Nonspecific Tumor Markers

Two criteria, namely specificity and sensitivity, are often employed to evaluate the clinical utility of a tumor marker. Few tumor markers discovered today have a desirable specificity and sensitivity. On the other hand, there are several nonspecific markers that are clinically useful for monitoring disease during treatment and for detecting recurrence. Although these tumor markers are detectable nonspecifically in a large variety of cancers, their concentrations are nevertheless sensitive to changes of the tumor activity. Many of these nonspecific tumor markers are inexpensive and simple to measure, and are therefore useful for monitoring therapy and detecting recurrence for patients with a known diagnosis. For example, Lipid associated sialic acid in the plasma (LASA-P) can be quantified with a simple, rapid, and inexpensive calorimetric procedure and its serum concentration closely parallels the serum concentrations of many tumor markers of higher specificity. Nonspecific tumor markers could also be useful in multiple marker formats to improve both the sensitivity and specificity of individual tumor marker assays.

Serum tissue polypeptide specific antigen (TPS), despite its nonspecificity, has been shown to be complementary to CA 15-3 in the management of breast cancer. The addition of TPS to CA 15-3 not only increases the sensitivity of CA 15-3 from 28.6% up to 44.4% in the overall population, and from 71.9% to 87.6% in patients with metastases but also increased the overall sensitivity by 12.7% during postsurgical follow-up (37). Changes in the TPS level showed the strongest association with clinical response after the first course of chemotherapy. TPA and TPS were better indicators of disease progression than CA 15-3 in breast cancer patients treated with chemotherapy (38).

8.1. Proliferation Marker

Despite its nonspecificity, proliferation markers have been widely used clinically in cancer patient management because the deregulated cell proliferation is one of the major factors contributing to tumor growth. The overall rate of proliferation may be indirectly related to the clinical outcome of many types of tumors. Because the cell cycle is the major mechanism controlling cell proliferation, expression of these proliferation markers is usually related to various phases of cell cycle progression. There are several proliferation markers that have demonstrated clinical utility.

Ki-67 is identified by MIB-1 MAb utilizing immunohistochemistry. MIB-1, recognizes proliferating cells in all phases of the cell cycle except Go. Ki-67 works well in formalin-fixed paraffin-embedded sections with appropriate antigen retrieval. Ki-67 antigen expression generally correlates well with mitotic activity. The Ki-67 antigen was expressed in S phase cells although not in G1 cells in human mitogen-stimulated peripheral blood lymphocytes entering the first cell cycle. The monoclonal antibody (mAb) Ki-67 has been used for about 10 yr, mainly to monitor proliferating cells in tissue sections, but to date little is known about the proteins it recognizes. The new monoclonal Ki-S3 and Ki-S5 antibodies detect proliferating cells in frozen and paraffin-embedded tissues. They recognize proteins with the same molecular mass as Ki-67 in Western blot. In immunoprecipitation experiments, the measurement of Ki-67 (as MIB-1 proliferation index) has proven useful in predicting the clinical outcome of the neuroendocrine tumors of the pancreas. The index also appeared useful for determining the prognosis for the survival of an individual (39). Soluble Ki-67 was not detectable in blood circulation. The failure of Ki-67 detection is likely to the result of its instability in blood circulation.

Proliferating cell nuclear antigen (PCNA) is a 36-kD nuclear protein present in highest amounts during the S phase. PC10, a MAb against PCNA, is used to stain PCNA in paraffin-fixed tissue (40).

CYFRA 21-1 is the serum fragments of cytokeratin 19, which has been widely assessed as a serum marker of several malignancies. Assay for CYFRA 21-1 is commercially available. Cytokeratins are proteins of the intermediate filament family and a main component of the cell cytoskeleton. Cytokeraton is composed of different types of filaments with different sizes; actin, intermediate filaments, myosine, and microtubules. At present, 20 cytokeratins have been described, and all are proteins restricted only to epithelial cells.

CYFRA 21-1 appears to be a useful marker for non-small cell lung cancer (NSCLC), especially the squamous type with a sensitivity of 55%. Increased levels correlate with the severity of the disease (41). In a group of squamous-cell lung cancer patients at different stages of disease, measurement of CYFRA 21-1 and SCC have showed significant prognostic value for clinical stages. A significant relationship between marker level and survival was observed for CYFRA 21-1 as well as SCC levels. In a multivariate analysis, CYFRA 21-1 and/or TPS remained significant predictors of survival (42). The Combination of proliferation markers with other tumor markers appears most effective. Combination of CYFRA 21-1 and NMP22 help determine the need for cystoscopy in patients with bladder cancer (43).

Cytosolic thymidine kinase 1 (TK1) is one of the enzymes involved in DNA replication. TK1 is activated at late G1 of cell cycle, and its activity correlates with cell proliferation. A polyclonal anti-TK1 antibody against a synthetic peptide from the C-terminus of human TK1 is available. TK1 is located in the cytoplasm of cells, and is strongly expressed in the cells in S+G2 period, raised at late G1 and decreased during mitosis (44).

8.6. Mitosin

Mitosin is a 350 kD nuclear phosphoprotein involved in cell division. It is expressed in the late G1, S, G2, and M phases of the cell cycle but is absent in Go. Presently, only the immunohistochemical method has been used for its detection in formalin-fixed, paraffin-embedded tumors. Mitosin has been determined useful in node-negative breast cancer (45).

Sialic acids (N-acetylneuraminic acids) are the acylated derivatives of neuraminic acid and are the terminal residues at the nonreducing end of the carbohydrate chains in many glycoproteins, glycolipids, and proteoglycans. Sialoglycoproteins on the tumor cell surface have a long history of being associated with invasiveness and metastases (46). LASA-P is found elevated in a variety of malignant diseases, such as in the breast, or in those diseases associated with the gastrointestinal tract and the lung—leukemia, lymphoma, Hodgkin's disease, and melanoma—but also in nonmalignant inflammatory diseases. Apparently LASA-P is not specific to any specific type of tumor and is used in conjunction with other tumor markers for increased levels of sensitivity and specificity (47,48). This lack of tumor specificity substantially limits its use as a tumor marker for diagnosis; however, it compares favorably with the most widely used tumor markers for following a patient's response to therapy and for the early detection of recurrent disease (49). The sensitivity of LASA-P assay for various cancers was reported to range from 77 to 97%.

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