Kidney cancer, also known as renal cancer, is one of the ten
most common cancers in both men and women. The American Cancer Society’s most
recent estimates state that of the predicted 63,920 new cases of kidney cancer this
year, roughly 20% of patients will die
from the disease. By far, the most common type of kidney cancer is renal cell
carcinoma (RCC). The majority of RCCs are clear cell RCCs (ccRCCs), a subtype characterized
by metabolic alterations, specifically increased carbohydrate and fat storage.
More than 90% of ccRCCs have been found to have mutations in the von
Hippel-Lindau (VHL) tumor suppressor gene; however, kidney specific VHL deletion in mice does not induce
tumorigenesis or cause metabolic changes similar to those seen in ccRCC tumors.
So what additional factors are needed for ccRCC tumor formation and progression?
A recent study by Penn researchers published in the journal Nature identified the rate-limiting
gluconeogenesis enzyme fructose-1,6-bisphosphatase (FBP1) as a key regulator of
ccRCC progression.
To better understand ccRCC progression, the study’s first
author, Bo Li, a post-doctoral researcher in the lab of Dr. Celeste Simon, performed
metabolic profiling on human ccRCC tumors while also analyzing ccRCC metabolic gene
expression profiles. Compared to the adjacent normal kidney tissue, ccRCC
tumors had increased amounts of metabolites involved in sugar metabolism and significantly
lower expression of carbohydrate storage genes, including FBP1. Further
investigation revealed FBP1 expression was reduced in almost all tumor samples
tested (>600) and reduced FBP1 expression strongly correlated with advanced tumor
stage and poor patient survival. Thus, understanding the role of FBP1 in ccRCCs
could significantly impact the treatment of this disease.
How do reduced levels of FBP1 promote ccRCC tumor
progression? The authors found that FBP1 depletion in ccRCC cells stimulates
growth and relieves inhibition of sugar breakdown (glycolysis), which provides energy
for the growing cancer cells. In addition, VHL
mutations associated with ccRCCs prevent the degradation of a transcription
factor that responds to decreases in oxygen, known as hypoxia-inducible factor
α (HIFα), thus stabilizing it. Stabilized HIFα does not cause FBP1 depletion, but
its activity is tightly regulated by FBP1. This study emphasized the importance
of the interaction between HIFα and FBP1, particularly when glucose and oxygen
levels are low, for the formation and progression of the ccRCC.
Why is this work so important? Little is known about how
changes in cell metabolism contribute to the formation and progression of ccRCC
tumors. As stated by Li, “elucidating how FBP1 impacts the altered metabolic
and genetic programs of ccRCC improves our knowledge of the molecular details
accompanying ccRCC progression, and identifies novel therapeutic targets for
this common malignancy.” Future work may focus on identifying how FBP1 is
suppressed and whether reversing FBP1 suppression could improve patient
outcomes.
-Renske Erion
-Renske Erion