5, FAT3, NF1, MDC1, TP53 and CHEK2. In addition, in vitro and in vivo functional studies provided evidence for the tumor suppressor role for Neurofibromin 1 (NF1) gene in different subtypes of LPS. Pathway analysis of recurrent mutations demonstrated signaling through MAPK, ErbB, Wnt, JAK-STAT, axon guidance, apoptosis, DNA damage repair and cell cycle pathways were involved in liposarcomagenesis. In brief, these studies provide insight into the genomic complexity of LPS and highlight potential druggable pathways for targeted therapeutic approach.
Molecular-based therapeutics are not routinely used in liposarcoma, where surgery, radiotherapy, and chemotherapy remain the mainstay of treatment. Translation of targeted molecular therapeutics in sarcoma has been successfully demonstrated with Imatinib mesylate therapy in c-Kit positive gastrointestinal stromal tumor (GIST). A major challenge with the use of molecularly targeted therapeutics is to translate disease control into disease eradication. One strategy to achieve this goal is to combine two or more independent molecularly targeted agents in a disease where all of the targets are relevant. Recent studies point towards RTK involvement in MLPS oncogenesis, particularly signaling through the PI3K/Akt pathway. This provides an important approach for new research due to the large number of clinical trials currently underway that targets this pathway.
Creative Biogene, as a leading biotechnology company, is able to offer various liposarcoma pathway related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.