genetic and metabolic disorders

7/29/2019 Genetic and Metabolic Disorders

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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.

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