Lecture 7: Biochemistry of cancer and tumor markers
Prof. Dr. H.D.El-Yassin 2013
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Biochemistry of Cancer and Tumor Markers
The term cancer applies to a group of diseases in which cells
grow abnormally and form a malignant tumor. It is a long term
multistage genetic process. The first stage is when the DNA is
damaged by some form of carcinogen: physical, chemical, and
biologic agents (e.g. smoking, radiation, chemicals, and virus).
These agents damage or alter DNA, so that cancer is truly a
disease of the genome. At some later time, additional damage
occurs that eventually leads to chromosome breakdown and
rearrangement. This process produces a new phenotype that
loses control over the process of mitosis. The process of mitosis
continues and unlimitedly produces malignant tumor cells.
Eventually, there is a production of a growing mutant cell that
expresses oncogenes. Oncogenes are mutated derivatives of
normal genes (proto-oncogenes) whose function is to promote
proliferation or cell survival. (Oncogenes: are genes capable of
inducing or maintaining transformation of cells). Benign tumor
cells have lost growth control but do not metastasize.
Much current interest in cancer is focused on the study of
oncogenes and tumor suppressor genes. Normal cells contain
potential
precursors
of
oncogenes,
designated
proto-
oncogenes. Activation of these genes to oncogenes is achieved by at least five
mechanisms:
1. promoter and
2. enhancer insertion
3. Chromosomal translocation,
4. gene amplification
5. Point mutation.
Activated oncogenes influence cellular growth by perturbing normal cellular
mechanism of growth control, by acting as growth factors or receptors, and probably
by other means as well.
Lecture 7: Biochemistry of cancer and tumor markers
Prof. Dr. H.D.El-Yassin 2013
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Tumor suppressor genes (normal growth suppressor genes) encode proteins that
inhibit proliferation, promote cell death, or repair DNA; both alleles need to be
inactivated for transformation (a loss of function). Growth suppressor genes have
been called the guardians of the cell.
Tumor suppressor genes are now recognized as key players in the genesis of
cancer.
Important tumor suppressor genes include RB1 and P53, both of which are nuclear
phosphoproteins and probably affect the transcription of genes involved in regulating
events in the cell cycle.
Tumor progression reflects instability of the tumor genome probably due at least in
part to defects in DNA repair systems, activation of additional oncogenes, and
inactivation of additional tumor suppressor genes.
The extensive biochemical analyses of the Morris minimal-deviation
Hepatomas
(tumors originally induced in rats by feeding them the carcinogens
fluorenylphthalamic acid, fluorenylacetamide compounds,
or trimethylaniline. These hepatocellular carcinomas are transplantable in an inbred host strain
of rats and have a variety of growth rates and degrees of differentiation. All these tumors are
malignant and eventually
kill the host. The term “minimal deviation” was coined by Potter to
convey the idea that some of these neoplasms differ only slightly from normal hepatic
parenchymal cells)
led Weber to formulate the “molecular correlation concept” of
cancer, which states
that “the biochemical strategy of the genome in neoplasia
could be identified by elucidation of the pattern of gene expression as revealed
in the activity, concentration, and isozyme aspects of key enzymes and their
linking with neoplastic transformation a
nd progression.”
Weber proposed three general types of biochemical alterations associated with
malignancy:
1. transformation-linked alterations that correlate with the events of malignant
transformation and that are probably altered in the same direction in all malignant
cells;
2. progression-linked alterations that correlate with tumor growth rate, invasiveness,
and metastatic potential; and
3. coincidental alterations that are secondary events and do not correlate strictly
with transformation or progression.
Lecture 7: Biochemistry of cancer and tumor markers
Prof. Dr. H.D.El-Yassin 2013
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Those metabolic pathways that contained enzymes which fulfilled one or more of
these criteria are indicated in Table (1) along with the alteration that was observed in
cancer.
Table(1) Molecular Correlation Concept and Affected Processes
Biochemical Process
Alteration in Cancer Cells
Pyrimidine and purine synthesis
Increased
Pyrimidine and purine catabolism
Decreased
RNA and DNA synthesis
Increased
Glucose catabolism
Increased
Glucose synthesis
Decreased
Amino acid catabolism (for gluconeogenesis)
Decreased
Urea cycle
Decreased
Enzymes in Malignancy
Plasma total enzyme activities may be raised or an abnormal isoenzyme detected,
in several neoplastic disorders.
• Serum prostatic (tartrate-labi!e) acid phosphatase activity rises in some cases of
malignancy of the prostate gland.
• Any malignancy may be associated with a non-specific increase in plasma LD
1
( H B D ) and. occasionally, transaminase activity.
• Plasma transaminase and alkaline phosphatase estimations may be of value to
monitor treatment of malignant disease. Raised levels may indicate secondary
deposits in liver or of alkaline phosphatase, in bone. Liver deposits may also cause
an increase in plasma LD or GGT.
• Tumors occasionally produce a number of enzymes, such as the 'Regan' ALP
isoenzyme.' LD (HBD) or CK-BB. assays of which may be used as an aid to
diagnosis or for monitoring treatment.
A number of oncodevelopmental tumor-associated antigens appear on tumor cells as
a result of the apparent re-expression (or increased expression) of embryonic genes,
and a number of these are useful as tumor markers for cancer diagnosis and disease
progression.
These include alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and a
number of inappropriately (ectopically) produced hormones. (Table (2).
Lecture 7: Biochemistry of cancer and tumor markers
Prof. Dr. H.D.El-Yassin 2013
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Classification of Tumor Markers
Tumor markers come from a variety of groups:
Enzymes, glycoproteins, hormones and hormone-like substances, hormone
receptors, oneogenes, and oneogene reseptors. The list of tumor markers that arise
from this list is quite extensive. However, because of the low sensitivity and
specificity of most tumor markers, the Food and Drug Administration (FDA) has
approved only a few assay kits as tumor markers.
What are they?
Tumor markers are substances, usually proteins that are produced by the body in
response to cancer growth or by the cancer tissue itself. Some tumor markers are
specific, while others are seen in several cancer types. Many of the well-known
markers are also seen in non-cancerous conditions. Consequently, these tumor
markers are not diagnostic for cancer.
There are only a handful of well-established tumor markers that are being routinely
used by physicians. Many other potential markers are still being researched. Some
marker tests cause great excitement when they are first discovered but, upon further
investigation, prove to be no more useful than markers already in use.
The goal is to be able to screen for and diagnose cancer early, when it is the most
treatable and before it has had a chance to grow and spread. So far, the only tumor
marker to gain wide acceptance as a general screen is the Prostate Specific Antigen
(PSA) for men. Other markers are either not specific enough (too many false
Lecture 7: Biochemistry of cancer and tumor markers
Prof. Dr. H.D.El-Yassin 2013
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positives, leading to expensive and unnecessary follow-up testing) or they are not
elevated early enough in the disease process.
Some people are at a higher risk for particular cancers because they have inherited a
genetic mutation. While not considered tumor makers, there are tests that look for
these mutations in order to estimate the risk of developing a particular type of cancer.
BRCA1 and BRCA2 are examples of gene mutations related to an inherited risk of
breast cancer and ovarian cancer.
Why are they done?
Tumor markers are not diagnostic in themselves. A definitive diagnosis of cancer is
made by looking at biopsy specimens (e.g., of tissue) under a microscope. However,
tumor markers provide information that can be used to:
Screen: Most markers are not suited for general screening, but some may be used in
those with a strong family history of a particular cancer. In the case of genetic
markers, they may be used to help predict risk in family members. (PSA testing for
prostate cancer is an example).
Help diagnose: In a patient that has symptoms, tumor markers may be used to help
identify the source of the cancer, such as CA-125 for ovarian cancer, and to help
differentiate it from other conditions.
Stage: If a patient does have cancer, tumor marker elevations can be used to help
determine how far the cancer has spread into other tissues and organs.
Determine prognosis. Some tumor markers can be used to help doctors determine
how aggressive a cancer is likely to be.
Guide Treatment. Some tumor markers will give doctors information about what
treatments their patients may respond to.
Monitor Treatment. Tumor markers can be used to monitor the effectiveness of
treatment, especially in advanced cancers. If the marker level drops, the treatment is
working; if it stays elevated, adjustments are needed.
Determine recurrence. Currently, one of the biggest uses for tumor markers is to
monitor for cancer recurrence. If a tumor marker is elevated before treatment, low
after treatment, and then begins to rise over time, then it is likely that the cancer is
returning. (If it remains elevated after surgery, then chances are that not all of the
cancer was removed.)
Lecture 7: Biochemistry of cancer and tumor markers
Prof. Dr. H.D.El-Yassin 2013
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