Order results

Result details

Select all

Export citation of selected articles as:

Research

Jump to: Review

15 pages, 11157 KiB

Open AccessArticle

PD-L1 and HIF-2α Upregulation in Head and Neck Paragangliomas after Embolization

by Alessa Fischer, Umberto Maccio, Katharina Wang, Juliane Friemel, Martina A. Broglie Daeppen, Diana Vetter, Kuno Lehmann, Astrid Reul, Mercedes Robledo, Constanze Hantel, Nicole Bechmann, Karel Pacak, Kathrin Zitzmann, Christoph J. Auernhammer, Ashley B. Grossman, Felix Beuschlein and Svenja Nölting

Cancers 2023, 15(21), 5199; https://doi.org/10.3390/cancers15215199 - 29 Oct 2023

Viewed by 936

Abstract

Hypoxia activates pathways associated with tumor progression, metastatic spread, and alterations in the immune microenvironment leading to an immunosuppressive phenotype. In particular, the upregulation of PD-L1, a target for therapy with checkpoint inhibitors, is well-studied in several tumors. However, the relationship between hypoxia and PD-L1 regulation in pheochromocytomas and paragangliomas (PPGL), and especially in paragangliomas treated with embolization, is still largely unexplored. We investigated the expression of the hypoxia-marker HIF-2α and of PD-L1 in a PPGL-cohort with and without embolization as potential biomarkers that may predict the response to treatment with HIF-2α and checkpoint inhibitors. A total of 29 tumor samples from 25 patients who were operated at a single center were included and analyzed utilizing immunohistochemistry (IHC) for PD-L1 and HIF-2α. Embolization prior to surgery was performed in seven (24%) tumors. PD-L1 expression in tumor cells of head and neck paragangliomas (HNPGLs) receiving prior embolization (median PD-L1 positivity: 15%) was significantly higher as compared to PD-L1 expression in HNPGLs without prior embolization (median PD-L1 positivity: 0%) (p = 0.008). Consistently, significantly more HNPGLs with prior embolization were positive for HIF-2α (median nuclear HIF-2α positivity: 40%) as compared to HNPGLs without prior embolization (median nuclear HIF-2α positivity: 0%) (p = 0.016). Our results support the hypothesis that embolization with subsequent hypoxia leads to the upregulation of both PD-L1 and HIF-2α in HNPGLs, and could thus facilitate targeted treatment with HIF-2α and checkpoint inhibitors in the case of inoperable, locally advanced, or metastatic disease. Full article

(This article belongs to the Special Issue Cancers Driven by HIF)

► Show Figures

Graphical abstract

18 pages, 3154 KiB

Open AccessArticle

HDAC8 Deacetylates HIF-1α and Enhances Its Protein Stability to Promote Tumor Growth and Migration in Melanoma

by Ji Yoon Kim, Hayoung Cho, Jung Yoo, Go Woon Kim, Yu Hyun Jeon, Sang Wu Lee and So Hee Kwon

Cancers 2023, 15(4), 1123; https://doi.org/10.3390/cancers15041123 - 09 Feb 2023

Cited by 7 | Viewed by 1833

Abstract

Melanoma is the most lethal type of skin cancer, and it causes more than 55,000 deaths annually. Although regional melanoma can be surgically removed, once melanoma metastasizes to other regions of the body, the survival rate drops dramatically. The current treatment options are chemotherapy, immunotherapy, and targeted therapy. However, the low response rate and the development of resistance necessitate the search for a novel therapeutic target in melanoma. Hypoxia-inducible factor-1 α (HIF-1α) is overexpressed in melanoma and plays a crucial role in driving malignant transformation in cancer cells. Here, we identified that histone deacetylase 8 (HDAC8) enhances the protein stability of HIF-1α. HDAC8 directly binds to and deacetylates HIF-1α, thereby promoting its protein stability. This, in turn, upregulates the transcriptional activity of HIF-1α and promotes the expressions of its target genes, such as hexokinase 2 (HK2) and glucose transporter 1 (GLUT1). The inhibition of HDAC8 suppresses the proliferation and metastasis of melanoma cells. Furthermore, HDAC8 is correlated with HIF1A expression and poor prognosis in samples from patients with melanoma. These findings uncover a novel epigenetic mechanism that maintains HIF-1α stability and implicates the potential of HDAC8 inhibitors for melanoma therapy. Full article

(This article belongs to the Special Issue Cancers Driven by HIF)

► Show Figures

Graphical abstract

Review

Jump to: Research

23 pages, 1809 KiB

Open AccessEditor’s ChoiceReview

Downstream Targets of VHL/HIF-α Signaling in Renal Clear Cell Carcinoma Progression: Mechanisms and Therapeutic Relevance

by Sonia Mazumder, Paul J. Higgins and Rohan Samarakoon

Cancers 2023, 15(4), 1316; https://doi.org/10.3390/cancers15041316 - 19 Feb 2023

Cited by 11 | Viewed by 4936

Abstract

The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several types of tumors including ccRCC. Normally, the Hypoxia Inducible Factor alpha (HIF-α) subunits of the HIF heterodimeric transcription factor complex are regulated by oxygen-dependent prolyl-hydroxylation, VHL-mediated ubiquitination and proteasomal degradation. Loss of pVHL function results in elevated levels of HIF-α due to increased stability, leading to RCC progression. While HIF-1α acts as a tumor suppressor, HIF-2α promotes oncogenic potential by driving tumor progression and metastasis through activation of hypoxia-sensitive signaling pathways and overexpression of HIF-2α target genes. One strategy to suppress ccRCC aggressiveness is directed at inhibition of HIF-2α and the associated molecular pathways leading to cell proliferation, angiogenesis, and metastasis. Indeed, clinical and pre-clinical data demonstrated the effectiveness of HIF-2α targeted therapy in attenuating ccRCC progression. This review focuses on the signaling pathways and the involved genes (cyclin D, c-Myc, VEGF-a, EGFR, TGF-α, GLUT-1) that confer oncogenic potential downstream of the VHL-HIF-2α signaling axis in ccRCC. Discussed as well are current treatment options (including receptor tyrosine kinase inhibitors such as sunitinib), the medical challenges (high prevalence of metastasis at the time of diagnosis, refractory nature of advanced disease to current treatment options), scientific challenges and future directions. Full article

(This article belongs to the Special Issue Cancers Driven by HIF)

► Show Figures

Journal Menu

Journal Browser

Cancers Driven by HIF

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (3 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI