Cancer metabolism Flashcards
One-carbon metabolism is central to many cancer-related processes. Which of the
following therapeutic approach/drug leverages that vulnerability?
a) Methotrexate
b) Cisplatin
c) Surgery
d) Neoadjuvant anti-PD-1
e) Radiotherapy
a) Methotrexate
Which of these metabolites is an oncometabolite?
a) isocitrate
b) alpha-ketoglutarate
c) s-adenosylselenocyteine
d) s-adenosylphenylalanine
e) D-2-hydroxyglutarate
e) D-2-hydroxyglutarate
The phosphoinositide 3-kinase pathway is frequently deregulated in cancer. However, inhibitors targeting the phosphoinositide 3-kinase pathway performed poorly in clinical trials. How response to phosphoinositide 3-kinase pathway inhibitors can be enhanced?
a) Combination with high fat diet
b) Combination with a ketogenic diet
c) Combination with methotrexate
d) Combination with checkpoint blockade
e) Combination with histidine
b) Combination with a ketogenic diet
What are the key hallmarks of cancer as outlined in 2000?
The hallmarks identified in 2000 include resisting cell death, inducing angiogenesis, enabling replicative immortality, activating invasion and metastasis, evading growth suppressors, and sustaining proliferative signaling
According to the 2011 udpate, what additional features characterize cancer
The 2011update adds features such as deregulating cellular energetics avoidinc immune destruction, promoting tumor related inflammation, and contributing to genome instability and mutation
Define the Warburg effect in cancer metbolism
The warburg effect refers to the tumors favoring anaerobic glycolysis over oxidative phosphorylatio, for energy prodution, even in the presence of oxygen, leading to increased lactate production and providing glycolytic intermediates for tumor growth
How does the warburg effect support tumor growth
Through anaerobic glycolysis, tumors generate glycolytic intermediates that serve as building blocks for tumor growth and metastases, supporting various nalabolic pathways that promote rapid growth
Explain the metabolic differences within tumors and implications
Tumor cells distant from blood vessels, experience nutrient scarcity and exhibit a different metabolism, undergoing autophagy, utilizing specific nutrients like branched-chain amino acids (BCAA) and undergoing beta oxidation of fatty acids contrasting with cell nearer to the tumor periphery
How do changed in angiogenesis affect cancer metabolism
Angiogenic processes alter the tumors nutrients supply, leading to disequilibrium in cellular metabolism. As new blood vessels supply nutrients and remove lactate from the tumor microenvironment the tumors metabolic dynamic change
Detail the role of glucose and glutamine in supporting cancer metabolism
Glucose supports one-carbon metabolism, aiding nucleotide biosynthesis and methylation. Glutamine provides a carbone backbone for various building blocks necessary for tumor growth
What are the pros and cons of standard cell cultures enriched with glutamine and glucose for studying cancer metabolism
Pros include cost-effectiveness, easy measurement of flux and levels, and compatibility with high-throughput genetic and chemical screens
Cons include the absence of cellular heterogeneity, lack of microenvironmental physical factors (like ECM), and the use of non-physiological supplied nutrients.
Describe the advantages and limitations of 3D tissue culture or mouse models in studying cancer metabolism.
3D culture or mouse models use more glucose, mimicking the production of lactate. Pros involve better representation of physical microenvironments
cons include limited cell heterogeneity, incomplete representation of physical factors, non-physiological nutrient supplies, higher costs, and less tractability for high-throughput experiments.
What is FDG-PET used for in cancer imaging, and why might it fail for some tumors?
FDG-PET visualizes glucose uptake and anabolic processes. It can fail for tumors not avid for glucose; for instance, prostate cancer relies less on glucose and uses alternative substrates like lipids or acetate, requiring PET/CT imaging with acetate or choline tracers
Explain the impact of nucleotide biosynthesis inhibitors on rapidly dividing cells and highlight specific chemotherapy medications targeting this pathway.
Drugs inhibiting nucleotide biosynthesis affect normal rapidly dividing cells (e.g., intestinal cells). Chemotherapy medications such as Pemetrexed, 6-MP, 6-TG, 5-FU, and Methotrexate target nucleotide biosynthesis pathways in cancer.
What are the consequences of IDH mutants in cancer metabolism, and how do they affect cellular functions?
IDH mutants convert a-KG to D-2-hydroxyglutarate, disrupting metabolic homeostasis and depleting the a-KG pool, leading to a broken TCA cycle. They affect DNA methylation via TETs and IDH1, impacting histone demethylation, CpG islands, and gene regulation. Clinically, IDH1/2-mutants are targetable.
What does metabolomics measure, and what comprehensive information does it provide in cancer studies?
Metabolomics measures and interprets changes in the metabolome, encompassing small molecules (MW < 1500 Da) in biofluids, cells, tissues, or organisms. It offers functional information and integrates genetic, transcriptomic, and proteomic variation, along with the exposome, for phenotype characterization.
What are the categories of approaches used in studying metabolism?
Approaches are categorized as static (global untargeted/targeted metabolic profiling like NMR, GC-MS, LC-MS/MS), dynamic (fluxomics utilizing 13C or 1H fluxes), and imaging (MS-based imaging, MR-spectroscopy imaging, Positron Emission Tomography).
What are the applications of metabolic studies in disease research and treatment?
Metabolic studies offer insights into disease biology, aid in identifying therapeutic targets, assess drug safety, efficacy, and mechanisms of action, provide biomarkers for target engagement, patient diagnosis, prognosis, and therapy selection, assist in pharmacometrics modeling, and even support surgeries via tools like the i-knife for real-time tissue analysis.
What components and factors constitute the tumor microenvironment?
The tumor microenvironment includes cancer cells, lymphocytes, neurons, adipocytes, TAMs (tumor-associated macrophages), ECM (extracellular matrix), vasculature, nutrients, oxygen, metabolic waste, and pH variations. Lactate, produced under hypoxic conditions, affects redox balance, angiogenesis, the TCA cycle, bioenergetics, and biosynthesis.
How does the tumor microenvironment affect nutrient availability and impact T cell function?
Cancer cells often consume more glucose and tryptophan, depriving other cells in the microenvironment and impacting T cell function. TAMs uptake tryptophan and arginine, further depriving T cells.
How does diet influence tumor growth, and what experimental evidence supports this?
Diet impacts tumor growth differently depending on cancer stage and cellular genetic makeup. Studies on mice with PTEN and/or PTPN1 deficiency show increased cell proliferation with a high-fat diet. Dietary restriction affects cell proliferation differently based on genetic alterations (PTEN loss vs. hyperactive Ras).
In what ways does a high-fat diet affect cancer progression in specific oncogene-driven models?
A high-fat diet fuels prostate cancer progression by altering the metabolome and amplifying oncogenic programs like MYC. Reverting to a normal diet can normalize transcriptomic profiling.
What happens when diet and exercise improve before surgery?
Patients tend to walk further post-operatively compared to their pre-operative walking distance.
How does radiation therapy affect cancer cells?
Ionizing radiation causes double-strand breaks that can kill non-replicating cancer cells. It’s used in prostate cancer treatments before or after surgery and can be administered systemically.
