Hallmarks of cancer

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).

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.

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 .

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)

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.


• 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.


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 .


• 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.


• 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