Sarcomas are a group of heterogeneous tumours with varying genetic basis. Cytogenetic abnormalities range from distinct genomic rearrangements such as pathognomonic translocation events and common chromosomal amplification or loss, to more complex rearrangements involving multiple chromosomes. The different subtypes of liposarcoma are spread across this spectrum and constitute an interesting tumour type for molecular review. This paper will outline molecular pathogenesis of the three main subtypes of liposarcoma: well-differentiated/dedifferentiated, myxoid/round cell, and pleomorphic liposarcoma. Both the molecular basis and future avenues for therapeutic intervention will be discussed.
An estimated 13,000 people were diagnosed with soft tissue and bone sarcoma in 2009 in America, of which liposarcomas constitute 20% [
Treatment is multimodal with surgical removal and radiotherapy used as cornerstones for local control, along with chemotherapy for systemic disease. Few therapeutic options are available for aggressive local or metastatic disease. Chemotherapy sensitivity varies considerably between subtypes with higher response rates in MLPS compared with WD/DDLPS (48% versus 11%) [
A recent histological and molecular review of 163 liposarcoma and lipomas at the Netherlands Cancer Institute resulted in 23% of tumours being reclassified based on cytogenetic information. This highlights the importance of molecular classification in these tumours and genetic alterations now considered an integral part of the WHO classification [
WDLPS represents 40%–45% of all diagnosis of liposarcoma [
DDLPS represents progression from low grade to high-grade nonlipogenic morphology within a WDLPS. DDLPS is more aggressive and exhibits an increased rapidity of disease in contrast to WDLPS, with a metastatic rate of 10%–20% and overall mortality of 50%–75% [
A characteristic feature of WD/DDLPS is the presence of supernumerary ring and/or giant rod chromosomes [
MDM2 binds to the transcriptional activation domain of p53, blocking transcription. MDM2 functions as a ubiquitin ligase, facilitating proteasomal degradation of p53. MDM2 releases p53 in response to cellular stress and p53 translocates to the nucleus where it acts as a transcription factor to enable growth arrest and apoptosis.
Cyclin dependent kinase CDK4 binds with cyclin D to form active complexes. This results in phosphorylation of Rb and dissociates pRb from the pRb-E2F complex. E2F binds DNA to upregulate transcription of genes required to progress to S phase.
Recent studies into the WDLPS de-differentiation process have suggested a role for the c-Jun N-terminal kinase (JNK) pathway. Co-amplification of 1p32 and 6q23, that contain c-Jun, and Apoptosis Signaling Kinase 1 (ASK1), are seen in DDLPS but not WDLPS [
MLPS is the second most common subtype of liposarcoma and accounts for more than one third of liposarcomas and 10% of all adult soft tissue sarcomas. MLPS is characterized by the presence of spindle or ovoid cells set in a myxoid stroma with signet ring lipoblasts and a distinctive chicken-wire pattern vasculature. The presence of areas with greater cellularity, known as round cell (RC) de-differentiation, is associated with a worse prognosis [
MLPS is characterised by the recurrent translocation t(12;16)(q13;p11) that results in the
There are currently 11 different
FUS belongs to the FET family of RNA-binding proteins that consists of FUS, EWS, and TAF15 as well as the closely homologous, Drosophila SARFH (Cab) [
Both FUS and EWS have been shown to localize to the nucleus and the cytoplasm, bind RNA, and are also involved in nucleo-cytoplasmic shuttling [
CHOP is induced in response to endoplasmic reticular stress and is involved in mediating cell death in response to such stress stimuli [
As C/EBP
An emerging clinically relevant targetable pathway in MLPS involves the receptor tyrosine kinases (RTKs) MET, RET, and the PI3K signaling cascade (see Figure
The PI3K pathway is highly active in MLPS, and this is potentiated at least in part by overexpression, and/or activation through RTKs such as MET, RET and VEGFRs. Upon ligand binding, RTKs activate downstream activation of genes involved in multiple cell processes such as cell survival, proliferation, and angiogenesis. These signals are mediated through the PI3K/Akt pathway and also through RAS. PIK3CA and PTEN mutations and Akt activation have also been documented in MLPS.
Akt activation, particularly in the RC variant, suggests a role for phosphoinositide 3-kinases (PI3K) [
PLPS accounts for only 5% of liposarcomas and occurs mainly within the 55–65 year-old group [
Molecular studies of PLPS are limited by the scarcity of this disease. Tumours tend to show complex arrangements including gains: 1p, 1q21-q32,2q, 3p, 3q, 5p12-p15, 5q, 6p21, 7p, 7q22 (see reviews) [
The current modalities available (chemotherapy, surgery and radiotherapy) for the treatment of liposarcoma are limited, creating a need to identify novel therapeutics.
Given MDM2 is consistently amplified in WD/DDLPS, and sensitivity to MDM2 antagonists (such as Nutlin-3a) is predicted by MDM2 amplification and an intact wild-type
Translation from
Two oral MDM2 inhibitors have recently entered the clinical setting [
Targeting CDK4 is an attractive therapeutic strategy given its frequent overexpression in WD/DDLPS [
Newer generation CDK inhibitors include PD0332991, P27600, ZK 304709, R 547 and P1446A05. All are available in Phase I and II solid tumour trials [
A critical regulator of terminal differentiation for the adipocytic lineage is a nuclear receptor peroxisome proliferator-activated receptor
A Dana-Farber Cancer Institute Phase II clinical trial used Troglitazone, a synthetic PPAR
Trabectedin (also known as Ecteinascidin or ET-743) is an antitumor drug isolated from the Caribbean marine tunicate, Ecteinascidia turbinata [
Trabectedin relies on intact nucleotide excision repair (NER) machinery and induces lethal DNA strand breaks in a transcription-couple NER dependant manner [
FUS-CHOP modulates immune genes by activating NF-
The high frequency of
As MET is activated in MLPS and there are many MET pathway inhibitors currently in development and in clinical trials (as reviewed in [
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 tumour (GIST) [
It is hoped that emerging technologies, such as next-generation sequencing, will be fundamental in revealing new molecular targets in liposarcoma. Similarly, advances in drug development should enable improvement of molecular therapies with greater sensitivity, specificity, potency, and limited toxicity. Combining technologies in both areas will allow for efficient clinical translation.
No potential conflict of interest is disclosed.
The authors acknowledge Dr. Maya Kansara and Dale Garsed for reviewing the manuscript and Dr. Catherine Mitchell for reviewing the histopathology. D. M. Thomas is a recipient of a Victorian Cancer Agency clinician scientist fellowship. S. Young is a recipient of an Australian Postgraduate Award. R. Conyers is a recipient of an NHMRC Postgraduate Scholarship. R. Conyers and S. Young contributed equally to this work.