Current research and management of undifferentiated pleomorphic sarcoma/myofibrosarcoma

Abstract

Undifferentiated pleomorphic sarcoma (UPS), once termed as malignant fibrous histiocytoma, has always been diagnosed exclusively in clinical practice because it lacks any defined resemblance to normal mesenchymal tissue. Although myxofibrosarcoma (MFS) has been separated from UPS due to its fibroblastic differentiation with myxoid stroma, UPS and MFS are still identified as a sarcoma group in terms of molecular landscapes. In this review article, we will describe the associated genes and signaling pathways involved in the process of sarcoma genesis and make a summary of conventional management, targeted therapy, immunotherapy, and some novel potential treatments of UPS/MFS. With the progressive advancements in medical technology and a better understanding about the pathogenic mechanism of UPS/MFS in the coming decades, new lights will be shed on the successful management of UPS/MFS.

Keywords: myxofibrosarcoma; sarcomagenesis; signaling pathways; treatment; undifferentiated pleomorphic sarcoma.

FIGURE 1

Model summarizing the role of Skp2 and p16 in UPS/MFS. TP53 deficiency renders UPS/MFS cells dependent on Skp2 which survives sarcoma cells by degrading p21 and p27; p16 is an important regulator in cell cycle through interaction with cyclin-dependent kinases (CDK).

FIGURE 2

Working model of confluent network summarizing GPCR/Rho/ROCK, RTK/Ras/MAPK, TGFβ/YAP/NF-κB/mTOR, IGFR/PI3K/mTOR, and HGF/MET pathways in UPS/MFS. (A). The decoupling of miR-138 from RHO-ROCK adhesion pathway promotes UPS cell migration; (B). miR-152 downexpression disinhibits target genes production with receptor tyrosine kinase activity, and thus upregulates the downstream MAPK signaling; (C). Hepatocyte growth factor/MET (HGF/MET) pathway was aberrantly activated due to its receptor overexpression. (D). The significant secretion of TGFβ cytokine by tumor-infiltrating macrophages (TAMs) in the sarcoma microenvironment activates downstream signaling; (E). Yes-associated protein (YAP) is constitutively activated by upstream pathways including TGFβ pathway; (F). TAZ and YAP are normally inhibited by Hippo pathway or Angiomotin (AMOT), but unusually stable in UPS/MFS; (G). YAP activates mTOR signaling, exhibiting NF-κB independent effect of on autophagy; (H). YAP controls the expression of ubiquitin specific protein 31 (USP31), and thus phosphorylated NF-κB persistently suppresses the circadian clock activity, leading to cellular metabolism shift and unfold protein response (UPR) dysfunction; (I). Stabilized YAP and TGFβ signaling cooperatively regulate hyaluronan-mediated motility receptor (RHAMM/HMMR) expression, enhancing sarcomagenesis and distant metastasis; (J). The complex between transcriptional co-activator with PDZ-binding motif (TAZ) and YAP translocate into the nucleus and upregulate FOXM1 expression, which is pro-growth factor in UPS/MFS; (K). The transcriptional product of ITAG10 is associated with RICTOR which is subunit of rapamycin complex 2 (mTORC2); (L). ITAG10 encodes TRIO, and promote cell survival via RAC/PAK signaling; (M). PPP2R2B encoding product directly interacts with PDK1 and suppresses AKT/mTOR signaling in UPS/MFS.

FIGURE 3

A schematic imaging showing the potential involvement of pathways in the UPS/MFS. (A). The Hedgehog (Hh) and Notch signaling modulation are activated, and impose paracrine and autocrine effects on the sarcoma cells, maintaining mesenchymal stromal or stem cells in a less differentiated state. Pharmocological blockade by triparanol, cyclopamine and DAPT successfully inhibits Hh or Notch signaling. (B). Phosphorylated STAT3 dimer functions as transcriptional complex (TC) in the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Suppressor of cytokine signaling 3 (SOCS3) overexpression has an effect on STAT3 dephosphorylation. (C). Both Wnt2/β-catenin and Wnt5a/JNK non-canonical signaling inactivation inhibit developmental program in UPS/MFS. Wnt5a/JNK non-canonical signaling might be the upstream regulator of NF-κB signaling.