Epithelioid hemangioendothelioma (EHE)

Gene fusion and EHE

Epithelioid hemangioendothelioma (EHE) is a rare cancer which arises from the cells lining the blood vessels (endothelial cells). This occurs when two genes fuse together. Generally, there are several different gene fusions which lead to cancer, predominantly in prostate, ovarian, blood, and sarcomas (soft tissue cancer). These arise from two genes which bind together to create a fusion oncogene, such as the classical example of the BCR-ABL1 fusion gene, called the “Philadelphia chromosome,” in chronic myeloid leukaemia. EHE is a rare vascular sarcoma caused by a fusion between two genes, primarily TAZ and CAMTA1. TAZ is part of the Hippo signalling pathway (see below) and is a transcriptional co-activator (it binds to a transcription factor to activate the first step in gene expression, which is the conversion of DNA to RNA). Less is known about CAMTA1, although it is a transcription activator found primarily in the brain. However, there are also a small number of cases (10%) caused by a YAP1-TFE3 fusion. YAP1 is also part of the Hippo pathway, whilst TFE3 is a transcription factor. EHE is a prime example of the importance of gene fusions (and other chromosomal rearrangements) in the genetic origin of many cancers. Therefore, further understanding of this disease may provide clues into the tumourigenesis of other different cancers.

EHE is extremely rare at a prevalence of 1 in 1 million and presents more often in females, but it can occur in either sex at any age. It is most common in the liver and lung and has an unusual pathology, as it can present as an aggressive or indolent (slow-growing) cancer. Similarly to many cancers, symptoms can present as any or all the following: a mass, fever, fatigue, pain, and weight loss. It may also have no symptoms and be highlighted by chance whilst undergoing other investigations.

Cellular signalling behind EHE: the Hippo pathway

The Hippo pathway controls tissue growth and is the signalling mechanism behind EHE. YAP/TAZ are vital members of this pathway and are oncogenic transcription (co-) factors in many solid tumours. They have also been shown to be crucial for cancer initiation, progression, and metastasis. However, surprisingly, certain blood cancers, such as leukaemia, myeloma, and lymphoma, show reduced levels of YAP/TAZ. Therefore, it seems YAP/TAZ behave differently depending on cell type. High expression of YAP/TAZ (or nuclear localization) is related to poor prognosis in breast, colorectal, liver, lung, gastric, pancreatic, ovarian, endometrial, oesophageal, and bladder cancers.

YAP/TAZ are phosphorylated and degraded in the cytoplasm when the Hippo pathway is ‘on.’ However, when the Hippo pathway is ‘off,’ YAP/TAZ move to the nucleus, where they are involved in transcription (see the signalling pathway diagram). However, in EHE disease, even when Hippo is ‘on,’ TAZ-CAMTA1/YAP1-TFE3 override this and move to the nucleus to be involved in aberrant (atypical) transcription. YAP/TAZ bind to TEAD (DNA-binding domain) in the nucleus, whilst CAMTA1 and TFE3 are thought to be involved in chromatin remodelling. Chromatin consists of tightly packed DNA and histones (proteins). Chromatin remodelling results in the chromatin unwinding and the DNA becoming more accessible for transcription (i.e. ‘switching on’ certain genes). Therefore, this may lead to overexpression and subsequently, cancer. 

EHE treatment

There are no standard treatments for EHE, but indolent cancers are often treated by monitoring, a ‘watch-and-wait’ strategy. Surgery is a common form of treatment for single tumours. Ablation (burning/freezing), isolated limb perfusion (drug treatment to one limb), vascular embolization (blocking tumour blood supply), and radiation therapy are also other forms of possible treatment, along with the mammalian target of rapamycin (mTOR) inhibitors (the mTOR pathway controls cell proliferation/metabolism). Tyrosine kinase inhibitors (tyrosine kinases activate proteins in related pathways) and interferon (immune system modulators) are two other possible treatments. A transplant could also be an option if there is an organ with multiple tumours (most often the liver). However, more effective treatments are needed and research into this disease is currently underway. 

Summary

EHE is a rare cancer which arises from the cells lining the blood vessels. It occurs from gene fusions, primarily TAZ-CAMTA1. TAZ is part of the Hippo signalling pathway, which controls tissue growth. Therefore, Hippo is a vital pathway involved in many cancers, and understanding this pathway in EHE disease may provide clues as to the tumourigenesis of other cancers.

Written by Eleanor R. Markham

Related article: The Hippo signalling pathway / Apocrine carcinoma (a rare form of breast cancer)