The document summarizes Hanahan and Weinberg's hallmarks of cancer. It describes the six original hallmarks proposed in 2000 of self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evading apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. In 2011, they added two emerging hallmarks of deregulating cellular energetics and avoiding immune detection, as well as two enabling characteristics of genome instability and tumor-promoting inflammation.

1. Hallmarks of Cancer
Dilip P. Pandya, June 10, 2019

2. Summary
 In 2000, Hanahan & Weinberg (1) proposed most cancer cell genotypes are manifestation of six essential
alterations in cell physiology that collectively dictate malignant growth that become known as Hallmarks of
Cancer:
Self-sufficiency in growth signals, insensitivity to growth-inhibitory (antigrowth) signals, evasion of programmed cell
death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis.
 Each of these physiologic changes—novel capabilities acquired during tumor development—represent the
successful breaching of an anticancer defense mechanism hardwired into cells and tissues.
 Authors proposed that these six capabilities are shared in common by most and perhaps all types of human
tumors and that this multiplicity of defenses may explain why cancer is relatively rare during an average human
lifetime.
 In 2011, Hanahan & Weinberg (2) updated these Hallmarks with addition of two Emerging Hallmarks and two
Enabling Characteristics:
Emerging Hallmarks: Deregulating cellular energetics, avoiding immune detection
Enabling Characteristics: Genome instability and mutation, Tumor-promoting Inflammation
References:
1. Hanahan D. and Weinberg R.A. (2000) The Hallmarks of Cancer. Cell 100: 57-70.
2. Hanahan D. and Weinberg R.A. (2011) The Hallmarks of Cancer: The Next Generation. Cell 144: 646-674.

3. Hallmarks illustrated
Six original Hallmarks proposed in 2000(1).
References:
1. Hanahan D. and Weinberg R.A. (2000) The Hallmarks of Cancer. Cell 100: 57-70.
2. Hanahan D. and Weinberg R.A. (2011) The Hallmarks of Cancer: The Next Generation. Cell 144: 646-674.
Six original Hallmarks definitions updated in 2011(2).

4. Hallmarks illustrated
References:
1. Hanahan D. and Weinberg R.A. (2000) The Hallmarks of Cancer. Cell 100: 57-70.
2. Hanahan D. and Weinberg R.A. (2011) The Hallmarks of Cancer: The Next Generation. Cell 144: 646-674.
Two additional Emerging Hallmarks & Two Enabling Characteristics added in 2011(2).

5. Hallmarks Detailed
1. Acquired Capability: Self-Sufficiencyin growth signals /
Sustaining proliferative signaling
Acquired GS (growth signal) autonomy: Tumor cells generate many of their own growth signals, thereby reducing their
dependence on stimulation from their normal tissue microenvironment.
Three common molecular strategies for achieving GS autonomy include involving alteration of extracellular growth
signals, of transcellular transducers of those signals, or of intracellular circuits that translate those signals into action.
Cancer cells can also switch the types of extracellular matrix receptors (e.g. integrins) they express, favoring ones that
transmit progrowth signals.
The SOS-Ras-Raf-MAPK cascade plays a central role here. In about 25% of human tumors, Ras proteins are present in
structurally altered forms that enable them to release a flux of mitogenic signals into cells, without ongoing stimulation by
their normal upstream regulators.

6. Hallmarks Detailed
2. Acquired Capability :Insensitivity to anti-growth signals /
Evading growth suppressors.
STOP signals are disabled – in analogy to failed brakes. Normal cell division is controlled by tumor suppressor genes,
in cancer, these tumor suppressor proteins are altered so that they don't effectively prevent cell division, even when
the cell has severe abnormalities.
 Normal cells response to antigrowth signals is associated with the cell cycle clock, specifically the components
governing the transit of the cell through the G1 phase of its growth cycle.
Antigrowth circuit converge onto tumor suppressors encode the RB (retinoblastoma-associated) and TP53 proteins
that operate as nodes in cellular regulatory circuits that govern the decisions of cells to proliferate or, alternatively,
activate senescence and apoptotic programs.
Cell proliferation depends on avoidance of cytostatic antigrowth signals. It is apparent that tumor cells use various
strategies to avoid this terminal differentiation. One strategy for avoiding differentiation directly involves the c-myc
oncogene, which encodes a transcription factor.

7. Hallmarks Detailed
3. Tissue invasion & metastasis / Activating invasion &
metastasis.
In most human cancer, primary tumor masses spawn pioneer cells that move out, invade adjacent tissues,
and thence travel to distant sites where they may succeed in founding new colonies, this process of metastases—
are the cause of 90% of human cancer deaths. Invasion and metastasis are exceedingly complex processes, and their
genetic and biochemical determinants remain incompletely understood.
 Several classes of proteins are alerted in cells possessing invasive or metastatic capabilities. These include
cell–cell adhesion molecules (CAMs)—notably members of the immunoglobulin and calcium-dependent cadherin families,
both of which mediate cell-to-cell interactions—and integrins.
 The multistep process of invasion and metastasis has been schematized as a sequence of discrete steps, often termed the
invasion-metastasis cascade that includes: local invasion, then intravasation by cancer cells into nearby blood and lymphatic
vessels, transit of cancer cells through the lymphatic and hematogenous systems, followed by escape of cancer cells from the
lumina of such vessels into the parenchyma of distant tissues (extravasation), the formation of small nodules of
cancer cells (micrometastases), and finally the growth of micrometastatic lesions into macroscopic tumors, this last step
being termed “colonization.”

8. Hallmarks Detailed
4. Limitless replicative potential / Enabling replicative
immortality.
All mammalian cells carry an intrinsic, cell-autonomous program that limits their multiplication to 60–70 doublings,
also known as Hayflick limit, after which they reach senescence.
The senescence of cultured human fibroblasts can be circumvented by disabling their pRb and p53 tumor suppressor
proteins, enabling these cells to continue multiplying for additional generations until they enter into a second state termed
crisis that results in massive cell death and occasional immortalized cell able to multiply without limit.
The counting device for cell doublings is the telomere, which decreases in size (loses nucleotides at the ends of
chromosomes) during each cell cycle. About 85% of cancers upregulate telomerase to extend their telomeres and the
remaining 15% use a method called the Alternative Lengthening of Telomeres.
Telomerase, the specialized DNA polymerase that adds telomere repeat segments to the ends of telomeric DNA,
is almost absent in non-immortalized cells but expressed at functionally significant levels in the vast majority (∼90%) of
spontaneously immortalized cells, including human cancer cells. These cells acquire the unlimited replicative potential—
termed cellular immortality—that is required to spawn large tumor masses.

9. Hallmarks Detailed
5. Sustained angiogenesis / Inducing angiogenesis
Like normal tissues, tumors require sustenance in the form of nutrients and oxygen as well as an ability to evacuate
metabolic wastes and carbon dioxide. The tumor-associated neovasculature, generated by the process of angiogenesis,
addresses these needs.
 The cells within aberrant proliferative lesions initially lack angiogenic ability, curtailing their capability for expansion.
In order to progress to a larger size, incipient neoplasias must develop angiogenic ability
 The ability to induce and sustain angiogenesis seems to be acquired in a discrete step (or steps) during tumor development,
via an “angiogenic switch” from vascular quiescence. Tumors appear to activate the angiogenic switch by
changing the balance of angiogenesis inducers and countervailing inhibitors.
 The angiogenesis-initiating signals are exemplified by vascular endothelial growth factor (VEGF) and acidic and basic
fibroblast growth factors (FGF1/2). Each binds to transmembrane tyrosine kinase receptors displayed by endothelial cells

10. Hallmarks Detailed
6. Evading apoptosis / Resisting cell death.
The ability of tumor cell populations to expand in number is determined not only by the rate of cell proliferation but
also by the rate of cell attrition. Programmed cell death—apoptosis—represents a major source of this attrition.
 Evidence suggest that that acquired resistance toward apoptosis is a hallmark of most and perhaps all types of cancer.
 The apoptosis machinery can be broadly divided into two classes of components—sensors and effectors. The sensors
are responsible for monitoring the extracellular and intracellular environment for conditions of normality or
abnormality that influence whether a cell should live or die. These signals regulate the second class of components,
which function as effectors of apoptotic death e.g. IGF-1/IGF-2 ligand pair via their receptor.
 The ultimate effectors of apoptosis include an array of intracellular proteases
termed caspases.

11. Emerging Hallmarks Detailed
7. Deregulating cellular energetics.
Since early twentieth century Otto Warburg first observed an anomalous characteristic of cancer cell energy metabolism:
even in the presence of oxygen, cancer cells can reprogram their glucose metabolism, and thus their energy production,
by limiting their energy metabolism largely to glycolysis, leading to a state that has been termed “aerobic glycolysis.”
Cancer cells exhibiting the Warburg effect upregulate glycolysis and lactic acid fermentation in the cytosol and prevent
mitochondria from completing normal aerobic respiration (oxidation of pyruvate, the citric acid cycle, and the
electron transport chain).
A functional rationale for the glycolytic switch in cancer cells has been elusive, given the relatively poor efficiency of
generating ATP by glycolysis relative to mitochondrial oxidative phosphorylation.
Altered energy metabolism is proving to be as widespread in cancer cells as many of the other cancer-associated traits
that have been accepted as hallmarks of cancer.

12. Emerging Hallmarks Detailed
8. Avoiding immune destruction
Unresolved issue surround the role that the immune system plays in resisting or eradicating formation and progression of
incipient neoplasias, late-stage tumors, and micrometastases.
 Immune surveillance is supposed to be responsible for recognizing and eliminating the vast majority of incipient cancer cells
and nascent tumors, in practice though solid tumors that do appear have somehow managed to avoid detection by the
various arms of the immune system or have been able to limit the extent of immunological killing, thereby evading
eradication.
The role of defective immunological monitoring of tumors would seem to be validated by the striking increases of certain
cancers in immunocompromised individuals.
 However, it may be too simplistic to assume highly immunogenic cancer cells may well evade immune destruction by
disabling components of the immune system that have been dispatched to eliminate them.
 Immunoevasion is presented as another emerging hallmark, whose generality as a core hallmark capability remains to be
firmly established.

13. Emerging Characteristics Detailed
9. Genome instability & mutation
A diverse array of defects affect various components of the DNA-maintenance machinery—often referred to
as the “caretakers” of the genome.
 Caretaker genes are responsible for 1) detecting DNA damage and activating the repair machinery,
(2) directly repairing damaged DNA, and (3) inactivating or intercepting mutagenic molecules before they have damaged the
DNA.
 Caretaker genes behave much like tumor suppressor genes, in that their functions can be lost during the course of tumor
progression, with such losses being achieved either through inactivating mutations or via epigenetic repression.
 Telomerase is also now been added to the list of critical caretakers responsible for maintaining genome integrity
 Advances in economical DNA-sequences reveal distinctive patterns of DNA mutations in different tumor types. In the not-
too-distant future, the sequencing of entire cancer cell genomes promises to clarify the prevalence of ostensibly random
mutations scattered across cancer cell genomes. Thus, recurring genetic alterations may point to a causal role of particular
mutations in tumor pathogenesis.

14. Emerging Characteristics Detailed
10. Tumor promoting inflammation
By 2000, there were already clues that the tumor-associated inflammatory response had the unanticipated,
paradoxical effect of enhancing tumorigenesis and progression, in effect helping incipient neoplasias to acquire
hallmark capabilities.
 It is now believed that inflammation can contribute to multiple hallmark capabilities by supplying bioactive molecules to
the tumor microenvironment, including growth factors that sustain proliferative signaling, survival factors that limit cell
death, proangiogenic factors, extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, and metastasis,
and inductive signals that lead to activation of EMT and other hallmark-facilitating programs.
Importantly, inflammation is in some cases evident at the earliest stages of neoplastic progression and is demonstrably
capable of fostering the development of incipient neoplasias into full-blown cancers.
Additionally, inflammatory cells can release chemicals, notably reactive oxygen species, that are actively mutagenic for
nearby cancer cells, accelerating their genetic evolution toward states of heightened malignancy.