Abstract
Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor arising from vascular endothelial cells. This study delves into the molecular mechanisms underlying EHE, with a specific focus on the Hippo-YAP/TAZ pathway. EHE is characterized molecularly by transcriptional co-activator with a PDZ-motif (TAZ)-calmodulin binding transcription activator 1 (CAMTA1) or Yes-associated protein (YAP)-transcription factor E3 (TFE3) fusions. YAP/TAZ, a transcription co-activator, binds to transcription factors and regulates gene expression. The YAP/TAZ and its upstream Hippo pathway are involved in cell proliferation and cell contact inhibition, regulating organ size and carcinogenesis. In addition to oncogenic effects, dysfunction or gene duplication of the Hippo pathway results in a poor prognosis due to epithelial-mesenchymal transformation of epithelial cells, stem cell transformation, and increased drug resistance. Notably, the TAZ-CAMTA1 fusion is specific to EHE, and genetic alterations in the Hippo pathway other than this fusion gene are absent in EHE. The TAZ-CAMTA1 fusion is a promising therapeutic target. This review summarizes recent advances in EHE, focusing on the role of the Hippo-YAP/TAZ pathway in EHE and its potential as a therapeutic target for drug development.
Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor arising from vascular endothelial cells (1). Weiss and Enzinger named it “epithelioid hemangioendothelioma” in 1982 due to its similarities with hemangiomas and angiosarcomas (2). EHE is a low-grade sarcoma that can occur anywhere in the body and metastasizes to the liver and lungs in more than 50% of cases (3, 4).
This unique sarcoma is characterized molecularly by transcriptional co-activator with a PDZ-motif (TAZ)-calmodulin binding transcription activator 1 (CAMTA1) or Yes-associated protein (YAP)-transcription factor E3 (TFE3) fusions (5, 6) (Figure 1 and Figure 2). YAP/TAZ, a transcription co-activator, binds to transcription factors and regulates gene expression. YAP/TAZ is phosphorylated and inactivated by the upstream Hippo pathway (7). The Hippo-YAP/TAZ pathway is involved in cell proliferation and cell contact inhibition and regulates organ size and carcinogenesis (8-10).
Schematic representation of wild-type TAZ, YAP, CAMTA1, and TFE3. TAZ: Transcriptional co-activator with a PDZ-motif; YAP: Yes-associated protein; CAMTA1: calmodulin binding transcription activator 1; TFE3: transcription factor E3; TEAD: transcriptional enhanced associated domain; WW: WW domain; TAD: transactivation domain; PDZ: postsynaptic density-95/Discs large/Zonula occludens 1; TIG: transcription-factor immunoglobulin domain; ANK: ankyrin repeats; IQ: IQ calmodulin-binding motifs; NLS: nuclear-localization signal; bHLH: basic helix–loop–helix domain; LZ: leucine-zipper domain.
Schematic of TAZ-CAMTA1 and YAP-TFE3 fusions. TAZ: Transcriptional co-activator with a PDZ-motif; CAMTA1: calmodulin binding transcription activator 1; YAP: Yes-associated protein; TFE3: transcription factor E3; TEAD: transcriptional enhanced associated domain; WW: WW domain; TAD: transactivation domain; TIG: transcription-factor immunoglobulin domain; ANK: ankyrin repeats; IQ: IQ calmodulin-binding motifs; NLS: nuclear-localization signal; bHLH: basic helix–loop–helix domain; LZ: leucine-zipper domain.
Nuclear translocation of YAP and its paralog, TAZ, occurs when the Hippo signal is disabled. YAP/TAZ interacts with the transcriptional enhanced associated domain (TEAD) family of transcription factors in the nucleus and functions as a transcriptional co-activator of TEAD, inducing TEAD-dependent genes involved in cellular survival and repair programs. Increased cell density activates a serine/threonine kinase cascade involving mammalian Ste20-like kinases (MST) 1/2 and large tumor suppressor kinases (LATS) 1/2, leading to YAP/TAZ activation (11-13).
In human cancers, Hippo pathway dysfunction or gene duplication results in increased activity, leading to poor prognosis due to increased epithelial-mesenchymal transition, stem cell transformation, and drug resistance, making it a novel therapeutic target (14-18). Loss of Hippo pathway activity or forced activation of YAP or TAZ has been shown to promote the formation and progression of sarcomas other than EHE (19, 20). Notably, the TAZ-CAMTA1 fusion is specific to EHE, and EHE lacks other genetic alterations in the Hippo pathway frequently observed in other malignancies.
In this review, we summarize recent advances, focusing on the role of the Hippo-YAP/TAZ pathway in EHE and drug development as a therapeutic target.
Etiology and Clinicopathological Features of EHE
Etiology. The incidence of EHE is extremely rare, at 0.038 per million persons per year (21). EHE occurs more frequently in women than in men, generally reaching its peak incidence around the age of 40 years (22).
Clinical features. The clinical course of EHE is less aggressive than angiosarcoma but more aggressive than hemangiomas. EHE is a malignant endothelioma that can occur anywhere in the body, with approximately 30% of cases occurring as pulmonary EHE (1, 22). Other reported sites of involvement include the liver (21%), liver and lung (18%), lung alone (12%), and bone alone (14%) (1). The clinical presentation and prognosis of EHE depend on the primary site. Primary lung and liver EHE often present as multifocal lesions, with two or more sites in the same organ. Common symptoms of pulmonary EHE include chest pain (29%), shortness of breath (16%), hemoptysis (13%), and cough (12%) (23). As hepatic EHE progresses, it may result in right upper quadrant pain, Budd-Chiari syndrome, portal hypertension, jaundice, or liver failure (24). Approximately 80% of hepatic EHE occurs as a multifocal disease (25). In contrast, soft-tissue EHEs metastasize at a rate of approximately 20% and are responsible for 17% of patient deaths (26).
Prognosis. The prognosis of EHE is variable, with some cases having an indolent clinical course and others being prone to metastasis. Risk factors for a worse prognosis include increased mitotic activity and tumor size. The 5-year disease-specific survival rate for 49 patients with EHE was 81%, while it was 59% for high-risk patients (>3 mitotic figures/50 high-power fields, and a size >3 cm) (27).
Morphology. EHE has a distinctive mucous-watery stroma with occasional hemorrhagic foci and epithelial cells arranged in chains, cords, or rigid nests, often with vitreous-like acidophilic cytoplasm with cytoplasmic vacuoles. Rarely, in EHE, tumor cells may form a cribriform pattern similar to invasive carcinoma, but typically, low mitotic activity and mild nuclear atypia are observed (1, 28). EHE associated with YAP1-TFE3 fusion consists of epithelioid tumor cells with more abundant bright eosinophilic cytoplasm, often forming a robust growth pattern. In contrast, EHE associated with TAZ-CAMTA1 fusion does not exhibit these features (6).
Immunohistochemistry. EHE consistently displays endothelial differentiation markers, such as CD31, ERG, CD34, and FLI-1 when examined using immunohistochemistry (29, 30). CD34 is expressed in more than 90% of vascular tumors and is relatively sensitive but not very specific for EHE. In contrast, CD31 is a more specific vascular tumor marker than CD34 (31). Therefore, CD31 is considered diagnostic for EHE. Approximately 30-50% of patients with EHE show focally positive epithelial markers (27, 32).
Hippo-YAP/TAZ Pathway
The primary function of the Hippo pathway is to limit organ growth by inhibiting proliferation and promoting apoptosis (9). In the mammalian Hippo pathway, MST1/2 regulates LATS1/2 via phosphorylation (33). Activated LATS1/2 then interacts with the transcriptional cofactors YAP or TAZ through their PPxY motif in the WW domain (34). This physical contact allows LATS1/2 to repress YAP and TAZ by phosphorylating multiple HXRXXS amino acid motifs (12, 35). Phosphorylation of these motifs promotes the inactivation of YAP and TAZ through translocation and degradation from the nucleus to the cytoplasm (Figure 3).
Schematic representation of the Hippo pathway. The left panel illustrates the activation of the Hippo pathway by phosphorylated MST1/2 and LATS1/2. Phosphorylated YAP/TAZ remains in the cytoplasm after binding to 14-3-3 proteins and/or undergoing polyubiquitination and proteolysis. The right panel represents the inactivation of the Hippo pathway, where YAP/TAZ translocates to the nucleus, allowing it to bind to transcriptional enhanced associated domain (TEAD) cofactors and activate transcription. The red X denotes that cell proliferation is inhibited when the Hippo signal is ‘ON’ and apoptosis is inhibited when the Hippo signal is ‘OFF’. MST: Mammalian Ste20-like kinases; LATS: larger tumor suppressor; SAV1: Sav family containing protein 1; MOB1: MOB kinase activator 1; P: phosphorylation; U: ubiquitin.
The nuclear active form of YAP, first discovered by Marius Sudol (36), and its paralog, TAZ, are thought to exert their tumorigenic function primarily through the TEAD transcription factor (37). Specifically, YAP and TAZ recruit transcriptional repressors by derepressing and activating TEAD transcription factors (38). In addition, YAP and TAZ can coordinately regulate other transcription factors, including the Smad family and Tbx5 (39, 40).
Studies in mammals have demonstrated that upstream growth suppressor Hippo proteins and growth-promoting Hippo transcriptional regulators act as potential tumor suppressors and oncogenes, respectively. TAZ is crucial in early embryonic development, organogenesis, determining organ size, and tissue repair (7, 10, 41). CAMTA1 encodes a transcription factor that acts as a tumor suppressor in neuroblastoma (42). This gene is primarily expressed in the human brain, with its functions largely remaining unclear. Research indicates CAMTA1’s involvement in memory and behavior (43, 44).
Aberrant activation of TAZ transcription and loss of the Hippo pathway contribute to the development and progression of many cancer types (10, 15, 45). Studies have shown that loss of Hippo pathway activity or aberrant activation of YAP or TAZ is also observed in sarcomas, promoting sarcoma formation and progression (20). However, among the genetic alterations in the Hippo-YAP/TAZ pathway, only EHE shows the WWTR1-CAMTA1 fusion. This indicates that EHE is more specific than other cancers and has the potential to be a valid therapeutic target.
Development of Targeted Therapies
As a promising therapeutic strategy, the precise targeting and inhibition of disease-specific fusion genes such as WWTR1-CAMTA1 and YAP-TFE3 are conceivable. However, this approach has not yet become feasible. Currently, the main method focuses on targeting the YAP/TAZ-TEAD interaction. The TAZ-CAMTA1 fusion protein acts as a transcriptional co-activator that interacts with the TEAD family of transcription factors, altering transcription dependent on TEAD activity. Thus, designing small molecules to inhibit the interaction between the TAZ-CAMTA1 fusion protein and TEAD can strongly suppress the transcriptional activity of the entire complex. Since the TAZ-CAMTA1 fusion protein largely mimics the action mechanism of YAP/TAZ, it can be inhibited using TEAD inhibitors or YAP/TAZ-TEAD inhibitors (46, 47).
TEAD Inhibitors
Their palmitoylation is necessary for the interaction between TEAD proteins and YAP or TAZ (48, 49). VT3989 is one of many small molecules designed to block the palmitoylation of TEAD, thereby inhibiting the interaction between YAP and TEAD necessary for transcriptional regulation. In a phase I trial (ClinicalTrials.gov ID: NCT04665206), the orally administered YAP-TEAD inhibitor VT3989 demonstrated safety, tolerability, and sustained antitumor effects in patients with advanced malignant mesothelioma and solid tumors harboring neurofibromatosis type 2 (NF2) mutations. These results were reported by Yap et al. from the MD Anderson Cancer Center at the American Association for Cancer Research Annual Meeting 2023, marking the first clinical trial results using small molecules targeting post-translational modifications necessary for YAP/TAZ-TEAD interaction. Additionally, Shen et al. reported that BPI-460372, which irreversibly inhibits TEAD palmitoylation through covalent binding, suppresses the expression of major YAP/TAZ-TEAD target genes such as CTGF and CYR61, as well as the TEAD reporter gene (ClinicalTrials.gov ID: NCT05789602). Similarly, clinical trials for the pan-TEAD inhibitor SW-682 are ongoing (ClinicalTrials.gov ID: NCT06251310). Ikena Oncology (Boston, MA, USA) developed IK-930, a tailor-made molecule specific to TEAD that is expected to enhance antitumor activity (ClinicalTrials.gov ID: NCT05228015). The orally administered YAP/TEAD inhibitor IAG933 inhibits the interaction of YAP and TEAD (50). Clinical trials are underway for tumors with dysregulated Hippo-YAP/TAZ-TEAD pathways, including mesothelioma, NF2, LATS1/2 mutant tumors, and functional YAP/TAZ fusion tumors (ClinicalTrials.gov ID: NCT04857372) (Table I).
Current transcriptional enhanced associated domain (TEAD) inhibitors in clinical trials.
Conclusion
YAP/TAZ plays a crucial role as an oncogenic driver in tumor formation, including EHE. Generally, YAP/TAZ is considered challenging to target with drugs; therefore, therapeutic approaches focus on its cofactor TEAD, advancing drug development. Drugs targeting upstream factors, such as LATS1/2, as well as combination therapies, are expected to be further developed.
Acknowledgements
The Author would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Conflicts of Interest
The Author declares no conflicts of interest in relation to this study.
Funding
This research received no external funding.
- Received July 13, 2024.
- Revision received July 31, 2024.
- Accepted August 1, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
