Signal Transduction and Hallmarks of Cancer (STHoC)
14th of march – 25th of April
Questions before the lecture
Name at least 5 consecutive steps taking place during tumor progression.
1. Initiation: where a genetic alteration occurs in a cell, resulting in the formation of a pre-
cancerous cell.
2. Promotion: where the pre-
cancerous cell is stimulated to
divide and multiply, resulting in the
formation of a small cluster of
cells.
3. Angiogenesis: where the tumor
releases chemicals that stimulate
the formation of new blood
vessels, allowing the tumor to
receive nutrients and oxygen.
4. Invasion: where the tumor cells
invade nearby tissues and organs,
spreading cancer.
5. Metastasis: where the tumor cells break away from the primary tumor and spread to other
parts of the body through the bloodstream or lymphatic system.
Describe the components which compose signal transduction.
1. Signal transduction is the process by which a signal or stimulus is transmitted from the outside
of a cell to the inside, leading to a response or change in the cell. It involves several
components, including:
2. Ligands: signaling molecules that bind to specific receptors on the cell surface.
3. Receptors: proteins on the cell surface that bind to ligands and initiate the signaling cascade.
4. Second messengers: molecules that are generated inside the cell in response to the ligand-
receptor binding and amplify the signal.
5. Effectors: proteins that are activated by the second messengers and carry out the response,
such as transcription factors or enzymes.
Give one example of a signaling pathway controlling a cancer hallmark.
The PI3K/Akt/mTOR pathway is frequently activated in cancer cells and controls cell growth and
proliferation. Activation of this pathway leads to increased protein synthesis, cell cycle progression,
and decreased apoptosis, all of which contribute to tumor growth.
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,What is the difference between catabolism and anabolism?
Catabolism and anabolism are two types of metabolic pathways.
Catabolism = the breakdown of complex molecules into simpler ones, releasing energy in the process.
Anabolism = the synthesis of complex molecules from simpler ones, requiring energy input.
In cancer, there are a lot of anabolisms because of cell proliferation.
Which metabolic pathways generate energy?
- Glycolysis: the breakdown of glucose to produce ATP.
- Citric acid cycle (or Krebs cycle): the oxidation of
acetyl-CoA to produce ATP and reducing
equivalents for the electron transport chain.
- Electron transport chain: the transfer of electrons
from reduced molecules to oxygen, generating a
proton gradient across the mitochondrial
membrane and ATP synthesis through oxidative
phosphorylation.
ATP-generating metabolic pathways. In cancer metastasis,
it switches to Glycolysis. Cancer cells undergo a process
called aerobic glycolysis, also known as the Warburg
effect, which is characterized by increased glucose uptake
and metabolism through the glycolytic pathway, even in the presence of oxygen.
Cancer cells undergo glycolysis to generate energy, provide intermediates for biosynthesis, acidify the
microenvironment, and reduce oxidative stress.
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,Lecture 1 - “Deregulating cellular energetics” – Le Devedec – 14th of March
Metabolic alterations in cancer
1. Tumor environment
2. Cancer cell metabolic rewiring
3. Dysregulated normal tissue metabolism.
4. Endocrine system dysfunction
Factors that affect metabolism
1. Genetics
2. Therapy
3. Diet
4. Physical activity
Learning objectives:
1. Know the basic principles of the Warburg
effect and how it benefits tumor cells.
The Warburg effect = the phenomenon in which tumor cells tend to use glycolysis as their primary
source of energy, even in the presence of oxygen (aerobic glycolysis). This contrasts with normal cells,
which rely primarily on oxidative phosphorylation in the mitochondria to generate ATP. The Warburg
effect allows tumor cells to produce energy more quickly and efficiently than through oxidative
phosphorylation, which may be beneficial for their rapid proliferation. It also provides tumor cells with
metabolic intermediates that can be diverted for use in biosynthesis, such as nucleotides, amino acids,
and fatty acids.
2. Know examples of signaling pathways that contribute to the altered metabolism in tumor
cells.
Several signaling pathways contribute to the altered metabolism in tumor cells. For example, the
PI3K/AKT/mTOR pathway promotes cell growth and survival by upregulating glycolysis and inhibiting
oxidative phosphorylation. The HIF-1 pathway is activated in response to hypoxia and promotes the
Warburg effect by upregulating glucose transporters and glycolytic enzymes. The MYC pathway is a
transcription factor that regulates many genes involved in cell growth and metabolism, including those
involved in the Warburg effect. In addition, oncogenic mutations in genes such as TP53, KRAS, and
BRAF can also promote altered metabolism in tumor cells.
3. Know examples of oncogenic drivers and outside signals which regulate.
Oncogenic drivers are mutations in genes that promote tumor growth and survival. Examples of
oncogenic drivers include mutations in KRAS, BRAF, EGFR, and ALK, which are commonly found in
various types of cancer. These mutations can activate signaling pathways that promote cell growth
and survival, such as the MAPK/ERK and PI3K/AKT pathways.
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, The Warburg Theory of Cancer of “Warburg hypothesis”
Measured oxygen level in two different
cell types:
High malignancy – smaller respiration and
high lactic acid production
Low malignancy – more oxygen
Cancer cells use the mitochondria in
different stages.
The higher the malignancy, the greater
the fermentation and the smaller the
respiration
Tumor metabolism: how is it different?
Tumor metabolism = the unique ways in which
cancer cells produce and use energy. Compared to
normal cells, tumor cells undergo significant
metabolic changes to support their rapid growth
and proliferation. Here are some key ways in
which tumor metabolism is different:
Þ Increased glucose consumption: Tumor
cells have a higher demand for glucose,
which they use as a fuel source for energy
production. This phenomenon is known as
the Warburg effect, and it is a hallmark of
cancer metabolism.
Þ Altered glucose metabolism: Tumor cells
convert glucose to lactate at a much higher rate than normal cells, even in the presence of
oxygen. This is known as aerobic glycolysis or the Warburg effect.
Þ Increased reliance on glutamine: Tumor cells also rely heavily on glutamine, an amino acid
that serves as a precursor to many other biomolecules required for cell growth and division.
Þ Increased fatty acid synthesis: Tumor cells also have an increased capacity for synthesizing
fatty acids, which are essential building blocks for cell membranes and other cellular
structures.
Þ Increased dependence on the pentose phosphate pathway: Tumor cells also rely on the
pentose phosphate pathway (PPP) to produce NADPH, a molecule that is essential for
protecting cells against oxidative stress and DNA damage.
Higher glucose uptake correlates with more aggressive phenotypes and poorer clinical outcomes, with
hypoxia correlates with more aggressive phenotypes.
Warburg effect in the clinic: tumor cells use much more glucose than normal cells – clinical FDG
(fluorodeoxyglucose) – PET scanning exploits cancer metabolism.
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