Hallmarks
Evolution of a Species
• is the change in the inherited characteristics of
biological populations over successive
generations.
• Evolutionary processes give rise to diversity at
every level of biological organization, including
species, individual organisms and molecules such
as DNA and proteins.
Natural Selection
• is the gradual process by which biological traits
become either more or less common in a
population as a function of the effect of
inherited traits on the differential reproductive
success of organisms interacting with their
environment.
• “Survival of the fittest.”
Evolution of Cells
Cells of the human body are constantly growing,
moving, dividing, and dying.
• The steady occurrence of division allows for
the possibility and reality of genetic mutations.
• The accumulation of genetic mutations can
lead to either suitable conditions for the
human or conditions that compromise the
function of the body.
Cancer
• Is the unregulated growth of cells, dividing and growing
uncontrollably.
• Stage 0 – A cluster of cancer cells that is in the position where it
started. It poses little or no threat to life.
• Stage 1- Localized cancer. Cancer cells begin to pass through the
thin fibrous membrane that separates cancer tissue from healthy
tissue. Indicates that growing cancer cells may threaten life.
• Stage 2 & 3 – Regional spread. Cancer daughter cells begin to
invade through lymph vessels and get caught in lymph nodes.**
• Stage 4- Distant Spread. Cancer cells get into the blood stream
and go elsewhere in the body and form colonies in other organs.
Accumulation of Mutations
• Cancer requires the accumulation of various genetic
mutations that allow for the proliferation of these
cancerous cells.
• Hallmarks outlines 6 acquired capabilities that are shared
by most and perhaps all types of human cancer.
• Self-sufficiency in growth signals
• Insensitivity to anti-growth signals
• Tissue invasion & metastasis
• Limitless replicative potential
• Sustained angiogenesis
• Evading apoptosis
Self Sufficiency in Growth
Signals
• Healthy cells require growth signals to move from G0 into G1,
an active proliferative state. These signals are usually received
from neighboring tissue.
• These signals are transmitted into the cell by transmembrane
receptors that bind distinctive classes of signaling molecules:
diffusible growth factors, extracellular matrix components, and
cell-to-cell adhesion/interaction molecules. **
• Tumor cells are liberated from this dependence on outside
growth signals.
• These cells synthesize their own GS creating autocrine
stimulation.
• In many instances Growth Factor receptors (Tyrosine Kinase
Receptors) are overexpressed in many cancers, which causes cell to
become hyperresponsive to levels of GF that would not normally
trigger proliferation
Self Sufficiency in Growth
Signals
• Proliferation can also be caused independent from
ligands if the structural integrity of GF receptors is
altered.
• The issue that arises from the acquired Growth Signal
autonomy is the alteration of downstream pathways (e.g.
SOS-Ras-Raf-MAPK pathway) that control and influence
proliferation.
• Altered Ras proteins can enable the release of signals into
the cells without stimulation from upstream regulators.
• Altered Ras proteins are found in about half of the tumors
studied of human colon carcinomas.
Insensitivity to Antigrowth
Signals
• In healthy tissue, there are Antiproliferative signals that keep
cells in cellular quiescence. These Growth Inhibitory signals
act just like their counterparts and are received by cell surface
receptors coupled to intracellular signaling circuits.
• These Growth Inhibitory signals can pull cells from active
proliferation (G1) into the quiescent state (G0), from which they
can reemerge on some future occasion when they are permitted
by GS.
• A normal cell’s proliferative potential can be permanently
relinquished by being induced into a postmitotic state, which
usually occurs in differentiation. **
Insensitivity to Antigrowth
Signals
• Cancer cells must evade these antiproliferative signals if they
are to prosper within the body.
• These cells may turn off expression of integrins that send
antigrowth signals and instead favor those that have progrowth
signals.
• The antigrowth circuit which influences the cell cycle is
disrupted in a majority of cancer and tissues lose this essential
tumor suppression characteristic.
• Our healthy cells also limit cell multiplication by instructing
cells to become differentiated and therefore in postmitotic
states.
• Cancer cells use various strategies to avoid or reverse this
terminal differentiation.
Evading Apoptosis
• The apoptotic program, programmed cell death, is present in
virtually every cell in the body. Once triggered by physiologic
signals, the program follows a set of precise choreographed
steps leading to the cells demise.
• Intracellular sensors monitor the cell’s wellbeing. When
detecting abnormalities (DNA damage, signaling imbalance by
oncogene action, survival factor insufficiency, or hypoxia) and
begins death pathway.
• A potent catalyst of apoptosis is cytochrome C, a proapoptotic
signal, is released by the mitochondria.
• Tumor suppressor proteins can elicit apoptosis by upregulating
expression of proapoptotic proteins in response to sensing DNA
damage
• Ultimately intracellular proteases, caspases, are the effectors of
apoptosis.
Evading Apoptosis
• Apoptosis is a great barrier to cancer. In a 1972 study, in
populations of cells that were rapidly growing there was
massive apoptotic activity.
• This aggressive apoptotic activity shows that mutant cells that
arise and multiply largely can still be controlled and removed
from the body’s tissues if apoptosis is able to occur.
• Cells that lose this behavior often mutate a gene that
produces p53 which is a key component of the DNA damage
sensor that can induce the apoptotic effector cascade.
• Apoptotic program is lost of the cell’s sensors are damaged and
cannot relay the signal that conditions in the cell are abnormal.
Evading Apoptosis
• Evidence has been found that the regulatory and effector
components of the apoptotic signaling circuitry are redundant.
• “This redundancy holds important implications for the
development of novel types of antitumor therapy since tumor
cells that have lost proapoptotic components are likely to retain
other similar ones.”
• A treatment restoring the apoptotic defense mechanism
inherent in cells is a primary goal.
Limitless Replicative Potential
• Most kinds of mammalian cells have an intrinsic program that
determines a finite replicative potential. Senescence is the
process by which cell populations stop growing after their
allotted number of doublings.
• Telomeres, the nonsensical sequences of base pairs at the end
of chromosomes, regulate the amount of doubling in each
generation of cells.
• In each cell cycle 50-100 base pairs are lost. Eventually essential
chromosomal DNA will be impaired through this shortening and
the generation will effectively end.
Limitless Replicative Potential
• In malignant cells the telomeres are maintained by
upregulating the expression of the telomerase enzyme, which
adds hexanucleotide repeats onto the telomeric end of DNA.
• Telomeres are then kept at a critical threshold allowing for the
unlimited multiplication of their cells.
• Senescence is a protective mechanism that can be activated
by cells with shortened telomeres and force them into a G0
state in which they won’t be able to further proliferate.
Sustained Angiogenesis
• All cells in a tissue require a nearby (within 100 μm)
blood supply, a capillary blood vessel, to supply essential
compounds to the cell (oxygen, nutrients).
• Once tissue is formed, new blood vessels are formed
through angiogenesis to provide access to nutrients.
• Angiogenesis is encouraged or blocked by
counterbalancing positive and negative signals.
• Vascular Endothelial Growth Factor (VEGF) encourages,
throbospondin-1 inhibits.
Sustained Angiogenesis
• Malignant cells initially lack angiogenic ability and must
acquire this capability in order to become macroscopic.
• An “angiogenic switch” must be turned on to induce and sustain
angiogenesis by changing the balance of angiogenesis inducers
and inhibitors.
• Angiogenesis was found to be activated in tumors prior to their
appearance as large full blown tumors.
• Studies have been executed where anti-VEGF antibodies were
able to impair the growth of tumors in mice, providing
evidence to show the necessity of angiogenesis of explosive
growth of tumors.
• VEGF (angiogenesis encourager) inhibitors are now being tested
in clinical trials to downregulate proteins that aid in angiogenesis
of tumors.
Tissue Invasion & Metastasis
• Cell-cell adhesion molecules (CAMs) are proteins that tether
cells to their surrounding tissues.
• Many of the adherence interactions convey regulatory signals
to the cell.
• For example, E-cadherin, the most widely observed CAM, bridges
the transmission of antigrowth signals.
• When E-cadherin expression was upregulated in cancer cells,
invasion and metastasis were impaired.
• When malignant cells lose their capability to use CAMs, the
cells break off from the tumor and are able to travel to new
sites in the body.
Tissue Invasion & Metastasis
• After malignant cells are able to detach from the primary body
of the tumor successful colonization of new sites requires
adaptation to the new microenvironment.
• The cancer cells facilitate this adaptation by shifting the
expression of extracellular proteins (integrins) to ones that are
favored by the ECM of the new site.
• If malignant cancers are able to upregulate proteases, they
can degrade the matrix of nearby cells and invade the stroma
where they will have access to blood vessel walls.
A Different Approach to Cancer
• The natural selection that occurs within the body to create an
aggressive cancer is difficult to understand as one disease and
also difficult to treat as one disease.