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Tumor Discovery HIF1α treatments in renal cell carcinoma

occur in 2 – 5% of patients without adjuvant treatment. and Southern blotting techniques can be used on
Treatment can be challenging due to the poor response to peripheral leukocytes to detect VHL gene mutations. The
chemotherapy and frequent recurrence. 1-3 disease usually manifests in patients in their 20s, with

There are five types of RCCs: clear cell, chromophilic 95% of patients presenting with symptoms by the age
(papillary), chromophobic, oncocytic, and collecting duct. of 34. The most common initial symptom is cerebellar
Clear cell RCC (ccRCC) is the most common, accounting hemangioblastomas, occurring in 35% of cases. RCC is
for 75 – 85% of all RCCs. Defects in the Von Hippel– rarely the first symptom, with only 7% of cases presenting
3,4
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Lindau (VHL) gene account for 60% of sporadic ccRCC RCC initially. Genotype-phenotype correlations in VHL
cases. VHL is a tumor suppressor gene that regulates syndrome create subtypes based on the type of mutation
hypoxia-inducible genes (vascular endothelial growth in the VHL gene and disease features. Types 1A and 2B
factor [VEGF], transforming growth factor-alpha, and are associated with a higher incidence of RCC than the
GLUT1) by controlling hypoxia-inducible factor (HIF). other types. In these cases, somatic inactivation of the
2
HIF is a heterodimer that comprises alpha and beta VHL gene is the second requirement before progressing to
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subunits. HIF-ꞵ is constitutively expressed, and unlike the malignancy. RCC and renal cysts develop bilaterally and
alpha subunit, its expression is not influenced by oxygen typically appear in patients in their 30s and 40s. By the age
levels in the cellular environment. In normoxic conditions, of 60, 70% of patients with VHL syndrome develop RCC.
HIF-α is hydroxylated and acetylated for recognition by Hemangiomas and RCC are the leading causes of death in
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VHL. Once bound to VHL, HIF-α is ubiquitinated and patients with VHL syndrome.
targeted for proteasomal degradation, thus preventing RCC is highly vascularized tumors, tumors, primarily
the transcription of hypoxia-inducible genes. Under due to VHL mutations that activate the HIF pathway,
hypoxic conditions, the oxygen-dependent degradation leading to hyperactive angiogenesis. These tumors
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domain senses the oxygen levels and interacts with the exhibit elevated levels of HIF1-α. ccRCC shows the
NH2-terminal transactivation domain to stabilize HIF- highest nuclear accumulation of HIF1-α among RCC
α; this prevents its recognition by VHL and subsequent types. VHL gene mutations on chromosome 3p are
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degradation. Stabilized HIF-α translocates to the nucleus, present in over 80% of ccRCC cases, and more than 90%
dimerizes with HIF-β, and initiates gene transcription. of all RCCs have a mutated or inactivated VHL gene.
The COOH-terminal transactivation domain binds ccRCC is the most aggressive RCC subtype, and elevated
co-activators to modulate HIF-α gene transcription. HIF1-αα levels are linked to a poorer prognosis. A study
4,12
The HIF pathway regulates metabolic adaptation, cell examining the correlation between HIF1-α levels and
proliferation, migration, angiogenesis, and apoptosis. disease severity found that higher HIF1-α levels are linked
5,6
Loss of VHL results in the constitutive expression of HIF- to renal pelvis invasion, renal capsule rupture, and renal
α, which then leads to the overexpression of hypoxia- hilar invasion, along with increased nodal involvement.
inducible genes and proliferation of epithelial cells. Patients with these characteristics had a worse prognosis
2
HIF-α is encoded by three genes: HIF1-α, HIF2-α, and and were more challenging to treat. Another study
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HIF3-α. HIF1-α and HIF2-α both respond to hypoxia investigated the survival of patients with RCC based
and contribute to tumorigenesis when the HIF pathway is on their HIF1-α expression levels. It was found that the
uncontrolled. The role of HIF3-α is less understood. 7 median survival of those with high HIF1-α expression
VHL syndrome is an autosomal dominant familial (>35%) was 13.5 months compared to 24.4 months for
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cancer syndrome that is caused by mutations in the VHL those with low HIF1-α expression (<35%). In a study
gene on chromosome 3p. This disorder occurs in 1/36,000 by Xu et al., downregulation of HIF1-α in vitro inhibited
3
– 45,000 live births. Common manifestations of the RCC cell growth, migration, and invasion, and induced
disease include retinal and central nervous system (CNS) caspase-dependent apoptosis. In vivo animal studies with
hemangiomas, ccRCC, pheochromocytomas, pancreatic downregulated HIF1-α RCC cell lines showed significant
neuroendocrine tumors, and endolymphatic sac tumors. suppression of RCC cell proliferation, migration, and
13
Further, this syndrome can be diagnosed using one of invasion under both normoxic and hypoxic conditions.
the following three criteria: (1) the presence of at least Overexpression of HIF1-α is associated with more
two CNS/retinal hemangioblastomas; (2) the presence aggressive biological behavior and reduced overall survival
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of at least one CNS/retinal hemangioblastoma and one (OS).
other manifestation; or (3) at least one manifestation There are various treatments for RCC due to its poor
and a pathogenic mutation in the VHL gene or a first- response to traditional chemotherapy and its tendency
degree relative with VHL syndrome. DNA sequencing to develop resistance. Inhibiting the HIF pathway has

Volume 3 Issue 4 (2024) 2 doi: 10.36922/td.4346