Cancer cells have altered metabolism compared to normal cells. They rely more on glycolysis even in the presence of oxygen (Warburg effect). This produces less ATP but helps cancer cells proliferate rapidly. Glutamine can also be used as an energy source. Targeting cancer cell metabolism through drugs like dichloroacetate is a potential treatment strategy. Cancers are heterogeneous so their metabolic profiles vary between cancer types and individual cells.

2. Cancer Cell Metabolism
Submitted by: Asif Shahzad
Submitted To: Dr. Mahwish Salman
M.Phill Biochemistry
GCUF

3. Outlines
⚫ Definition of Cancerand Tumor
⚫ Types of Tumor
⚫ Properties of cancer cell
⚫ Cancer cell VS normal cell
⚫ Cancer Metabolism
⚫ Glycolysis in cancer cell
⚫ Glutamine used as a energy source in cancer cell
⚫ Cancer treatments

4. ⚫An uncontrolled divisionof abnormal cells in a partof the body is
called cancer.
⚫When good cellsgo bed.
⚫Lossof Cell-cycle Control.
⚫Before a cell divides, the DNA is checked to make sure it has
replicated correctly. (If DNA does not copy itself correctly, a gene
mutationoccurs.
Cancer

5. Tumor
⚫Tumoris an abnormal massof tissue resulting from uncontrolled
division (cancer).
⚫Tumor is of two types;
(1) Malignant tumor (cancerous)
(2) Benign tumor (non-cancerous)

6. Malignant Tumor
⚫Invadeorspread tootherpartsof the body
⚫High rateof division.
⚫Spread by forming Metastasis.
⚫Cells travel through circulation.
⚫Very difficult to treat.

7. Benign Tumor
⚫Do notspread tootherpartof the body.
⚫Generally localized and of small size
⚫Slow rateof division.
⚫Cells thatclosely resemble, and may function, like normal cells.
⚫Do not break outof originating organ.
⚫Easily toremoved bysurgery.

8. Properties of Cancer Cells
⚫ Cancercells show uncontrolled mitoticdivisionscausing unorganised
growth.
⚫ Due touncontrolled growthand divisionof cells, a tumor(alsocalled Neoplasm isgenerally
formed).
⚫ Theyare far less adhesive than the normal cells.
⚫ Theyexhibita numberof alterationson cell surface, in thecytoplasm and in theirgenes.
⚫ Theydo not undergodifferentiation.
⚫ They lose theability tocommunicatewith othercells through chemical
signals.
⚫ Theyalso lose sensitivitytoanti-growth signals from surrounding cells.
⚫ They lose theadhesion molecules that keep them bonded to neighboring cells.
⚫ Cancerarises froma loss of normal growthcontrol.

9. Cont….
⚫ Cancer is ageneticdisease:
–Inherited cancer
–Sporadiccancer (people who do not have a family history of that cancer)
⚫ Cancertypically involvesachange in geneexpression/function:
–Qualitativechange
–Quantitativechange
⚫ lack of contact inhibition
⚫ Lossof limitationson the numberof cell divisions
⚫ Abilitytogrow in culture (medium) – normal cells do notgrowwell in
culture.
⚫ In laboratorycultures, normal cells divideonlywhen attached toa surface.
⚫ Angiogenesis – secretesubstances thatcause blood vessels togrow towards tumor.

10. Normal Cell VS Cancer Cell

11. Normal Cell VS Cancer Cell

12. Normal Cell VS Cancer Cell

14. • Cancers are extremely heterogeneous diseases and each cancer has its
individual metabolic features.
• Even in a single cancer, its constituent cells are also heterogeneous and
metabolic phenotypes vary from one cell to another.
• Although aerobic glycolysis is often found in malignant tumors,
OXPHOS still contributes to energy production in cancers, and may
play a major role in energy production in some cancers.

15. • Energy consumption from metabolic activities in normal cells relies primarily
on mitochondrial oxidative phosphorylation (OXPHOS).
• Which is efficient and generates more adenosine triphosphate (ATP) than
glycolysis.
• One of the metabolic features of cancer cells is to avidly take up glucose for
aerobic glycolysis.
• This inefficient pathway for energy production in cancer cells was first
described by German biochemist Otto Warburg in the 1928s, and is also known
as the Warburg effect

16. Warburg’s Effect
• Warburg’s Effect is a metabolic adaptations in cancer cells. Tumor microenvironment
effects the tumor metabolism.
• Mutations cause in a cell activates the oncogenes and deactivates the Tumor Suppressor
Genes which causes abnormal development.
• Tumor cells commonly experience hypoxia(limited oxygen supply) because they initially
lack an extensive capillary network to supply the tumor with oxygen.
• Fast growing cancer cells will require more energy for their survival and proliferation,
therefore cancer cell use a primitive inefficient reaction , aerobic glycolysis, to generate
considerate amount of energy.

17. • Cancer cells have lesser no. of mitochondria, therefore they rely upon inefficient
glycolytic mode of ATP synthesis rather than respiration.
• The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator
responsible for the induction of genes that facilitate adaptations.
• Mitochondrial Dysfunction : .Mitochondria are key components of the apoptotic cell
death process. Due to overexpression of Hexokinase II prevent interaction of
proapoptotic proteins with mitochondria.
• Alkalosis : Tumors shows a reversed pH gradient with a constitutively increased
intracellular pH that is higher than extracellular pH.
Warburg’s Effect

18. Oxidative
Phosphorylation
Pyruvate Lactate
ATP
O2
Glucose
Glycolysis
NORMAL CELL
Decreased
pH
CANCER CELL

19. ⚫The normal cells utilize aerobic respiration to completelycatabolize
glucose and generate cellular energy.
⚫Cancer cells rely primarily on glycolysis for their metabolism to
make lactate and it is called aerobicglycolysis.
⚫Glucose delivery inside the cell is mediated by glut 4 transporter
in normal cell and byglut 1 in tumorcell.
⚫Once inside thecell, glucose is metabolised togenerate pyruvate in
cytosole.

21. ⚫Mitochondrial oxidative phosphorylation requires oxygen—aerobic
respiration.
⚫Aerobicgylcolysis also generates ATP but less than aerobic respiration.
⚫Cancercells metabolizeglucose forpurposeother than generating ATPs.
⚫They must balance thecatabolism of nutrients togenerate ATP with other
metabolic needs to allow net biosynthesis and cell proliferation.
⚫Toproduce a daughter cell,a proliferating cell must replicate thegenome,
duplicate the ribosomes , protein syn machinery,generate new organelles,
synthesize de novo enough lipids toduplicatecellular membranes.

22. ⚫Lactate produced from aerobic gylcolysis causes acidification of
tumorcell which has been shown to promote invasionand
metastasis.
⚫Lactatecan alsoactas a nutrient forsomecells in the tumor..

23. Nutrients other than glucose..
⚫Glucose is not theonlysubstrateused bycancercells.
⚫Amino acid glutamine, source of carbon, can be metabolized via
two transamination reactions to the TCA cycle intermediatealpha
ketoglutarate.
⚫Acetatecan beconverted toacetyl-coAand serveas a precursor for
lipid synthesis.
⚫Nutrientssuch as aminoacid and iron arealso important for
some tumor..

24. Cancer cells may use Glutamine as energy
fuel
• It is widely accepted that glucose is the dominant energy fuel for most cancers, it is not
the only one.
• Glutaminolysis may be an alternative pathway for energy production in certain cancers
since it is known that elevation in glutamine consumption is frequently observed in
cancer.
• In 2020, Reitzer et al reported that glutamine, not sugar, was the major energy source for
cultured HeLa cells.
• Glutamine may be used as the energy fuel for cancer cells. In contrast to glucose,
glutamine as an energy fuel is only observed in a few cancer cell lines and plays an
important role in compensating for the shortage of glucose in some cases.

25. Targeting Metabolism To Treat Cancer
⚫Folate– it can enhance cell proliferation. So antifolate is
used as chemotherapy.
⚫Metformin– recently two studies have shown that cancer related mortality is
decreased with metformin use—may be toxix to the cancer cell—may decrease the effect
of IGF-1 on cell growth.
⚫Dichloroacetate– used to treat lactic acidosis in non cancer pt. it reduces lactate
production by inhibiting PDK, a negative regulator of PDH which catalyzes first step
of pyruvate in mitochondria.
⚫Thus PDK inhibition leads to activation of PDH which diverts pyruvate away from
lactate, so might be useful agent to target cancer metabolism.

26. Conclusion
• Cancers have different metabolic phenotypes of energy for several reasons.
• First, cancers are heterogeneous diseases and their genetic heterogeneity determines
metabolic heterogeneity. Even from a single cancer, its constituent cells are also
heterogeneous and reflect differences in metabolic phenotype from one cell to another. The
different subclones within a cancer benefit each other in the metabolism and form a
metabolic symbiont. This phenomenon is not cancer-specific, and cancer cells also use other
physiological mechanisms to support their rapid growth.
• Second, cancer cells continuously reprogram to adapt to environmental pressures and
alteration of growth conditions. The result is that the ratio between glycolysis and OXPHOS
to yield total ATP, the ratio between glucose and glutamine to yield total ATP, or the ratio
between glucose/glutamine and fatty acid to yield total ATP, are continuously changing.
• The result of these changes is that the unfavorable environment provides a selective
advantage to cancer cells.

27. Reference
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Tumor-intrinsic CD47 signal regulates glycolysis and promotes colorectal cancer
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 Dai, S., Peng, Y., Zhu, Y., Xu, D., Zhu, F., Xu, W., ... & Miao, Y. (2020).
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 Lehninger Principles of Biochemistry, seventh Edition