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Tumor Discovery Energy metabolism in bladder cancer

1. Introduction metabolic adaptations encompass increased oxygen
consumption, nutrient depletion, as well as the generation
Bladder cancer (BC) emerges as a significant global public of reactive nitrogen and oxygen intermediates. The
health concern due to the elevated morbidity and mortality Warburg effect is a prominent metabolic phenomenon
1
rates. Notably, BC tends to be recurrent and aggressive in observed in cancer cells. 11,12 This effect involves
terms of progression, even in cases at localized disease preference for aerobic glycolysis and lactate fermentation
stages. Patients diagnosed with BC often require multiple over oxidative phosphorylation, even in the presence of
1,2
intravesical treatments, while advanced and metastatic abundant oxygen and fully functional mitochondria.
cases are treated with intricate surgical and systemic This metabolic shift serves the essential purpose of
interventions. Consequently, BC imposes a substantial meeting the increased energy demands necessary for
burden on health-care resources, resulting in significant the synthesis of lipids, proteins, and nucleic acids of the
economic costs. 1,3 cancer cells. Thus, Warburg effect stands out as a pivotal
Non-muscle-invasive BC (NMIBC) accounts for the feature of BC cancer cells, as well as of different solid
majority of bladder tumor cases, comprising 70 – 75% tumor types. 11
of the cases. NMIBC is characterized by the confinement Metabolic activity in normal cells primarily relies on
of tumor to the urothelium as papillary tumor (pTa) or oxidative phosphorylation, which is a highly efficient
carcinoma in situ (pTis or CIS) without stromal invasion process that generates abundant adenosine triphosphate
4,5
or with limited invasion into the lamina propria (pT1). (ATP) in comparison to glycolysis. Glucose is converted
This cancer type encompasses a diverse group of tumors, into pyruvate through glycolysis within the cytosol in
with progression rates to the muscle-invasive phenotype physiologically normal cells, and subsequently, it is
ranging from 0.8% to 50% within 5 years, as indicated turned into carbon dioxide in the mitochondria, mainly
6,7
by previous studies. Notably, significant risk factors for under aerobic conditions. 11,13 However, glycolysis takes
NMIBC progression include the concurrent presence of precedence under anaerobic conditions, and it results
6,7
CIS, high tumor grade, and T1 stage. In addition, factors in limited pyruvate supply to the oxygen-consuming
such as multiplicity, tumor size ≥3 cm, and a history of mitochondria. 11,13 This metabolic shift is featured by high
relapse are also considered risk factors for this disease. 6,7 glucose consumption and by lactate production, regardless
Low-grade Ta tumors present relapse rates up to of oxygen availability. 11,13-16
50%, and they only progress in 5% of cases. Conversely, Several key proteins participating in both the oxidative
high-grade T1 tumors show relapse rates exceeding phosphorylation and glycolysis pathways can be utilized as
80%, and over 50% of cases progress within the initial markers to assess the activity of these metabolic processes.
3 years. Chromosomal changes stemming from DNA Glucose transporter-1 (GLUT1), phosphofructokinase
8,9
strand oxidation. Chromosomal changes resulting from (PFK), glyceraldehyde 3-phosphate dehydrogenase
DNA strand oxidation affect the functions of oncogenes (GAPDH), and lactate dehydrogenase A (LDH-A) are
and tumor suppressor genes, as well as trigger different used as glycolytic pathway markers. Moreover, pyruvate
biological behaviors in low- and high-grade BC. Notably, dehydrogenase (PDH), citrate synthase (CS), short
low-grade BC tends to manifest as superficial, papillary, chain 3-hydroxyacyl-CoA dehydrogenase (HADHSC),
and indolent tumors, whereas high-grade BC are prone mitochondrial ATP synthase F1-beta-subunit (β-F1-ATP
8
to relapse and to progress into invasive muscle tissue. synthase), and heat shock protein 60 (hsp60) are used as
Moreover, other prognostic factors, such as tumor size, oxidative phosphorylation pathway markers.
multifocality, papillary versus sessile appearance, and
10
lymphovascular invasion hold clinical significance. These Several previous studies have focused on investigating
behavioral variations may be intricately linked to cell energy the mitochondrial energy metabolism of neoplastic
metabolism profiles presented by different histological cells and assessed the β-catalytic subunit concentration
grades of NMIBC. Analyzing and understanding metabolic within the H+-ATP synthase complex as oxidative
adaptation strategies adopted by neoplastic cells to meet phosphorylation marker. These studies have also
the high cell growth and proliferation demands within investigated hsp60 as marker of mitochondrial structural
each histological grade of NMIBC is a promising approach proteins, in association with GAPDH, which was used as
to acquiring more comprehensive knowledge on their glycolytic pathway marker. These data make it feasible to
behavior. calculate the bioenergetic cellular index (IBEC) through
the following equation: 17-19
Cancer onset and advancement are intricately linked
F
to changes in cell metabolism, which provide energy IBEC 1 ATPase (1)
to support cell growth and fast proliferation. These hsp60 xGAPDH
11

Volume 3 Issue 1 (2024) 2 https://doi.org/10.36922/td.2290