Lecture #8: Tumor Markers

A tumor marker is a substance produced by a benign or malignant cell in response to the process of malignancy. These substances if they can be measured, aid in the diagnosis and characterization of disease and have potential use in the treatment and cure of cancers.

A cancer is a word used to describe a condition characterized by spreading destruction of any kind. Commonly, cancer is the name given to group of diseases associated with the development, growth and spread of destructive outgrowths of tissue, called malignant tumor or neoplasms. Malignant tumors are invasive, destructive and associated with a generally poor prognosis and high mortality rate. Many factors are involved in the transformation of a normal cell to a malignant tumor cell. Some are environmental and include diet and exposure to chemicals and in radiation. Some viruses are associated with malignant transformation. Host–related factors such as age, sex, immune response and heredity also play a part.

A tumor is said to be benign when it is restricted to its primary site. Benign tumors are generally well differentiated. The cells in a benign tumor are similar to the cells of the normal tissue, and the tumor markers produced are the products found in the normal tissue.

Mechanism of tumor invasion

When a normal cell is transformed into a tumor cell, gene expression changes. The affected cell may lose its ability to synthesize some specific cell product or it may manufacture greatly increased amounts. The cells may be less specialized than the tissue it evolved from and assume the characteristics of the less well differentiated cells of the embryo, synthesizing proteins found in the embryo but not in a normal adult. Cell proliferation rates change as the metabolic rate of the cells increases.

Tumors are assumed to be unicellular in origin. After the cells is transformed, it loses growth control and begins to invade the primary site. They then invade the adjacent organs and blood and lymph systems, which may carry the cells to distant organs. The cells may then lodge in a capillary bed and begin to invade the new site. As this invasion process takes place, new proteins are produced that actively aid in the invasion. These proteins can also be used as markers.

Tumors are generally classified according to stage, grade and primary site. Stage is an indicator of tumor size and invasiveness based on whether there is a lymph node involvement, and if so, which nodes are involved and the presence of distant metastases. Grade is based on the microscopic evaluation of tumor tissue. Tumor classification aids in the estimation of the probable disease course and helps determine which therapeutic measures are most effective.

Roles of tumor markers

1.      Detection of malignancies

2.      Identification of malignancies

3.      Monitoring of malignancies

4.      Radiolocalization of malignancies

5.      Therapy of malignancies

Characteristics of an ideal tumor marker

1.      Specificity for cancer – the substance should be produced only by the tumor. No benign condition should cause an elevation and the marker should not be present or should be found only in trace amounts in a normal population. To be ideal, the substance should be found in one type of tumor only.

2.      Sensitivity for cancer – a very small tumor growth will produce measurable amounts of markers.

3.      The amount of marker produced will correlate well with tumor load.

4.      The assay for the marker must be inexpensive, easy to perform, and sensitive (able to accurately measure small amounts of the marker).

5.      The half life of he marker must be short enough so that when production drops, the level falls off rapidly.

Classification of tumor markers

1.      Enzymes

2.      Hormones, neurotransmitter and their metabolites

3.      Receptors

4.      Serum proteins

5.      DNA

******  ENZYMES USED AS TUMOR MARKERS  ******

                       

HORMONES AND NEUROTRANSMITTER USED AS TUMOR MARKERS

******  RECEPTORS USED AS TUMOR MARKERS  ******

                                               

RECEPTORS                                              SITE / TUMOR OR ACTION

Estrogen, progesterone                               Breast

(antiestrogen: Tamoxifen)

Laminin                                                          Measures metastatic potential

Epidermal growth factor                              Breast

Interleukin – 2                                               Leukemia

·         Cell receptors are protein structures located on external cell membrane and within the cell. The purpose of the receptor is to recognize and bine a specific ligand such as hormone or neurotransmitter to initiate a biologic response.

******  PROTEINS USED AS TUMOR MARKERS  ******

·  CEA is also elevated in alcoholism, inflammation of the bowel, cystic fibrosis and heavy cigarette smokers. It can be measured using serum ascetic fluid or urine as specimen

******  DNA USED AS TUMOR MARKERS  ******

ONCOGENIC / VIRAL AGENT                     SITE / TUMOR

C–erb B–1 neu                                               Breast, ovary

Myc                                                                 Lung, lymphoma, gastrointestinal tract,

                                                                        Brain, colon

P53                                                                 Colon

Ph’ (Philadelphia chromosome)                  Chronic myelogenous leukemia

RB                                                                   Eye, lung, breast, bladder

Human papillomavirus                                 Cervic

Methods of DNA analysis

1.      Flow cytometry using fluorescent labelled antibody to identify whether the cell population is monoclonal by using surface marker.

2.      Ploidy analysis, a measurement of the amount of nuclear material present, which gives an estimation of tumor aggression.

3.      Southern blot

4.      Northern blot

GENERAL METHODS OF QUANTITATION OF DIFFERENT TUMOR MARKERS

1.      Immunoassay

2.      Electrophoresis

3.      Chromatography