variability in the individual cell expression of marker
substance within a tumor and variability in the level
of expression of the substance at different stages in
the malignant evolution of the cancer.
The clinical application of a marker substance
depends upon two forms of tissue specificity: a
specificity for cancerous tissue as opposed to
noncancerous tissue and a specificity for a particular
tissue or organ. Tissue specificity is achieved by
utilizing substances that arise predominantly in
cancers of the tissue of interest. Such substances are
usually identified in one of two ways. One approach
is to identify substances that show specificity for the
normal tissue hoping that they will also be specific
for cancer of the tissue. Not infrequently, however,
the candidate substances are less tissue specific in
cancer. One reason for this is that cancer cells of
the tissue may express the substance at a lower level
than normal tissue cells. Another reason is that
cancer cells from other tissues, especially embryo-
logically related tissues, may express the substance
at higher levels than normal. The second approach
is to identify substances expressed in cancer of the
tissue of interest hoping that some will be specific
for the cancer. This has often been done by inocu-
lating animals with human tumor cells to raise
antibodies to cancer cell substances. The substances
so identified are typically referred to as tumor
antigens (Sell 1980). In this approach, a lack of
tissue specificity of the candidate substance can be
due to expression of the substance in cancers of
other tissues or even expression of the substance in
other normal tissues.
As regards cancer specificity, in the few ways
that the genome of a cancer cell differs from the
normal genome, there is the potential for the produc-
tion of a substance that is truly specific for the
cancer producing it. The bcr/abl fusion protein
produced by the t(9;22) translocation of chronic
myelogenous leukemia is an example of such a
substance. Unfortunately, no substances of this sort
have yet been found that achieve clinically measur-
able concentrations in the body fluids.
The marker substances currently in clinical use
are products of that portion of the cancer genome
shared with the normal cell genome and, therefore,
have the potential for being produced by normal
cells (Table 11.2). That means that none of them is
absolutely specific for cancer. The degree of cancer
specificity they do attain depends in large part upon
the relative specificity of the attribute of cancer
reflected in the laboratory measurement of the sub-
stance. These attributes include: monoclonality,
altered expression of cellular constituents and
products, alteration in the dynamics of substance
release, and increased cell turnover. Of these attrib-
utes, monoclonality is the most specific for cancer.
As mentioned previously, monoclonality can be
demonstrated in B lymphocyte cancer by showing
homogeneity of the V(D)J rearrangement of the
immunoglobulin heavy chain gene in the cancerous
B lymphocytes. Monoclonality can similarly be
implied from the demonstration of structural
homogeneity of the immunoglobulins secreted by
cancerous B lymphocytes and plasma cells (Keren
1999).
Alpha-fetoprotein is an example of a marker
substance that is expressed at much higher levels
than normal in certain cancers (Abelev and Eraiser
1999). Alpha-fetoprotein is an albumin-like plasma
protein expressed at high levels in the yolk sac
during early embryonic development and in the liver
during late embryonic and early fetal development
(Deutsch 1991). In mature liver cells it is normally
Cancer
11-5
Table 11.2
Some Selected Marker Substances of Cancer
Class
Marker substance
Cancer
Cellular constituents
carcinoembryonic antigen
colorectal carcinoma
CA-125
ovarian carcinoma
Secreted products
Hormones
β
-chorionic gonadotropin
germ cell tumors, choriocarcinoma
calcitonin
medullary carcinoma of the thyroid
Enzymes
prostate-specific antigen
prostate carcinoma
Plasma proteins
immunoglobulin
multiple myeloma, B cell leukemia
alpha-fetoprotein
germ cell tumors, primary liver cancer
