Heterogeneous Contributing Factors in MPM Disease Development and Progression: Biological Advances and Clinical Implications

Abstract

Malignant pleural mesothelioma (MPM) tumors are remarkably aggressive and most patients only survive for 5-12 months; irrespective of stage; after primary symptoms appear. Compounding matters is that MPM remains unresponsive to conventional standards of care; including radiation and chemotherapy. Currently; instead of relying on molecular signatures and histological typing; MPM treatment options are guided by clinical stage and patient characteristics because the mechanism of carcinogenesis has not been fully elucidated; although about 80% of cases can be linked to asbestos exposure. Several molecular pathways have been implicated in the MPM tumor microenvironment; such as angiogenesis; apoptosis; cell-cycle regulation and several growth factor-related pathways predicted to be amenable to therapeutic intervention. Furthermore, the availability of genomic data has improved our understanding of the pathobiology of MPM. The MPM genomic landscape is dominated by inactivating mutations in several tumor suppressor genes; such as CDKN2A; BAP1 and NF2. Given the complex heterogeneity of the tumor microenvironment in MPM; a better understanding of the interplay between stromal; endothelial and immune cells at the molecular level is required; to chaperone the development of improved personalized therapeutics. Many recent advances at the molecular level have been reported and several exciting new treatment options are under investigation. Here; we review the challenges and the most up-to-date biological advances in MPM pertaining to the molecular pathways implicated; progress at the genomic level; immunological progression of this fatal disease; and its link with developmental cell pathways; with an emphasis on prognostic and therapeutic treatment strategies.

Keywords: developmental cell pathways; immunotherapy; malignant pleural mesothelioma (MPM); molecular pathways; tumor microenvironment heterogeneity; tumor suppressors.

Figure 1

Heterogeneous contributing factors in MPM disease progression. (A) The MPM genomic landscape is dominated by frequent gene inactivation in CDKN2A, NF2 and BAP1. (B) Several stem cellular signaling pathways, such as Hedgehog (Hh), Wnt/β-catenin, Hippo/YAP and Notch have been implicated in MPM pathobiology. (1) Hh ligands (DH, IH, and HH) bind patched (PTCH1) to relive inhibition of Smoothened (SMO) and this activates the Hh signaling pathway, via transcriptional activation of glioma-associated protein (Gli) factors; in the inactive state, Gli3 gets degraded when suppressor of fused homolog (Sufu) is inhibited. (2) Protein-serine O-palmitoleoyltransferase porcupine (PORCN) is required for efficient binding of Wnt ligands to cell-surface Frizzled (Fzd) receptors and to LRP5/6 which signals to the Dishevelled (Dvl) proteins. This causes an accumulation of β-catenin in the cytoplasm, followed by nuclear translocation and activation of transcription factors. (3) Hippo signaling consists of a cascade of kinases, which ultimately phosphorylate and activate serine/threonine-protein kinase (LATS)1/2 to inhibit two major downstream effectors of the Hippo pathway—YAP and Tafazzin (TAZ)—to stymie signaling (protein degradation). However, in NF2-mutant tumors, NAE activates CRL4^DCAF1 and thus sustains tumor growth. (4) The Notch pathway can be activated by CK2α and when the Notch transmembrane receptors bind to a Notch ligand, a cascade of events promote gene transcription via γ secretase. Therapeutics (red) to target these pathway components have been developed for Smoothened (Vismodegib), Gli (GLI-I, GANT61), PORCN (LGK-974), NAE (MLN-4924) and CK2α (CX-4945 and CIGB-300). Arrows indicate interaction or activating effect and T-bars indicate inhibition. Green arrows indicate cross-talk between pathways.