This tumor marker is a classic product of colon cancer but it also belongs to a family of glycoproteins found on granulocytes. Can you guess what it is?
December 2010 Tumor Marker of the Month
Carcinoembryonic antigen (CEA)
The "mother of all" tumor markers is only one of a very large family of cell surface adhesion molecules. On granulocytes, it is CD66e. Initially described as an “onco-fetal” antigen in colon cancer (i.e., not normally expressed in adults but up-regulated in tumors), CEA has been used in the clinical diagnosis and management of a variety of cancers. Its original promise of a sensitive and specific marker for screening, prognosis, and monitoring was never realized, and a large number of additional markers which are, perhaps, more specific for a number of different tumor types may have lessened CEA’s importance as a diagnostic test. However, research into the biology of the genes and proteins which form the family of CEA-like molecules has revealed a great amount of detail about epithelial cell growth and regulation.
This is not a tumor, but a recent study found that the receptors on the pink cells (which bind a commonly measured hormone) are also expressed on the blood vessels in a variety of solid tumors. Can you guess what it is?
FSH (Follicle Stimulating Hormone)
Normally, the receptor for FSH is expressed only on the granulosa cells of a developing follicle in the ovary (shown) or on the Sertoli cells of the testis. A recent study reported in the New England Journal of Medicine using monoclonal antibodies to the FSH-receptor revealed its presence of the endothelial cells of a wide variety of solid tumors. Because FSH induces angiogenesis, solid tumors may be borrowing this receptor in order to enhance their ability to grow.
This molecule is one of the largest circulating protein tumor markers and the fact that many patients make antibody against it complicates its measurement. Can you guess what it is?
In the thyroid gland, thyroglobulin is a mammoth protein, weighing in at over 300,000 daltons. Up to 20-30% of the amino acid residues are tyrosine, and these are iodinated by the enzyme thyroid peroxidase. (In the cartoon, these residues are shown as having 2 iodines, with condensation of two such residues resulting in thyroxine or T4.) The form that reaches the blood (in relatively tiny amounts) is used as a tumor marker for thyroid cancer. Because a significant percentage of thyroid cancer patients develop autoantibodies to thyroglobulin, these may interfere in thyroglobulin immunoassays. All specimens submitted for thyroglobulin measurement should also be screened for anti-thyroglobulin antibody and, if present, the physician should be alerted. Techniques to address potential antibody interference are controversial, but a recent study (Kim et al, J Endo Clin Med 2009;93:4683-4689) showed that the antibody seems to disappear when the patient’s tumor is treated successfully.
Reciprocal translocation of genetic material between chromosomes 9 and 22 as shown produces an abnormal chromosome (arrow) associated with leukemia, named for the city in which it was discovered 50 years ago. Can you guess what it is?
This chromosomal translocation creates a fusion gene called BCR-ABL because the Abl1 gene from chromosome 9 is juxtaposed to the BCR gene on chromosome 22. Abl1 encodes a tyrosine kinase which regulates cell division. Although the normal function of BCR is not clear, the fusion gene results in abnormal cell proliferation resulting in chronic myelogenous leukemia (CML). The chromosome was discovered by Peter Nowell and David Hungerford in Philadelphia, but the molecular basis for the abnormality was discovered by Janet Rowley in Chicago. Imatinib (Gleevec) is a tyrosine kinase inhibitor useful in the treatment of CML.
This protein is a key factor in the response of cells to heat stress, and may be implicated in the transformation of many cell types into malignant cells, especially in breast cancer. Can you guess what it is?
Heat shock protein (HSP)
Heat shock proteins are a class of intracellular proteins that act as chaperones – helping some newly synthesized proteins get out of the Golgi apparatus and easing others into the proteasome, a kind of cellular garbage disposal. When cells are heated, levels of certain HSPs increase and alter the cell’s metabolism. Other types of stress besides heat (such as toxins or hypoxia) can also trigger this increase. Recently, HSP inhibition of apoptosis (programmed cell death) has been implicated in the pathogenesis of some tumors, especially breast cancer. The exact mechanism is unclear, and may actually involve abnormalities in the regulation of “heat shock factor”, which alters transcription of HSPs.
The “light chain” (shown in dark blue) of this membrane protein is one of two markers utilized in the international multiple myeloma staging system. Can you guess what it is?
Beta-2-microglobulin (B2M) is the “light chain” associated with all of the various Class I major histocompatibility complex proteins, which present peptides derived from internal protein degradation to T cells. Although present on all nucleated cells and, therefore, theoretically a tumor marker for all kinds of cell types, elevations of B2M are particularly useful in monitoring multiple myeloma. Along with low albumin, B2M forms an important part of the international staging system for this malignancy.
Not cleaving this molecule as indicated may result in ectopic “ACTH” production which is not well detected by non-competitive (“sandwich”) immunoassay. Can you guess what it is?
This protein, precursor of adrenocorticotropin (ACTH) in the anterior pituitary, requires proper processing to produce ACTH (the orange portion), as well as other hormones such as melanocyte stimulating hormone. Most current commercially available immunoassays for ACTH utilize a non-competitive format (one antibody directed against the amino-terminal portion, with another directed against the carboxy-terminal portion). For some reason, ACTH precursors such as POMC or the smaller precursor pro-ACTH may not react well in such immunoassays, but can be detected using a competitive format (with one antibody and labeled antigen). Since occult tumors producing ectopic ACTH may not normally process the pro-hormone, these may be missed by more modern immunoassay approaches. At the Endocrine Society annual meeting in San Diego last month, an ELISA assay for POMC was described as potentially helpful in confirming the presence of ectopic ACTH production.
A new tumor marker for ovarian cancer, ironically first discovered in the epididymis, includes this motif of four disulfide bonds commonly seen in non-human mammalian milk proteins. Can you guess what it is?
The four-disulfide construct shown is called a WAP domain, named after whey acidic proteins which contain this core element. Other proteins with this domain have been described in humans, including HE4, previously thought to be similar to other WAP-containing proteins which probably function as protease inhibitors in the male reproductive system. A number of studies have indicated that HE4 is over-expressed in ovarian tumors, and a commercially available immunoassay for this marker has been developed. Recent evidence has also indicated HE4 expression in a number of tumor cell lines, including breast, colon and melanoma.
The discoverer of this tumor marker, probably one of the most frequently ordered, recently wondered whether it has done more harm than good. Can you guess what it is?
PSA (Prostate Specific Antigen)
Dr. Richard Ablin, research professor of Immunology and Pathology at University of Arizona College of Medicine, wrote an op-ed piece in the March 10, 2010 edition of the New York Times in which he called PSA testing “a profit-driven public health disaster”. Citing the non-“specificity” of the test (in terms of BPH and cancer, as well as the “benign” versus “malignant” forms of cancer), he echoed recent calls for limiting testing to screening only men with a family history and monitoring men for recurrence after definitive treatment. Of interest were the follow-up letters in response to the piece. The Times printed six on March 12. Two were from urologists (one opposed and the other in favor of PSA screening). Three were from prostate patients; two were thankful that PSA identified a tumor which was excised, while the other ignored his elevated PSA (and positive biopsy) over ten years ago and has been healthy since. The final comment was from a gastroenterologist: “Doctors order PSA because it is far easier to do so than to explain to a jury why they did not do so.”
The presence of receptors to this extracellular matrix protein on tumor cells is a marker of biological aggressiveness and a metastatic phenotype. Can you guess what it is?
Interactions between epithelial cells and the underlying connective tissue stroma are important for normal cell function. There are a number of non-collagenous proteins in the extracellular matrix that mediate these effects. Laminin is a large complex of three peptides arranged in the shape of a cross, with three binding domains: collagen, heparin, and the laminin receptor on the surface of epithelial cells. Cancer cells with increased numbers of laminin receptors may be able to move through tissue more easily, making them more likely to invade and metastasize.
The cross-linked blue domains shown to the right result from protease digestion of the large polymer shown at left, and this molecule has been proposed as a novel tumor marker. Can you guess what it is?
Plasmin bites out pieces of formed fibrin clot and the fragment containing crosslinked ends of the fibrin monomers is called D-dimer, because the two globular ends of the monomer are termed the “D” domains. There is a long history of cancer and coagulation. An interesting new tumor marker assay, called DR-70, is actually an ELISA immunoassay for D-dimer. Recently cleared by the FDA for the monitoring of colorectal cancer, this test, like carcinoembryonic antigen (CEA), does not appear to be specific for colorectal cancer. For more information, see the Winter 2010 issue of CDID’s on-line newsletter, Immunotes.
This tumor marker resembles albumin except that it has a prominent carbohydrate chain. The addition of a fucose (red) near the link to the protein makes it a much more specific marker for neoplastic (as opposed to inflammatory) lesions of the liver. Can you guess what it is?
AFP is the fetal version of albumin. The fetal liver begins to switch from AFP to albumin soon before birth and, although serum AFP levels are very high in neonates, they reach adult levels by about 6 months of age. (The high levels of AFP in the fetus explain the use of this test – in maternal serum and amniotic fluid – as a prenatal screen for neural tube defect.) As a tumor marker, AFP is primarily used to detect and follow patients with hepatocellular carcinoma, although it may also be expressed by a variety of germ cell tumors. Because AFP levels are elevated in other hepatic disorders, especially chronic viral hepatitis, its usefulness for detection of hepatocellular carcinoma may be limited. Recent findings have shown that the presence of the AFP isoform (called “L3”), with fucose added to the single carbohydrate chain, may be specific for hepatic tumors.