Malignant Transformation / j.gumulec@med.muni.cz1
Malignant transformation
Metabolism
MUDr. Jaromír Gumulec, Ph.D.
Dept. Of Pathological Physiology
Faculty of Medicine – Masaryk University
Malignant transformation
• The process of tumor formation is a
complex involving multiple alterations of
cells and their physiologic control
mechanisms.
• The complexity of this process is
reflected in the long time periods
required for most human cancers to
develop.
• Multi-step tumor progression can be
depicted as a form of Darwinian
evolution occurring within tissues.
• Some of the critical changes occurring
during tumorigenesis are epigenetic and
the rate of genetic diversification can
occur very rapidly.
Genetic alteration can appear
– (1) due to internal errors during DNA replication and cell division
– (2) as a consequence of exposure to the external factors (carcinogens)
physical – e.g. UV and ionising light
chemical – organic substances, toxins, heavy metals
biologic – some RNA and DNA viruses
Hallmarks of cancer
Continual unregulated proliferation of cancer cells
(sustaining proliferative signaling and evading
growth suppressors)
Replicative immortality
Genome instability
Resisting cell death and senescence
Inducing angiogenesis
Inflammation
Avoiding immune destruction
Altered metabolism
Invasion and metastasis
All these features do not have to be newly evolved,
because they are part of physiological processes
such as embryogenesis and wound healing.
Cancer cells only use these processes in wrong
intensity, time, and place. Cancer is a disease of
regulation.
Cancer cell
Cancer cells divide
excessively - they have too
many “GO” signals or not
enough “STOP” signals and
can also ignore “DIE”, “
DIFFERENTIATE “, or
“GROW OLD” signals.
Altered metabolism
The ability to acquire necessary nutrients from a nutrient-poor (low
glucosis) and hostile (hypoxia, oxidative stress) environment and
utilize these nutrients to maintain viability and build new biomass.
Cancer-associated metabolic reprogramming have profound effects
on gene expression, cellular differentiation, and the tumor
microenvironment.
These adaptations involve an ability to access normally inaccessible
nutrient sources.
Hallmarks of cancer metabolism
(1) deregulated uptake of glucose
and amino acids
(2) use of opportunistic modes of
nutrient acquisition
(3) use of glycolysis/TCA cycle
intermediates for biosynthesis
and NADPH production
(4) increased demand for nitrogen
(5) alterations in metabolite-driven
gene regulation – metabolites
influence enzymes involved in deposition
and removal of epigenetic marks.
(6) metabolic interactions with the
microenvironment.
Altered metabolism
Two principal nutrients that support survival and
biosynthesis are glucose and glutamine.
Glutamine provides the nitrogen required for the
biosynthesis of purine and pyrimidine nucleotides
and nonessential amino acids.
Warburg effect - a markedly increased
consumption of glucose by some tumors in
comparison to the nonproliferating normal tissues.
Positron emission tomography (PET)-based
imaging of the uptake of a radioactive fluorinelabeled
glucose analog, 18F˗fluorodeoxyglucose
(18F-FDG) has been successfully used in the clinic
for tumor diagnosis.
Oncogenic signaling proteins - Ras upregulate
GLUT1 mRNA expression and increase cellular
glucose consumption.
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0
400
800
PC-3 PC-3 (Zn 50)
ATPProductionRate
(pmol/min/10000Cells)
Bilions of ATP
Our metastatic prostate cancer
cells produce 3 bilions of
molecules of ATP every second.
The resistant ones produces
roughly doble 6 bilions of ATP.
Every second.
Ras or c-Src oncogenes allow to
recover free amino acids through the
lysosomal degradation of
extracellular proteins.
Macropinocytosis.
Macroautophagy (autophagy cannot
supply cells with new biomass and
thus cannot support proliferation in
nutrient-poor conditions).
Phagocytosis of apoptotic cellular
corpses.
Canibalism.
Use of opportunistic modes
of nutrient acquisition
Metabolic interactions
with the
microenvironment
Cancer cells alter the chemical
composition of the extracellular
milieu, which exerts pleiotropic
effects on the phenotypes of
normal cells that reside in the
vicinity of the tumor.
Reciprocally, the
microenvironment affects the
metabolism and signaling
responses of cancer cells.
The high metabolic demand of
cancer cells leads to an
accumulation of H+ ions in tumor
microenvironment – acidosis.
Metabolic symbiosis
Catabolic fibroblasts are rich source of energy and biomass for the growth
and survival of anabolic cancer cells.
A linear path of clonal succession oversimplifies the reality of cancer; number
of genetically distinct subclones of cells coexist within a single tumor mass:
intra-tumor heterogenity - oxidative and glycolytic tumor cells in one tumor.
j.gumulec@med.muni.cz | @jarogumulec | www.med.muni.cz/masariklab