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Cellular Communities: Tissues,

Stem Cells, and Cancer


(3rd half)

Stem cells Generate a continuous


supply of terminally differentiated cells
Differentiated cells that need continual replacement
are themselves unable to dividereferred to as
terminally differentiatedtheir replacements are
generated from a stock of proliferating precursor
cellsthemselves usually derive from small
numbers of dividing stem cellsStem cells are not
terminally differentiated & can divide without limit
When a stem cell divides hough, each daughter has
a choice: either it can remain a stem cell, or it can
embark on a course leading irreversibly to terminal
differentiationstem cells of adult tissues are
nonetheless specializedpattern of cell replacement
varies from one stem-cell-based tissue to another
e.g. In the lining of the small intestine.

The absorptive & secretory cellsare arranged as a


simple epithelium covering the surfaces of the
fingerlike villi that project into the gut lumenThis
epithelium is continuous with the epithelium lining
the cryptsthe stem cells lie near the bottom of the
cryptsNewborn absorptive and secretory cells
generated from stem cells begin to differentiate in
the cryptsMost of these differentiating cells are
carried upward by a sliding movement in the plane
of the epithelial sheet until they reach the exposed
surfaces of the villi; at the tips of the villi the cells
die and are shed into the gut. Often, a single type of
stem cell gives rise to several types of differentiated
progeny e.g the stem cells of the intestine, bloodcell formation, or hemopoiesis, both the red &
white blood cells are derived from a shared
hemopoietic stem cell found in the bone marrow.

Fig: When a stem cell divides, each


daughter can either remain a stem cell
or go on to become terminally

Fig: Renewal occurs continuously in the


lining of the adult intestine

Specific signals maintain the stemcell populations


Stem-cell system requires control mechanisms
depend on molecular signalsa class of signal
molecules known as the Wnt proteinsserve to
keep the stem cells and precursor cells at the base of
each intestinal crypt in a proliferative statethe cells
in these regions both secrete Wnt proteins & express
the receptors for these proteins and, apparently
through positive feedback, they stimulate
themselves to continue dividingAt the same time,
these cells produce other signals, which act at longer
range to prevent activation of the Wnt pathway
outside the crypts. Disorders of these signaling
mechanisms disrupt the structure of the gut lining

Figure 2040 The Wnt signaling


pathway
helps to control the production of
differentiated cells from stem cells in
the intestine

Stem cells can Be used to repair


damaged tissues
Stem cellsproliferate indefinitely, provide for both continual
renewal of normal tissue and repair of tissue lostStem cells
taken directly from adult tissues hold promise for use in tissue
repairthrough cell culture, to derive from early mouse
embryos an extraordinary class of stem cells called
embryonic stem cells, or ES cellsretain unrestricted
developmental potential and are thus said to be pluripotent
if they are put back into an early embryo then they can give
rise to all the tissues & cell types. Similar to mouse ES cells
cells can now be derived from early human embryosused
for the replacement and repair of mature human tissues.
Perhaps one day it might even become possible to grow entire
organs from ES cells. One major problem concerns immune
rejection. A possible way around this problem is to use a
strategy known colloquially as therapeutic cloning

Fig: ES cells derived from an embryo can


give rise to all of the tissues and cell types
of the body

Therapeutic cloning could provide a


way to generate personalized es cells
Cloninga clone is simply a set of individuals that are
genetically identicalone can take a single epidermal
stem cell & let it grow & divide in cultureobtain a large
clone & help reconstruct the skin. The cloning of entire
multicellular animalscalled reproductive cloning
an individual is not genetically identical to any of his
parentachieved in mice and sheep and some other
domestic animals by a technique called nuclear
transplantationbegins with an unfertilized egg cell
The nucleus of this haploid gamete cell is sucked out,
and in its place a nucleus from a regular diploid cell is
introducedThe hybrid cell is allowed to develop for a
short while in culturecan give rise to an early embryo,
which is then put into the uterus of a foster mother.

If the experimenter is lucky, development


continues as it would in a normal embryogiving
rise to a whole new animal.
Another procedureIn this case, the cell that has
received the transplanted nucleus is allowed to
undergo the earliest steps of development
giving rise to a very early embryonot
transferred to the uterusused as a source from
which ES cells are derived in culture, with the
aim of generating various cell typescan be
used for tissue repair. This so-called
therapeutic cloning is an elaborate technique
for generating personalized ES cells, rather than
whole cloned animalscells obtained by this
route can be grafted back into the donor without
fear of immunological rejection

Fig: Cells from adult tissue can be used for


cloning in two quite different senses of the
word.

Cancer

Cancers arise from violations of the basic rules of social cell


behavior
Cancer cells proliferate, invade, and metastasize
The cell must divide when new cells of its specific type are
needed& refrain from dividing when they are notin a
large organism, no significant harm is done if a single cell
misbehavesBut a potentially devastating breakdown of
control occurs when a single cell suffers a genetic alteration
that allows it to survive and divide when it should not.
Cancer cells are defined by two heritable properties(1)
proliferate in defiance of the normal constraints and (2)
invade and colonize territories normally reserved for other
cellsCells that have the first property but not the second
are said to be benignusually be removed cleanlyif its
cells have the ability to invade surrounding tissue, in which
case the tumor is said to be malignantform secondary
tumors (metastases) at other sites in the body.

Epidemiology identifies preventable


causes of cancer
Epidemiologythe statistical analysis of
human populations that is used to look
for factors that correlate with disease
incidenceThis approach has provided
strong evidence that the environment
plays a part in the causationcancer is
not an infectious diseasee.g. tobaccosmoking causing lung & bladder cancer
If we could stop the use of tobacco, it
is estimated that we could prevent

Cancers develop by an
accumulation of mutations
Cancer is fundamentally a genetic diseasearises
as a consequence of pathological changes in the
information carried by DNAmutations underlying
cancer are mainly somatic mutationsidentified
agents known are ionizing radiation and most
chemical carcinogensmutations may occur
spontaneously as a result of fundamental
limitations on the accuracy of DNA replication and
DNA repairmost human cancer cells not only
contain many mutations but also are genetically
unstable. This genetic instability results from
mutations that interfere with the accurate
replication and maintenance of the genome.

Cancer cells evolve properties that


give them a competitive advantage
Natural selection favors cells carrying mutations
enhance cell proliferation and cell survival,
regardless of the effects on neighborsThat cell
and its progeny must also be able to displace their
normal neighbors and to attract a blood supply to
nourish continued tumor growthhave ability to
spread to other tissues, an ability known as
metastasisDifferent cancers require different
combinations of properties1. They have a
reduced dependence on signals from other cells
for their growth, survival, and division2. Cancer
cells are less prone than normal cells to kill
themselves by apoptosis.

3. Unlike most normal human cells,


cancer cells can often proliferate
indefinitely
4. Most cancer cells are genetically
unstable, with a greatly increased
mutation rate
5. Cancer cells are abnormally invasive,
and this is often in part because they lack
specific cell-adhesion molecules, such as
cadherins, that hold normal cells in their
proper place.
6. Cancer cells can often survive and
proliferate in foreign tissues to form

Many diverse types of genes are


critical for cancer
The dangerous mutations are ones that make the
affected gene product hyperactiveonly one gene copy
needs to be mutatedthe resulting mutant gene is called
an oncogenethe corresponding normal form of the
gene is called a proto-oncogenemutations are
generally recessive: both gene copies must be lost or
inactivated before an effect is seen; the affected gene is
called a tumor suppressor geneindividuals are
encountered who have inherited a mutation in a tumor
suppressor gene. Proto-oncogenes and tumor suppressor
genes are of many sortsSome of these genes code for
growth factors, for receptors, or like Rasfor
components of the intracellular signaling pathways that
growth factors activate. Others code for DNA repair
proteins

Colorectal cancer illustrates how loss of


a Gene can lead to Growth of a tumor
Colorectal cancer arises from the epithelium lining the
colon and rectumthe predisposition to cancer has been
traced to an inherited mutation in a DNA repair enzyme.
In another class of hereditary colorectal cancer patients
by the development of hundreds or thousands of little
tumorous growths, called polyps in the lining of the
colon and rectumcan be traced to deletion or
inactivation of a gene called the Adenomatous
Polyposis Coli (APC) geneAffected individuals
inherit one mutant copy of the gene and one normal
APC as a tumor suppressor geneencode an inhibitory
protein that normally restricts the activation of the Wnt
signaling pathway, which is involved in stimulating cell
proliferation in the crypts of the gut lining

An understanding of cancer cell Biology


opens the way to new treatments
Cancer cells rapidly evolve resistance to
treatmentsare not detected until the primary
tumor has reached a diameter of 1 cm or more
Surgery remains the most effectiveif a cancer
has not spread far, it can often be cured by simply
cutting it outcancer cells can often be killed by
doses of radiotherapy or DNA-damaging
chemotherapy that leave adjacent normal cells
relatively unharmedthe cancer cells survive by
relying on other machinery that provides
alternative types of DNA repairA drug that inhibits
one of these alternative DNA repair pathways kills
the cancer cells

Another promising strategy is to block


formation of the new blood vessels that
normally invade a growing tumor
another set of strategies aim in various
ways to use the immune system to kill
the tumor cellsVaccination with tumorspecific molecules can stimulate the
patients own immune system to turn
against the tumoror antibodies against
these tumor molecules can be produced
in vitro and injected into the patient to
mark the tumor cells for destructionIn
some cancers, it is becoming possible to
target the products of specific oncogenes