Page 231 - Textbook of Pathology, 6th Edition

4. AVOIDING CELLULAR AGING: The examples of mutator genes exist in the following 215
TELOMERES AND TELOMERASE IN CANCER inherited disorders associated with increased propensity to
As discussed in pathology of aging in Chapter 3, after each cancer:
mitosis (cell doubling) there is progressive shortening of i) Hereditary non-polyposis colon cancer (Lynch syndrome) is
telomeres which are the terminal tips of chromosomes. characterised by hereditary predisposition to develop
Telomerase is the RNA enzyme that helps in repair of such colorectal cancer. It is due to defect in genes involved in DNA CHAPTER 8
damage to DNA and maintains normal telomere length in mismatch repair which results in accumulation of errors in
successive cell divisions. However, it has been seen that after the form of mutations in many genes.
repetitive mitosis for a maximum of 60 to 70 times, telomeres ii) Ataxia telangiectasia (AT) has ATM (M for mutated) gene.
are lost in normal cells and the cells cease to undergo mitosis. These patients have multiple cancers besides other features
Telomerase is active in normal stem cells but not in normal such as cerebellar degeneration, immunologic derangements
somatic cells. and oculo-cutaneous manifestations.
Cancer cells in most malignancies have markedly iii) Xeroderma pigmentosum is an inherited disorder in which
upregulated telomerase enzyme, and hence telomere length there is defect in DNA repair mechanism. Upon exposure to Neoplasia
is maintained. Thus, cancer cells avoid aging, mitosis does sunlight, the UV radiation damage to DNA cannot be
not slow down or cease, thereby immortalising the cancer repaired. Thus, such patients are more prone to various forms
cells. of skin cancers.
iv) Bloom syndrome is an example of damage by ionising
5. CONTINUED PERFUSION OF CANCER: radiation which cannot be repaired due to inherited defect
TUMOUR ANGIOGENESIS
and the patients have increased risk to develop cancers,
Cancers can only survive and thrive if the cancer cells are particularly leukaemia.
adequately nourished and perfused, as otherwise they cannot
grow further. Neovascularisation in the cancers not only v) Hereditary breast cancer patients having mutated BRCA1
and BRCA2 genes carry inherited defect in DNA repair
supplies the tumour with oxygen and nutrients, but the mechanism. These patients are not only predisposed to
newly formed endothelial cells also elaborate a few growth develop breast cancer but also cancers of various other
factors for progression of primary as well as metastatic organs.
cancer. The stimulus for angiogenesis is provided by the
release of various factors: 8. CANCER PROGRESSION AND HETEROGENEITY:
i) Promoters of tumour angiogenesis include the most CLONAL AGGRESSIVENESS
important vascular endothelial growth factor (VEGF) (released Another feature of note in biology of cancers is that with
from genes in the parenchymal tumour cells) and basic passage of time cancers become more aggressive; this
fibroblast growth factor (bFGF). property is termed tumour progression. Clinical parameters
ii) Anti-angiogenesis factors inhibiting angiogenesis include of cancer progression are: increasing size of the tumour,
thrombospondin-1 (also produced by tumour cells themselves), higher histologic grade (as seen by poorer differentiation and
angiostatin, endostatin and vasculostatin. Mutated form of p53 greater anaplasia), areas of tumour necrosis (i.e. tumour
gene in both alleles in various cancers results in removal of outgrows its blood supply), invasiveness and distant
anti-angiogenic role of thrombospondin-1, thus favouring metastasis.
continued angiogenesis. In terms of molecular biology, this attribute of cancer is
due to the fact that with passage of time cancer cells acquire
6. INVASION AND DISTANT METASTASIS: more and more heterogeneity. This means that though cancer
CANCER DISSEMINATION cells remain monoclonal in origin, they acquire more and
One of the most important characteristic of cancers is more mutations which, in turn, produce multiple-mutated
invasiveness and metastasis. The mechanisms involved in subpopulations of more aggressive clones of cancer cells (i.e.
the biology of invasion and metastasis are discussed already heterogeneous cells) in the growth which have tendency to
along with spread of tumours. invade, metastasise and be refractory to hormonal influences.
Some of these mutations in fact may kill the tumour cells as
well.
7. DNA DAMAGE AND REPAIR SYSTEM:
MUTATOR GENES AND CANCER 9. CANCER A SEQUENTIAL MULTISTEP MOLE-
Normal cells during complex mitosis suffer from minor CULAR PHENOMENON: MULTISTEP THEORY
damage to the DNA which is detected and repaired before It needs to be appreciated that cancer occurs following several
mitosis is completed so that integrity of the genome is sequential steps of abnormalities in the target cell e.g.
maintained. Similarly, small mutational damage to the initiation, promotion and progression in proper sequence.
dividing cell by exogenous factors (e.g. by radiation, chemical Similarly, multiple steps are involved at genetic level by
carcinogens etc) is also repaired. p53 gene is held responsible which cell proliferation of cancer cells is activated: by
for detection and repair of DNA damage. However, if this activation of growth promoters, loss of growth suppressors,
system of DNA repair is defective as happens in some inactivation of intrinsic apoptotic mechanisms and escaping
inherited mutations (mutator genes), the defect in unrepaired cellular aging. A classic example of this sequential genetic
DNA is passed to the next progeny of cells and cancer results. abnormalities in cancer is seen in adenoma-carcinoma