Hallmarks of cancer.

1. HALLMARKS OF CANCER
By
Dr. N. Sreekanth
DNB-RT, BIACH&RI

2. What is Normal?
Dependence on growth factors
–Cell and tissue specific signals
–Loss of these signals leads to apoptosis
Anchorage dependent proliferation
–Requires interaction of transmembrane proteins
(integrins) with components of the ECM
Contact inhibition
–Contact with other cells inhibits proliferation and
movement
Limited proliferative capacity
–Normal somatic cells have a limited number of
divisions before entering senescence

3. New capabilities or Loosing control ?
• The hallmarks of cancer are the distinctive
and complementary capabilities that enable
tumor growth and metastatic dissemination.

6. Oncogene and Tumor Suppressor
Genes
• Oncogene: Mutated forms of normal cellular
genes generally involved in promoting cell
proliferation.
– These mutations result in dominant gain of
function.
• Tumor suppressor: Genes whose normal
function in regulating proliferation is to stop it.
– Mutation results in recessive loss of function.

10. Hallmarks of Cancer
• Sustaining proliferative signaling,
• Evading growth suppressors
• Resisting cell death
• Enabling replicative Immortality
• Inducing angiogenesis
• Activating invasion and metastasis
• Deregulating cellular energetics
• Evading immune destruction

11. Douglas hanahan Robert weinberg

15. Sustaining Proliferative Signaling

17. (1) Produce their own growth factors autocrine
stimulation.
(2) Produce paracrine signals  produce growth factors
to support the cancer cells.
(3) Growth factor receptor levels elevated  Hyper
responsive cancer cells.
(4) Independent from growth factors  Activation of
downstream signaling pathways or the disruption of
negative-feedback mechanisms.

19. Clinical implication of KRAS mutation
• Patients with mutated KRAS CRC are unlikely
to benefit from anti-EGFR therapy
(Cetixumab).
• Patients with metastatic CRC who are being
considered for anti-EGFR antibody therapy
should be tested for the presence of a KRAS
mutation prior to therapy.

20. Evading Growth Suppressors

21. The most prominent brakes:
Retinoblastoma protein (pRb) (Gatekeeper)
• Direct regulator of the cell division cycle.
• RB transduces growth-inhibitory signals and
decides whether or not a cell should proceed
through its growth-and-division cycle.
• Defects in the RB pathway function 
persistent cell proliferation.

22. p53 pathways : Guardian of the genome
• TP53 receives inputs from stress and
abnormality sensors that function within the
cell’s intracellular operating systems.
• TP53 can
– halt further cell-cycle progression
– trigger apoptosis

23. Merlin (cytoplasmic NF2 gene product)
• Contact inhibition by coupling cell-surface
adhesion molecules (e.g., E-cadherin) to
transmembrane receptor tyrosine kinases
(e.g., the EGF receptor).

24. Resisting Cell Death

25. • The most prominent of these programs :
1) Apoptosis  maintain tissue homoeostasis.
2) Necrosis  various conditions like oxygen and
energy deprivation.
3) Autophagy  generates the metabolites and
nutrients that cells are unable to acquire from
their surroundings.

26. Apoptosis
• Death receptors transmit signals leading to
apoptosis
– FAS ligand and FAS receptor
– TNF-α and TNF-αR1
– Decoy receptors that don’t signal can promote
survival
• Intracellular proteins that monitor DNA damage
– p53
• Pro-survival factors
– Bcl-2 family of proteins

27. • The loss of TP53 tumor suppressor function.
• Increasing the expression of anti-apoptotic
regulators Bcl-2 family.
• Down regulating proapoptotic Bcl-2– related
factors (Bax, Bim, Puma).

28. Enabling Replicative Immortality

29. • Cells have a finite lifespan and limited ability
to replicate
– Due to chromosome shortening
– Ends of chromosomes are called telomeres
(hexamer repeats -TTAGGG)
• Hayflick limit : approximately 50-80 doublings
– Cells reach replicative senescence
• Enzyme TOLEMERASE maintain
chromosome length (adds telomeres to the
ends of telomeric DNA)

30. • Cancer cells must have unlimited replicative
potential.
• All cancer cells maintain their telomeres. 90%
of them do so by increasing the production of
telomerase enzyme.
• Acquire the unlimited replicative potential—
termed cellular immortality

31. Inducing Angiogenesis

32. • All tumors require a blood supply to grow to a
significant size.
• Hypoxia will induce apoptosis by activation of
p53.
• The formation and maintenance of new blood
vessels (angiogenesis) plays a critical role in
tumour growth & metastasis.
• New blood vessels supply the cancer cells with
oxygen and nutrients, allowing the tumour to
grow.
• Angiogenesis is mediated principally through
vascular endothelial growth factor (VEGF)

34. • Tumor-associated angiogenic factors may be
produced by the tumor or by inflammatory
cells
• P53 inhibit angiogenesis by stimulation of
anti-angiogenesis molecules
• VEGF is under the control of RAS oncogene.

35. Activating Invasion and Metastasis

36. • Activation of Epithelial Mesenchymal
Transition (EMT): Normally during embryonic
morphogenesis
• Epithelial cells acquire Mesenchymal traits
– Loss of adherent junctions
– Change in cellular morphology
– Expression of proteases
– Increased motility

38. • Tumor cells binds to leukocytes, which protect
them from host defense mechanisms
• Tumor cells adhere to vascular endothelium &
pass through Basement membrane
• Site of extravasations & Mets depends on:
– Blood & Lymphatic supply
– Organ tropism/adhesion
– Functional loss of E-cadherin, which serves as a
widely acting suppressor of invasion

39. Deregulating Cellular Energetics

40. • Rapidly growing cancer cells need
–fuel for cell growth
–cellular building blocks to generate
new cancer cells

41. Warburg Effect or aerobic glycolysis
• Cancer cells reprogram their glucose metabolism,
by limiting their energy production largely to
glycolysis
• Consume more than 20 times as much glucose
compared to normal cells, but secrete lactic acid
instead of breaking it down completely into
carbon dioxide.
• Divert glycolytic intermediates to other
biosynthetic pathways to make macromolecules
which are used as building blocks for the
production of proteins, lipids and DNA required
by the rapidly dividing cells.

43. Evading Immune Destruction

44. • Cells and tissues are under constant
surveillance by the immune system
• The immune system detects and tries to kill
cancer cells.
• Cancer cells
– paralyze infiltrating CTLs and NK cells by secreting
TGF-β or other immunosuppressive factors.
– express immunosuppressive cell-surface ligands,
such as PD-L1, that prevent activation of the
cytotoxic mechanisms of the CTLs.

45. • New anti-cancer treatments have attempted
to stop these immune checkpoint signals.
– Ipilimumab (Yervoy)- Melanoma
– Nivolumab (Opdivo)- NSCLC
– Pembrolizumab (Keytruda)- Melanoma.

47. Enabling Characteristics:
–Genome Instability and Mutation
–Tumor-Promoting Inflammation

48. Genome Instability and Mutation
• Acquisition of the hallmarks in part depends on
genomic alterations
• Two of the most famous proteins in cancer, BRCA1 and
BRCA2, play a central role in DNA repair.
• Result in mutations that convey on cancer cells
hallmark capabilities
• This may be acquired through
– Clonal selection
– DNA methylation
– Histone modifications
• Alterations in DNA maintenance machinery

49. Tumor-Promoting Inflammation
• Tumors are “wounds that don’t heal”
• Immune cells that normally participate in wound
healing help cancer cells acquire hallmark
capabilities & become more aggressive
• Major risk factors for cancer
– Chronic infections, obesity, smoking, alcohol
consumption, environmental pollutants and high fat
diets
Linked to cancer through inflammation.

50. • Inflammation contribute to multiple hallmarks
by supplying bioactive molecules to the tumor
microenvironment, including growth factors
and survival factors.

51. TUMOR MICROENVIRONMENT

53. Whole Picture

55. THERAPEUTIC TARGETING OF THE
HALLMARKS OF CANCER