Post on 14-Apr-2018
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Genetic and Metabolic Disorders: Carcinogenesis
Cancer cells behave very much like normal cells, which have undergone a
mutation and become altered in an inherited fashion. Heredity is
determined by properties of the germinal cell line. Characteristics such
as eye or hair colour, while expressed in the somatic cells (the
differentiated cells of the mature organism), are passed down from
generation to generation through the sex cells or gametes. From the
heredity point of view of cancer production, however, such changes may
be crucial.
Chromosomal Changes in Cancer Cells
It is an almost invariable feature of advanced cancers, particularly solid
cancers, that they contain many examples of abnormal karyotypes.
Sometimes there is exactly double the normal complement ofchromosomes (tetraploid cells) but more commonly the number is
somewhere between the diploid and tetraploid number and therefore
represents a chromosome imbalance. This condition is called
aneuploidy.
In transplanted tumours in experimental animals, the same characteristic
phenomenon can be observed. If these tumours are followed through many
generations of transplantation, it is often found that the karyotype changes
progressively. Obviously, the tumour cells have an instability, which is
manifested by a propensity for changing their chromosome complement.
Whereas in normal cells exactly half of the chromosomes in the dividing cell
go to each daughter, in tumour cells, the division is often unequal, a
condition called non-disjunction.
From experiment in animals and in isolated cells, it is known that viruses
often cause the chromosomal breaks and that x-rays and some chemicals can
also do this. Since all these agents have been implicated as aetiological
factors in cancer, it is plausible hypothesis that damage to the chromosomes
or to the mitotic apparatus can initiate cancer and that the cancerous process
itself is a consequence of the chromosomal imbalance.
In some human cancers, characteristic chromosomal abnormalities appear.In particular, 90 percent of all cases of chronic granulocytic leukaemia show
an abnormality of chromosome 22. This is normally an asymmetric
chromosome with one short arm and one long arm. In chronic granulocytic
chromosome, leukaemia (CGL), the long arm is absent, giving rise to what
is called Philadelphia chromosome. However, the Philadelphia chromosome
is not present in all mitotic cells in the body in cases of CGL. It occurs only
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in the haemopoietic system where it can be seen not only in the myeloid
cells but also in erythroid precursors and megakaryocytes. This
chromosomal abnormality occurs so frequently in the disease that it is
almost certainly meaningful in relation to its causation. In advanced
leukemia, as in other cancers, progressive karyotypic abnormalities
eventually emerge but these late changes have no recognizable
distinguishing features.
This feature of chronic granulocytic leukemia appears to be unique and so
far nothing corresponding to it has been recognized in any other kind of
leukemia. In some acute leukemias, gross aberrations of chromosomes
occur. Burkitts lymphoma, which may be caused by a tumour virus, also
shows chromosomal aberrations rather frequently.
Hereditary Predisposition To Cancer
The chromosomal changes in tumour cells, which have been described seen
likely to be consequences rather than causes of the disease. However, there
is very convincing evidence for a hereditary element in many experimental
animal tumours, and it is clear that in some human tumours a hereditary
element is involved.
The inheritance of susceptibility to tumour has been quite extensively
studied in experimental animals. In the course of cancer research, many
strains of mice with a susceptibility to a particular kind of tumour have been
identified or bred. The C3H mouse came to prominence as already
mentioned because almost all the females develop mammary tumours due to
the transmission of the mammary tumour virus from mother to infant in the
mothers milk.
Among other mouse strains with inherited tendencies to develop cancer are
the BALB/c strain, which has a high susceptibility to spontaneous lung
tumours, the CBA strain, which develops hepatomas and the C58 strain,
which is prone to develop leukemia.
Breeding experiments also lead to the conclusion that genetic factors of a
general kind may be involved in cancer susceptibility. In two kinds of fish,
the playfish and the swordtail, melanoma tumours are virtually unknown yetin hybrids between them, they occur with a very high frequency. Similarly,
in crosses between different strains of mice, tumours are in general rather
more frequent in hybrids than in the parents.
Remarks: These kinds of observed in experimental animals have their
parallel in some cancers in man, most of which are rather rare.
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Chromosomal Abnormalities and Malignant transformation
Chromosomal abnormalities are a frequent consequence of malignant
transformation but from the studies described earlier there is not very strong
evidence that they regularly precede cancerous changes. However, there are
a number of human diseases, which are characterized by chromosomal
abnormalities and in which an increased incidence of cancer, particularly
leukemia, is observed.
The most common of these is Downs Syndrome or mongolism. This well-
known disease is due to the presence of an extra chromosome 21; in these
individuals, there are three of these chromosomes instead of the usual pair.
Their chromosomal imbalance is sufficient to cause all the stigmata of thedisease and one well-known feature of Downs syndrome is an increased
incidence of leukemias. Kleinfelters disease involves a similar imbalance.
In this condition, the individuals have three sex chromosomes (2X and 1Y)
instead of two. They also exhibit a higher incidence of leukemia than normal
persons.
Cancer associated with diseases inherited as genetic recessives
There is a group of diseases distinguished by a tendency for the
chromosomes to be fragmented and which is also associated with a high
incidence of cancer. All of these diseases are inherited as genetic recessives
and therefore the disease only becomes manifest when the defect is inherited
from both parents.
1. Falconis Anaemia: The first of the conditions exhibiting a tendency
to spontaneous chromosome breaks is called Falconis anaemia. Cells
from these patients are exceptionally sensitive to x-rays and to x-ray-
induced chromosome breakage. Interestingly enough, fibroblasts from
these patients are also particularly susceptible to transformation by the
SV40 virus. Patients with Fanconis anaemia have a quite highprobability of dying of leukemia.
2. Blooms syndrome and Ataxia-telangiectasia: Two other rare
diseases, Blooms syndrome and ataxia-telangiectasia, exhibit very
similar phenomena. They are both recessive characteristics, show
increased chromosomal fragility and pre-dispose to leukaemia. It is
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suspected that in all these disease, the underlying lesion is a defect of
DNA repair.
3. Xeroderma pigmentosum: It has already been remarked that
defective repair occurs. The manifestations of this disease are
particularly observed in the skin. The sufferers are exceedingly
sensitive to sunlight and other forms of irradiation and have a high
incidence of skin cancers.
Cancer associated with diseases inherited as genetically dominant:
Several other human cancers show an even hereditary element in that they
are inherited as a dominant characteristic.
1. Polyposis coli: The best known among is polyposis coli. The multiple
polyps occurring in the colon in this disease have a high likelihood of
developing into adenocarcinomas. These are not the only tumours towhich, these patients are susceptible for they sometimes have tumours
elsewhere, usually of the connective tissues.
2. Basal cell naevus syndrome: the basal cell naevus syndrome is also
inherited as a dominant characteristic. This is a complex condition
involving skeletal abnormalities, ectopic calcification and epidermal
cysts as well as the multiple basal cell carcinomas of the skin, which
characterize the disease and give it its name.
Some tumours, which occur in children have strong hereditary element.
Forty percent of all retinoblastomas are hereditary. About 40 percent of
Wilms tumours are also familiar and there is a hereditary element in over 20
percent of neuroblastomas. Other forms of cancer in which hereditary
elements are prominent are phaeochromocytomas, neurofibromatosis and the
multiple endocrine tumour syndrome, a rather rare condition which is
inherited as a dominant characteristic.
Cancer and metabolic diseases:
LKB1 activates AMPK and related subfamily of kinases: Potential
targets for cancer and metabolic disorders:
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The protein kinase LKB1 is a tumor suppressor that is mutated in the human
Peutz-Jeghers cancer syndrome. AMP-activated protein kinase (AMPK) is
activated by cellular energy depletion and is an established target in
treatment of Type 2 diabetes and the metabolic syndrome. LKB1 has been
shown to be an upstream activator of AMPK and 11 other related kinases,
and therefore has potential as a target for treatment of both cancer andmetabolic disorders, especially diabetes.
The AMP-activated protein kinase (APMK) is the downstream component
of a cascade that is a sensor of cellular energy. Metabolic stress, such as that
occurring in muscle during exercise, activates AMPK by phosphorylation of
a threonine residue on the subunit. Activated AMPK then switches on the
uptake and oxidation of extracellular fuels such as glucose and fatty acids,
whilst switching off biosynthetic pathways. The protein kinases that are
responsible for activating AMPK via phosphorylation of the threonine resi-
due were until recently unknown. AMPK is also activated by metformin, a
drug commonly used for the treatment of Type 2 diabetes. The
serine/threonine protein kinase LKB1 is a product of the gene mutated in the
human disorder Peutz-Jeghers syndrome (PJS). Sufferers of PJS develop
benign polyps in the gut and are predisposed to developing malignant
tumors in other tissues. LKB1 is therefore a suppressor of cell-proliferation
and tumor formation, but its downstream target(s) were until recently
unknown.
Calorie restriction and Cancer:
Metabolic control analysis is an area of biochemistry and bioenergetics that
attempts to define energy or more specifically metabolic flux through
pathways. These pathways involve glycolysis and respiration, the major
energy generating systems of cells. Organisms have evolved to survive
extreme changes in theirenvironment according to the Ecological Instability
theory of Rick Potts. The ability to survive under these extremes is encoded
Management of cellular
energy.
Inhibition of cell growth.
Regulation of cell polarity.
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within the genome. Consequently, stressful environments can alter metabolic
flux through pathways that facilitates survival. In the case of epilepsy,
caloric restriction produces a new metabolic state that reduces brain
excitation while enhancing inhibition. Epilepsy is thought to involve an
imbalance of brain excitatory and inhibitory systems. Calorie restriction
(CR) restores this balance following reductions in circulating glucose and
elevations in circulating ketone bodies. In the case of brain tumors and most
tumors for that matter, caloric restriction places tumor cells under
considerable metabolic stress. Tumor cells are almost completely dependent
on glucose for energy, due to defects in their mitochondria. Tumor cells
cannot metabolize ketone bodies for energy. Normal cells, on the other hand,
can metabolize either glucose or ketone bodies. The utilization of ketone
bodies for energy is a conserved adaptation to spare protein during periods
of caloric deprivation. All normal cells, with the exception of liver cells that
use fatty acids, can metabolize ketone bodies for energy. Caloric restrictiontherefore kills glycolysis-dependent tumor cells while enhancing the health
and vitality of normal cells through ketone body metabolism. Metabolic
control analysis provides a framework for identifying the mechanisms by
which CR manages these diseases.
Conclusion: It appears that chronic disease such as cancer and some neuro-
degenerative disorders may require longer therapeutic fasts than the simple
alternate day fasts.