Constitutive Expression of HIF-α Plays a Major Role in Generation of Clear-cell Phenotype in Human Primary and Metastatic Renal Carcinoma

Abstract

The extensive lipid accumulation occurred in clear cell renal cell carcinoma (ccRCC) resulted in a clear cell cytoplasm. Hypoxia inducible factor alpha (HIF-α) was constitutively expressed in many ccRCC and transcriptionally regulates greater than one hundred genes. In a recent breakthrough study, HIF-1α induced ccRCC in transgenic mice. Based on these findings, we developed a hypothesis that accounted for HIF-α generation of the clear cell phenotype. The aim of the present study to use immunohistochemical staining methods in tissue microarray (TMA) to determine the extent to which the clear cell phenotype coincided with HIF-α expression in primary and metastatic ccRCC. In addition, we studied whether the prolyl-hydroxylases (PHD2,3) play a role in promoting the elevated expression of HIF-α in tumor cells. The clear cell phenotype was observed in all primary and metastatic cases of ccRCC examined. A total of 168 renal cell carcinomas were evaluated by immunohistochemical methods; 141/168(84%) of tumors expressed HIF-α (HIF-1α and/or HIF-2α). In contrast, HIF-α was expressed in only 1/23 (4%) of non-clear cell renal cell carcinomas. These data supported the hypothesis that in the majority of the tumors HIF-α expression overlapped with the clear cell phenotype, and was indicative of a HIF-α mediated lipid accumulation. In a smaller percentage of ccRCC cases (16%) HIF-α was not detected in the tumor cells and suggested that lipid accumulation by HIF-α -lipid independent process. PHD3 was undetectable in both primary and metastatic ccRCC cases. We concluded that the undetectable PHD3 could contribute to the higher HIF-α expression in ccRCC.

Non-Coding Micro RNAs and Hypoxia-Inducible Factors Are Selenium Targets for Development of a Mechanism-Based Combination Strategy in Clear-Cell Renal Cell Carcinoma—Bench-to-Bedside Therapy

“…There is an unmet clinical need to identify a new treatment modality that is patient-centric, selective, and efficacious for metastatic ccRCC patients. Both primary and metastatic ccRCC tumors are uniquely characterized by the expression of altered biomarkers associated with increased angiogenesis, metastasis, and drug resistance, including deletion and/or mutation of the von Hippel–Lindau (VHL) tumor suppressor gene in the majority of ccRCC tumors, resulting in the stable expression of hypoxia-inducible factors 1α and 2α (HIFs), and vascular endothelial growth factor (VEGF) [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Programmed death 1 (PD-1) is expressed in the membrane and cytoplasm of activated T cells, B cells, and dendritic cells.…”

Obstructive sleep apnea and Fuhrman grade in patients with clear cell renal cell carcinoma treated surgically

“…Better understanding of the pathophysiology of clear cell RCC (ccRCC) in recent years has shown the important role of HIF-1α pathways [10,11], which has led to successful application of antiangiogenic drugs targeting VEGF [12] and has promoted the use of other related markers such as carbonic anhidrase-9 as prognostic markers [13]. Thus, HIF-1α and its downregulated genes have an important role in the pathophysiology of both OSA and ccRCC.…”

Selenium targets resistance biomarkers enhancing efficacy while reducing toxicity of anti-cancer drugs: preclinical and clinical development

“…Under hypoxia, the enzymatic activity of PHDs decreases, resulting in a decreased hydroxylation and degradation of HIFs. Unlike in many solid tumors, ccRCC tumors, at initial diagnosis, are normoxic, highly vascular and express high levels of HIFs [ 8 , 16 , 17 ]. With the recognition that HIFs are upregulated by both hypoxia-dependent and independent pathways and play a crucial role in dug resistance and angiogenesis, a number of HIFs inhibitors are currently under clinical development.…”

“…Studies in our laboratory have demonstrated that HIF1α and HIF2α proteins are overexpressed in 92% of primary ccRCC, 27% in colorectal, and 38% in head and neck tumors [ 16 , 17 ]. In contrast, VEGF-A was expressed in 54%, 79%, and 97% of ccRCC, colorectal, and, head and neck tumors, respectively.…”

“…In contrast, VEGF-A was expressed in 54%, 79%, and 97% of ccRCC, colorectal, and, head and neck tumors, respectively. The average immunoscore of VEGF-A in ccRCC, colorectal, and head and neck tumors were 2.3, 5.7, and 4.2, respectively [ 16 , 17 ]. ccRCC is known to respond to VEGF-targeted agents, but colorectal or head and neck cancers do not.…”