Abstract
Epithelioid hemangioendothelioma (EHE) is a rare soft-tissue sarcoma involving cells with histologic markers that suggest an endothelial origin. Around 90% of EHEs are caused by the fusion of Transcriptional Co-activator with a PDZ-motif (TAZ) with Calmodulin Binding Transcription Activator 1 (CAMTA1), a central nervous system-specific transcription activator. The 10% of EHEs that lack the TAZ–CAMTA1 fusion instead have a fusion of Yes-associated Protein (YAP) and Transcription Factor E3 (TFE3) genes (YAP-TFE3). YAP and TAZ are well-defined downstream effectors in the Hippo pathway that promote cell growth when translocated to the nucleus. The TAZ–CAMTA1 fusion transcript is insensitive to the Hippo inhibitory signals that normally prevent this process and thus constitutively activates the TAZ transcriptome. In EHE, this causes tumors to form in a variety of organs and tissue types, most commonly the liver, lung, and bone. Its clinical course is unpredictable and highly variable. TAZ activation is known to contribute to key aspects of the cancer phenotype, including metastasis and fibrosis, and increased expression of TAZ is thought to be causally related to the progression of many cancers, including breast, lung, and liver. Therefore, understanding TAZ biology and the molecular mechanisms by which it promotes unregulated cell proliferation will yield insights and possibly improved treatments for both EHE as well as much more common cancers.
Highlights
Experiments of nature are spontaneous phenomena that offer insights into otherwise mechanistically opaque events
Widespread cancer generally means aggressive disease and is correlated with limited life expectancy. This is not the case in EHE where the disease can be both widespread and dormant for years. This unusual feature, and the uncoupling of metastasis from adverse clinical outcomes, suggests that EHE might serve as a model for the cancer phenotype related uniquely to Transcriptional Co-activator with a PDZ-motif (TAZ) activation since patients with disseminated disease can survive for long periods without the co-morbidities that confound outcome studies of most cancers
An interesting rationale for using mTOR inhibitors in EHE is found in the report of Hansen et al [92] showing that Yes-associated Protein (YAP)/TAZ induces expression of the high affinity leucine transporter (LAT1), which increases the uptake of leucine, an activator of mTORC1 that can lead to cellular proliferation
Summary
Experiments of nature are spontaneous phenomena that offer insights into otherwise mechanistically opaque events. This is not the case in EHE where the disease can be both widespread and dormant for years This unusual feature, and the uncoupling of metastasis from adverse clinical outcomes, suggests that EHE might serve as a model for the cancer phenotype related uniquely to TAZ activation since patients with disseminated disease can survive for long periods without the co-morbidities that confound outcome studies of most cancers. This particular correlation of molecular to clinical phenotypes makes studying EHE a valuable model for dissecting and understanding the complex biology of TAZ in common cancers and EHE alike independent of the generally adverse effects of metastasis. TAZ-specific aspects of the malignant phenotype, thereby improving the lives of patients with EHE and, potentially, other more common cancers
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