New Flashcards
What is the difference between benign and malignant tumors?
Benign tumors do not invade or metastasize, whereas malignant tumors can invade nearby tissue, spread, and form secondary tumors in distant organs. This ability to metastasize is a key feature of cancer.
What is the role of VEGF in cancer?
Vascular Endothelial Growth Factor (VEGF) promotes angiogenesis, which is the formation of new blood vessels. Tumors rely on angiogenesis to provide a blood supply, which is essential for their growth and survival. Without blood supply, a tumor can only grow to a size of about 1-2 mm. VEGF production is stimulated by hypoxic conditions (low oxygen), which are common in rapidly growing tumors. VEGF-targeting agents are being developed as cancer treatments to block tumor blood supply.
How do tumors adapt to low oxygen environments?
In low oxygen conditions (hypoxia), tumors adapt by producing VEGF, which promotes angiogenesis to generate new blood vessels. Hypoxia is a common phenomenon observed in solid tumors due to rapid growth outpacing their blood supply. Additionally, erythropoietin (EPO), a growth hormone produced by the kidney, is also increased in hypoxic environments to stimulate red blood cell production and help increase oxygen transport.
How do tumors induce angiogenesis?
Tumors produce angiogenesis-stimulating factors like VEGF to promote the formation of new blood vessels. These new vessels allow the tumor to receive the oxygen and nutrients necessary for continued growth. The production of VEGF is often triggered by hypoxic conditions within the tumor, as the tumor outgrows its existing blood supply.
What is the Warburg effect in cancer metabolism?
The Warburg effect refers to the phenomenon where cancer cells rely heavily on aerobic glycolysis (the conversion of glucose to lactate) for energy, even in the presence of oxygen. This contrasts with normal cells that primarily rely on oxidative phosphorylation in the mitochondria. This metabolic shift supports the rapid growth of cancer cells by providing both energy and intermediates for anabolic processes needed for cell division.
Why do cancer cells rely on glycolysis despite the availability of oxygen?
Cancer cells preferentially use glycolysis (aerobic glycolysis) for energy production, even in the presence of oxygen, to support rapid growth. This process generates ATP quickly, which is necessary for the high metabolic demands of proliferating cancer cells. Additionally, glycolysis provides intermediates for biosynthesis, such as nucleotides and lipids, which are essential for building new cells.
What is 2-deoxyglucose (2-DG), and how does it affect cancer cells?
2-deoxyglucose (2-DG) is a glucose analog that lacks a hydroxyl group at the 2-position. It is phosphorylated by hexokinase, trapping it inside the cell as 2-DG-P. 2-DG-P competes with glucose-6-phosphate and inhibits key steps in glycolysis, effectively shutting down the pathway. This disrupts the energy metabolism of cancer cells, leading to impaired growth. Experimental models have shown that 2-DG can inhibit tumor growth by blocking glycolysis.
What is an oncometabolite, and what role does 2-hydroxyglutarate (2-HG) play in cancer?
An oncometabolite is a metabolite that can contribute to cancer development by altering cellular processes. 2-Hydroxyglutarate (2-HG) is an oncometabolite produced by mutations in isocitrate dehydrogenase (IDH) enzymes, which are common in certain cancers. 2-HG inhibits enzymes that require alpha-ketoglutarate, disrupting cellular processes and potentially promoting the survival and growth of cancer cells.
What is the relationship between glutamine and cancer cell metabolism?
Cancer cells often rely on glutamine, in addition to glucose, as a key metabolic fuel. Glutamine is converted into glutamate, which then enters the TCA cycle, providing energy and intermediates for biosynthesis. This allows cancer cells to adapt to nutrient-limited environments and continue proliferating. In addition to glucose, the uptake of glutamine is essential for the survival and growth of cancer cells.
How can inhibiting metabolic pathways affect cancer growth?
Inhibiting key metabolic pathways in cancer cells, such as glycolysis and glutaminolysis, can slow or stop tumor growth. Drugs like 2-DG, which block glycolysis, and CB-839, which inhibits glutaminase (GLS) and disrupts glutamine metabolism, can deprive cancer cells of essential energy sources. By targeting these metabolic vulnerabilities, cancer cell proliferation can be reduced. However, tumors may also adapt by switching to alternative energy sources, making the development of combination therapies crucial.
How does hypoxia trigger erythropoietin (EPO) production?
In a hypoxic environment (low oxygen levels), the kidneys sense decreased oxygen in the blood, stimulating increased EPO secretion. EPO stimulates the production of red blood cells (RBCs) to enhance oxygen delivery to tissues. This feedback loop ensures the body compensates for low oxygen levels.
What role does Hypoxia-Inducible Factor 1 alpha (HIF-1α) play in hypoxia?
Under hypoxia, HIF-1α accumulates in the nucleus, where it binds to ARNT and recruits specific genes, including those for VEGF (vascular endothelial growth factor). This helps the cell adapt to low oxygen by promoting angiogenesis, tissue invasion, and metastasis.
How is HIF-1α regulated under normal oxygen conditions?
Under normal oxygen levels, HIF-1α is hydroxylated by proline hydroxylase, which marks it for degradation via the proteasome. This prevents its activation. Under hypoxia, this hydroxylation does not occur, allowing HIF-1α to be stable and activate its target genes.
How does 2-hydroxyglutarate (2HG) function as an oncometabolite?
2HG is produced by mutant isocitrate dehydrogenase (IDH), a common mutation in cancers. It inhibits enzymes that require alpha-ketoglutarate, disrupting cellular processes like DNA repair, histone methylation, and promoting cancer cell survival. These disruptions support tumorigenesis by altering gene expression and promoting cancer cell growth.
What is the role of VEGF in angiogenesis?
VEGF (vascular endothelial growth factor) promotes the formation of new blood vessels (angiogenesis) to supply tumors with nutrients and oxygen. Tumors without blood supply cannot grow beyond a certain size (1-2mm). VEGF is upregulated in hypoxic conditions to help tumors grow by stimulating angiogenesis.
How does the body regulate erythropoietin (EPO) production in response to oxygen levels?
EPO is produced in the kidneys. When the blood has low oxygen carrying capacity (e.g., anemia), the kidney increases EPO secretion. EPO stimulates the production of RBCs to increase oxygen-carrying capacity, restoring normal oxygen levels in tissues.
Why is angiogenesis crucial for cancer cells?
Cancer cells induce angiogenesis to create new blood vessels that supply the growing tumor with nutrients and oxygen. Without angiogenesis, tumors cannot grow beyond a small size or metastasize, making it essential for their survival and spread.
How does HIF-1α contribute to cancer progression?
In tumors, HIF-1α is activated under hypoxic conditions, promoting the expression of genes that enhance angiogenesis, metastasis, and cell survival. This allows tumors to grow in low-oxygen environments, a hallmark of cancer adaptation to the tumor microenvironment.
How does mutant isocitrate dehydrogenase (IDH) affect cancer?
Mutant IDH converts isocitrate to 2HG, which disrupts normal metabolic processes, including DNA repair and gene expression regulation. These disruptions can promote cancer cell growth by interfering with alpha-ketoglutarate-dependent enzymes like histone demethylases.
How do tumors manage hypoxia-induced stress?
Tumors often experience hypoxia as they grow, leading to increased VEGF expression. VEGF stimulates angiogenesis, allowing tumors to form new blood vessels, ensuring an adequate oxygen and nutrient supply despite the challenging microenvironment.
What is the impact of HIF-1α on gene expression?
HIF-1α activates a wide range of genes involved in angiogenesis, glucose metabolism, and cell survival. These genes help tumor cells thrive in low-oxygen conditions, promoting tumor growth, invasion, and metastasis.
