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Hallmarks of cancer
Noha El Baghdady
Contents:
Definition of hallmarks.
Overview on hallmarks.
Hallmarks have been identified in Breast
Cancer.
• Cancer was first described
by the ancient Egyptians
The earliest description of
cancer was found in the
Edwin Smith Papyrus dating
back to 1600 B.C.
The document describes
breast tumors removed by a
tool called the fire drill.
However, it states that "there
is no treatment".
Early theories about cancer causes
From the earliest times, physicians have puzzled over
the causes of cancer.
Ancient Egyptians blamed cancers on the gods.
Humoral theory (Hippocrates)
Lymph theory (1700s)
Blastema theory (1800s)
Chronic irritation theory (1860)
Trauma theory (late 1800s until the 1920s)
Infectious disease theory
Early theories about cancer causes
Ancient Egyptians blamed cancers on the gods.
Humoral theory
Lymph theory
Blastema theory
Chronic irritation theory
Trauma theory
Infectious disease theory
Modern Knowledge about Cancer
causes
• 1915, Viral and chemical
carcinogens.
• During the 1970s, scientists
discovered 2 particularly
important families of genes
related to cancer:
“oncogenes and tumor
suppressor genes.”
Oncogene
Tumor
Suppressor
gene
• Cancer is a disease of extraordinary complexity,
at all levels (genetic, histological, pathological,
prognostic, therapeutic…)
• How can we rationalize this complexity?
• Are there common principles underlying this
daunting diversity?
Douglas Hanahan Robert A. Weinberg
Hallmarks of cancer
Most cited Cell Article of All Time in the
fundamental oncology literature (Strickaert et al., 2016)
Hallmarks of cancer
• Is this concept applicable to the goal of more
effectively treating human cancers?
The hallmarks concept is helping to rationalize
the wealth of new mechanistic data forthcoming
from the cancer research community
What are hallmarks of cancer?
What are hallmarks of cancer?
Posed by Douglas Hanahan and Robert Weinberg in 2000
As refined by Douglas Hanahan and Robert Weinberg in 2011
The hallmarks
1- The accelerator => full speed ahead;
signals instruct cells to grow and divide
chronically
Driver mutations that
convert normal cellular
genes into serve to
stimulate and sustain
progression of cells through
their growth-and-division
cycles.
Sustaining Proliferative signaling
Sustaining Proliferative signaling
• The most prominent of these
signaling channels being
growth-promoting signals
transmitted through the RAS-
RAF-MEK-MAPK pathway.
• one-third of human tumors
expressing a constitutively
activated mutant form of RAS.
• The main members of
the RAS gene family—
KRAS, HRAS, and NRAS
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.
2- The brakes have failed; signals to
STOP are disabled
Evading growth suppressors
• The most prominent brakes:
1- The direct regulators of the
cell division cycle, embodied in
the retinoblastoma protein (pRb)
2- ‘cyclindependent’ kinase
inhibitors that block progression
of an individual cell through its
growth-and-division cycle.
3- p53 pathways :p53 gene is
mutated in ~40% of all human
cancers
Palbociclib (Ibrance®)
ER-positive, HER2-negative breast cancer
3- Avoiding assisted suicide of outlaw cells;
abrogation of the inborn willingness of cells to die
for the benefit of the organism
Resisting cell death
• The most prominent of these
programs :
1- Apoptosis, which helps to
maintain tissue homoeostasis.
2- Necrosis, which may be
activated by various conditions,
including oxygen and energy
deprivation.
3- Autophagy , degrading cellular
organelles, autophagy generates
the metabolites and nutrients
that cells are unable to acquire
from their surroundings
Resisting cell death
• The loss of TP53 tumor
suppressor function.
• Increasing the expression
of antiapoptotic
regulators Bcl-2 family.
• Down regulating
proapoptotic Bcl-2–
related factors (Bax, Bim,
Puma).
Hallmarks of cancer
4- Circumventing a counting mechanism that disrupts
continuing cell division when a set limit is reached
Enabling replicative immortality
• This mechanism depends on up
regulating the expression of the
telomere-extending enzyme
telomerase.
• Destroying the cellular
timekeeper, the telomere.
• These cells acquire the
unlimited replicative
potential—termed cellular
immortality—that is required
to spawn large tumor masses.
Enabling replicative immortality
• All cancer cells maintain
their telomeres. 90% of
them do so by increasing
the production of
telomerase enzyme.
telomerase functions by
adding telomeric DNA to
the ends of chromosomes.
5- Turning on new blood vessel growth, to feed and
nurture the growing mass of cancer cells
Inducing angiogenesis
• Tumor require a steady supply of oxygen, glucose, and other
nutrients, as well as a means to evacuate metabolic waste to
sustain cell viability and proliferation; the vasculature serves
these purposes.
• hypoxia-inducible transcription factor (HIF) system, which
regulates hundreds of genes, including ones that directly or
indirectly induce angiogenesis and other stress-adaptive
capabilities.
Hallmarks of cancer
Hallmarks of cancer
6- Guerilla cells that growing by migrating and invading
into normal organs, locally and throughout the body,
‘living off the fertile land’
Activating invasion and metastasis
• the 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
• Hypoxia response system, which
triggers the activation of the
hypoxia-inducible transcription
factors HIF1a and HIF2a,
consequently altering expression
of hundreds of genes .
Hallmarks of cancer
7- Alternative energy sources – hybrid engines - tapped
to provide fuel for cell growth;
engines that also produce ample supplies of the cellular
building blocks needed to generate new cancer cells
Deregulating cellular engine
Warburg Effect or aerobic glycolysis
• Cancer cells 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.
• These molecules are used as
building blocks for the production
of proteins, lipids and DNA
required by the rapidly
dividing cells.
Deregulating cellular engine
• Low oxygen activates
the hypoxia stress
response, mediated
by the hypoxia
inducible factor (HIF)
Hallmarks of cancer
8- In many cases, the immune system detects a
problem and tries to kill cancer cells, an attack
which lethal tumors learn to circumvent
Avoiding immune destruction
• cancer cells evade immune
destruction is by delivering
signals that hold immune
cells in check.
• New anti-cancer treatments
have attempted to stop these
immune checkpoint signals.
 Ipilimumab (Yervoy)-
Melanoma
 Nivolumab (Opdivo) _NSCLC
 Pembrolizumab (Keytruda)-
Melanoma.
Enabling characteristics
Enabling Characteristics
(Facilitators of hallmarks capabilities)
How are these hallmark capabilities
acquired?
• Via Enabling Characteristics
Failure of crucial teams of proteins that protect the DNA of
the genome from being corrupted, rearranged, damaged; the
result is mutations that convey on cancer cells hallmark
capabilities
Genome Instability and Mutation
• Two of the most
famous proteins in
cancer, BRCA1 and
BRCA2, play a
central role in DNA
repair.
Tumors are “wounds that don’t heal”;
Immune cells that normally participate in wound
healing inadvertently help cancer cells acquire
hallmark capabilities & become more aggressive
Tumor Promoting inflammation
• Chronic infections, obesity,
smoking, alcohol
consumption,
environmental pollutants
and high fat diets are now
recognized as major risk
factors for most common
types of cancer; and,
importantly, all these risk
factors are linked to cancer
through inflammation.
Tumor Promoting inflammation
• There are many similarities
between
a cancerous tumor and the
process of wound healing. Both
involve the growth, survival
and migration of cells; both
require the growth of new
blood vessels.
Tumor Promoting inflammation
Therapeutic targeting of the hallmarks
of cancer.
Therapeutic targeting of the hallmarks
of cancer
• Drugs have been developed that
disrupt or interfere with all eight of the
hallmark capabilities, and with the two
enabling facilitators .
• Co-targeting multiple independent
hallmarks, it will be possible to limit or
even prevent the emergence of
simultaneous adaptive resistance to
independent hallmark-targeting drugs;
clinical and preclinical trials are
beginning to assess the possibilities.
Olaparib
Nivolumab
The hallmarks of cancer are thought to be
necessarily acquired during the multistep
pathogenesis pathways leading to most forms of
human cancer.
Certain forms of cancer may be less dependent
on one hallmark or another..
Hallmarks in Breast Cancer
Cancer Hallmarks and breast cancer
Dai et al., identified the
dominant hallmarks
driving breast cancer
heterogeneity by
focusing on identified
biomarkers and the
associated subtypes
(Dai, Xiang, Li, & Bai, 2016) .
• Why triple negative subtype
is the most aggressive
Breast tumor?
Hallmark 1: Sustaining proliferative
signaling
• In breast cancer, Among the
three hormonal receptors (ER,
PR, AR) and the growth
receptor (HER2), ER plays a
determinant role on
differentiating breast tumors
regarding their proliferation
ability (corresponding to the
‘sustaining proliferative
signaling’).
Hallmark 2: activating invasion and
metastasis
Taken together, basal, Epithelial
Mesenchymal Transition EMT
or stem cell markers, which
represent the properties of the
‘activating invasion and
metastasis’ hallmark, are more
likely to be enriched in triple
negative tumors.
• The poor prognosis of triple
negative tumors is associated
with the ‘activating invasion
and metastasis’ hallmark.
Hallmark 3: Evading immune
destruction
• The interferon-rich subtype is recently
identified from ER-PR-HER2- tumors, which is
characterized by the over-expression of
interferon-regulated genes.
Hallmark 4: Resisting cell death
• The protein BCL2 is a suppressor of apoptosis,
which has been verified in a variety of in vitro
and in vivo experiments.
• Moderate to strong BCL2 expression (BCL2+
tumors) is intensely associated with several
favorable prognostic features, such as low high
histological grade of differentiation.
Hallmark 4: Resisting cell death
• Clinically, Several recent projects found
superior survival observed for BCL2+ breast
patients.
• The predictive value of BCL2 is reported for
ER-PR-HER2- breast tumors, with ER-PR-HER2-
BCL2- patients found beneficial from
anthracycline-based regimen .
Hallmark 5: Genome instability and
mutation
TP53 dysfunction
increases tumor drug
resistance.
• An interaction between
TP53 and PR is
revealed, where TP53-
Pr tumors are found
associated with the
worst prognosis among
all breast cancers .
Hallmark 5: Genome instability and
mutation
• Increasing evidences have
suggested that TP53
dysfunction is responsible
for the development of
anti-oestrogen
(Tamoxifen) resistance
among ER+ tumors.
• ER-TP53- tumors may
suffer from chemotherapy
treatment failure.
Hallmark 5: Genome instability and
mutation
• These evidences altogether suggest that
‘genome instability and mutation’ contributes
to tumor drug resistance regardless of which
subtype it belongs to.
Hallmark 6: Deregulating cellular
energetics
• Higher level of circulating vitamin D
metabolites is shown to be associated with
decreased breast cancer risk.
Conclusion
• Triple negative tumors are often
associated with more aggressive
properties.
• Though the basic receptors (ER, PR,
HER2) classifying breast tumors stay
the same, novel biomarkers and
approaches in subtyping of such
tumors have been kept reported.
• With the arrival of the times of
precision medicine, precise molecular
characterization of the heterogeneity
of complex diseases such as breast
cancer has become of particular
importance.
Conclusion
• Certain forms of cancer may
be less dependent on one
hallmark or another.
• The hallmarks concept is
helping to rationalize the
wealth of new mechanistic
data forthcoming from the
cancer research community.
Acknowledgement
Douglas Hanahan
References
• Dai, Xiaofeng, Liangjian Xiang, Ting Li, and Zhonghu Bai.
2016. “J O U R N a L O F C a N c E R Cancer Hallmarks ,
Biomarkers and Breast Cancer Molecular Subtypes.”
• Hanahan, Douglas, and Robert A Weinberg. 2011. “Review
Hallmarks of Cancer : The Next Generation.” Cell 144(5):
646–74.
• Hanahan, Douglas,and Robert A Weinberg. 2000. “The
Hallmarks of Cancer Review University of California at San
Francisco.” 100: 57–70.
• David J. Kerr, Daniel G. Haller, Cornelis J. H. van de Velde,
and Michael Baumann. Oxford Textbook of Oncology (3 ed.)
THANK YOU !

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Hallmarks of cancer

  • 2. Contents: Definition of hallmarks. Overview on hallmarks. Hallmarks have been identified in Breast Cancer.
  • 3. • Cancer was first described by the ancient Egyptians The earliest description of cancer was found in the Edwin Smith Papyrus dating back to 1600 B.C. The document describes breast tumors removed by a tool called the fire drill. However, it states that "there is no treatment".
  • 4. Early theories about cancer causes From the earliest times, physicians have puzzled over the causes of cancer. Ancient Egyptians blamed cancers on the gods. Humoral theory (Hippocrates) Lymph theory (1700s) Blastema theory (1800s) Chronic irritation theory (1860) Trauma theory (late 1800s until the 1920s) Infectious disease theory
  • 5. Early theories about cancer causes Ancient Egyptians blamed cancers on the gods. Humoral theory Lymph theory Blastema theory Chronic irritation theory Trauma theory Infectious disease theory
  • 6. Modern Knowledge about Cancer causes • 1915, Viral and chemical carcinogens. • During the 1970s, scientists discovered 2 particularly important families of genes related to cancer: “oncogenes and tumor suppressor genes.” Oncogene Tumor Suppressor gene
  • 7. • Cancer is a disease of extraordinary complexity, at all levels (genetic, histological, pathological, prognostic, therapeutic…) • How can we rationalize this complexity? • Are there common principles underlying this daunting diversity?
  • 9. Hallmarks of cancer Most cited Cell Article of All Time in the fundamental oncology literature (Strickaert et al., 2016)
  • 10. Hallmarks of cancer • Is this concept applicable to the goal of more effectively treating human cancers? The hallmarks concept is helping to rationalize the wealth of new mechanistic data forthcoming from the cancer research community
  • 11. What are hallmarks of cancer?
  • 12. What are hallmarks of cancer?
  • 13. Posed by Douglas Hanahan and Robert Weinberg in 2000
  • 14. As refined by Douglas Hanahan and Robert Weinberg in 2011
  • 16. 1- The accelerator => full speed ahead; signals instruct cells to grow and divide chronically
  • 17. Driver mutations that convert normal cellular genes into serve to stimulate and sustain progression of cells through their growth-and-division cycles. Sustaining Proliferative signaling
  • 18. Sustaining Proliferative signaling • The most prominent of these signaling channels being growth-promoting signals transmitted through the RAS- RAF-MEK-MAPK pathway. • one-third of human tumors expressing a constitutively activated mutant form of RAS. • The main members of the RAS gene family— KRAS, HRAS, and NRAS
  • 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. 2- The brakes have failed; signals to STOP are disabled
  • 21. Evading growth suppressors • The most prominent brakes: 1- The direct regulators of the cell division cycle, embodied in the retinoblastoma protein (pRb) 2- ‘cyclindependent’ kinase inhibitors that block progression of an individual cell through its growth-and-division cycle. 3- p53 pathways :p53 gene is mutated in ~40% of all human cancers
  • 23. 3- Avoiding assisted suicide of outlaw cells; abrogation of the inborn willingness of cells to die for the benefit of the organism
  • 24. Resisting cell death • The most prominent of these programs : 1- Apoptosis, which helps to maintain tissue homoeostasis. 2- Necrosis, which may be activated by various conditions, including oxygen and energy deprivation. 3- Autophagy , degrading cellular organelles, autophagy generates the metabolites and nutrients that cells are unable to acquire from their surroundings
  • 25. Resisting cell death • The loss of TP53 tumor suppressor function. • Increasing the expression of antiapoptotic regulators Bcl-2 family. • Down regulating proapoptotic Bcl-2– related factors (Bax, Bim, Puma).
  • 27. 4- Circumventing a counting mechanism that disrupts continuing cell division when a set limit is reached
  • 28. Enabling replicative immortality • This mechanism depends on up regulating the expression of the telomere-extending enzyme telomerase. • Destroying the cellular timekeeper, the telomere. • These cells acquire the unlimited replicative potential—termed cellular immortality—that is required to spawn large tumor masses.
  • 29. Enabling replicative immortality • All cancer cells maintain their telomeres. 90% of them do so by increasing the production of telomerase enzyme. telomerase functions by adding telomeric DNA to the ends of chromosomes.
  • 30. 5- Turning on new blood vessel growth, to feed and nurture the growing mass of cancer cells
  • 31. Inducing angiogenesis • Tumor require a steady supply of oxygen, glucose, and other nutrients, as well as a means to evacuate metabolic waste to sustain cell viability and proliferation; the vasculature serves these purposes. • hypoxia-inducible transcription factor (HIF) system, which regulates hundreds of genes, including ones that directly or indirectly induce angiogenesis and other stress-adaptive capabilities.
  • 34. 6- Guerilla cells that growing by migrating and invading into normal organs, locally and throughout the body, ‘living off the fertile land’
  • 35. Activating invasion and metastasis • the 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 • Hypoxia response system, which triggers the activation of the hypoxia-inducible transcription factors HIF1a and HIF2a, consequently altering expression of hundreds of genes .
  • 37. 7- Alternative energy sources – hybrid engines - tapped to provide fuel for cell growth; engines that also produce ample supplies of the cellular building blocks needed to generate new cancer cells
  • 38. Deregulating cellular engine Warburg Effect or aerobic glycolysis • Cancer cells 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. • These molecules are used as building blocks for the production of proteins, lipids and DNA required by the rapidly dividing cells.
  • 39. Deregulating cellular engine • Low oxygen activates the hypoxia stress response, mediated by the hypoxia inducible factor (HIF)
  • 41. 8- In many cases, the immune system detects a problem and tries to kill cancer cells, an attack which lethal tumors learn to circumvent
  • 42. Avoiding immune destruction • cancer cells evade immune destruction is by delivering signals that hold immune cells in check. • New anti-cancer treatments have attempted to stop these immune checkpoint signals.  Ipilimumab (Yervoy)- Melanoma  Nivolumab (Opdivo) _NSCLC  Pembrolizumab (Keytruda)- Melanoma.
  • 44. Enabling Characteristics (Facilitators of hallmarks capabilities)
  • 45. How are these hallmark capabilities acquired? • Via Enabling Characteristics Failure of crucial teams of proteins that protect the DNA of the genome from being corrupted, rearranged, damaged; the result is mutations that convey on cancer cells hallmark capabilities
  • 46. Genome Instability and Mutation • Two of the most famous proteins in cancer, BRCA1 and BRCA2, play a central role in DNA repair.
  • 47. Tumors are “wounds that don’t heal”; Immune cells that normally participate in wound healing inadvertently help cancer cells acquire hallmark capabilities & become more aggressive
  • 48. Tumor Promoting inflammation • Chronic infections, obesity, smoking, alcohol consumption, environmental pollutants and high fat diets are now recognized as major risk factors for most common types of cancer; and, importantly, all these risk factors are linked to cancer through inflammation.
  • 49. Tumor Promoting inflammation • There are many similarities between a cancerous tumor and the process of wound healing. Both involve the growth, survival and migration of cells; both require the growth of new blood vessels.
  • 51. Therapeutic targeting of the hallmarks of cancer.
  • 52. Therapeutic targeting of the hallmarks of cancer • Drugs have been developed that disrupt or interfere with all eight of the hallmark capabilities, and with the two enabling facilitators . • Co-targeting multiple independent hallmarks, it will be possible to limit or even prevent the emergence of simultaneous adaptive resistance to independent hallmark-targeting drugs; clinical and preclinical trials are beginning to assess the possibilities.
  • 54. The hallmarks of cancer are thought to be necessarily acquired during the multistep pathogenesis pathways leading to most forms of human cancer. Certain forms of cancer may be less dependent on one hallmark or another..
  • 56. Cancer Hallmarks and breast cancer Dai et al., identified the dominant hallmarks driving breast cancer heterogeneity by focusing on identified biomarkers and the associated subtypes (Dai, Xiang, Li, & Bai, 2016) .
  • 57. • Why triple negative subtype is the most aggressive Breast tumor?
  • 58. Hallmark 1: Sustaining proliferative signaling • In breast cancer, Among the three hormonal receptors (ER, PR, AR) and the growth receptor (HER2), ER plays a determinant role on differentiating breast tumors regarding their proliferation ability (corresponding to the ‘sustaining proliferative signaling’).
  • 59. Hallmark 2: activating invasion and metastasis Taken together, basal, Epithelial Mesenchymal Transition EMT or stem cell markers, which represent the properties of the ‘activating invasion and metastasis’ hallmark, are more likely to be enriched in triple negative tumors.
  • 60. • The poor prognosis of triple negative tumors is associated with the ‘activating invasion and metastasis’ hallmark.
  • 61. Hallmark 3: Evading immune destruction • The interferon-rich subtype is recently identified from ER-PR-HER2- tumors, which is characterized by the over-expression of interferon-regulated genes.
  • 62. Hallmark 4: Resisting cell death • The protein BCL2 is a suppressor of apoptosis, which has been verified in a variety of in vitro and in vivo experiments. • Moderate to strong BCL2 expression (BCL2+ tumors) is intensely associated with several favorable prognostic features, such as low high histological grade of differentiation.
  • 63. Hallmark 4: Resisting cell death • Clinically, Several recent projects found superior survival observed for BCL2+ breast patients. • The predictive value of BCL2 is reported for ER-PR-HER2- breast tumors, with ER-PR-HER2- BCL2- patients found beneficial from anthracycline-based regimen .
  • 64. Hallmark 5: Genome instability and mutation TP53 dysfunction increases tumor drug resistance. • An interaction between TP53 and PR is revealed, where TP53- Pr tumors are found associated with the worst prognosis among all breast cancers .
  • 65. Hallmark 5: Genome instability and mutation • Increasing evidences have suggested that TP53 dysfunction is responsible for the development of anti-oestrogen (Tamoxifen) resistance among ER+ tumors. • ER-TP53- tumors may suffer from chemotherapy treatment failure.
  • 66. Hallmark 5: Genome instability and mutation • These evidences altogether suggest that ‘genome instability and mutation’ contributes to tumor drug resistance regardless of which subtype it belongs to.
  • 67. Hallmark 6: Deregulating cellular energetics • Higher level of circulating vitamin D metabolites is shown to be associated with decreased breast cancer risk.
  • 68. Conclusion • Triple negative tumors are often associated with more aggressive properties. • Though the basic receptors (ER, PR, HER2) classifying breast tumors stay the same, novel biomarkers and approaches in subtyping of such tumors have been kept reported. • With the arrival of the times of precision medicine, precise molecular characterization of the heterogeneity of complex diseases such as breast cancer has become of particular importance.
  • 69. Conclusion • Certain forms of cancer may be less dependent on one hallmark or another. • The hallmarks concept is helping to rationalize the wealth of new mechanistic data forthcoming from the cancer research community.
  • 71. References • Dai, Xiaofeng, Liangjian Xiang, Ting Li, and Zhonghu Bai. 2016. “J O U R N a L O F C a N c E R Cancer Hallmarks , Biomarkers and Breast Cancer Molecular Subtypes.” • Hanahan, Douglas, and Robert A Weinberg. 2011. “Review Hallmarks of Cancer : The Next Generation.” Cell 144(5): 646–74. • Hanahan, Douglas,and Robert A Weinberg. 2000. “The Hallmarks of Cancer Review University of California at San Francisco.” 100: 57–70. • David J. Kerr, Daniel G. Haller, Cornelis J. H. van de Velde, and Michael Baumann. Oxford Textbook of Oncology (3 ed.)