TUMOR MARKERS

MAJOR PROCESSES INVOLVED IN CELL GROWTH

Proliferation Differentiation

Terms to Remember:
Cancer is a disease of abnormal growth Tumorigenesis when the tumor cells begin to emerge when the growth and development of a normal cell loses control.

Neoplasia
Involves the possibility of normal cells undergoing cancerous proliferation Pathologic hyperplasia Unregulated and serves no purpose Elevation of tumor markers will be a long lasting phenomenon if not treated

Hyperplasia
Involves the multiplication of cells in an organ or tissue, which may consequently have increased in volume. Serves a useful purpose and is controlled by stimuli Elevation of tumor markers is transient.

Benign
Tumors remain at the primary site and present a smaller risk to the host At this stage the patient stands a good chance of being successfully treated by the complete removal of the tumor. Early detection is critical to cancer prevention in general to high risk families in particular Well differentiated and composed of cells resembling the nature of normal cells from the tissue of origin of the neoplasm.

Malignant
o Due to genetic instability of tumor cells.

Metastasis
Cause of the most cancer deaths Due to multiple genetic changes that result to uncontrolled proliferation Multistep processes involving numerous tumor cell-host cell and cell-matrix interactions. For tumor cells to metastasize, the tumor cells at the primary site have to first penetrate their adjacent surroundings, including the epithelial basement membrane and the interstitial stroma. Then invade blood or lymphatic vessels and are carried to distant sites, until they are finally arrested in the venous/capillary beds or solid tissue of a distant organ. It is a highly selective process.

Signal Transduction Pathway

Controls both cell cycle and apoptosis It is an orderly and specific transmission of growth-regulatory messages from outside the cell to the machinery controlling replication inside the cell nucleus.

Cell Cycle
It involves the passage of a cell through a complete round of replication. It is one of the most important determining factors controlling cell proliferation.

Cell Cycle
In most mammalian cells, the cell cycle is composed of four phases
G1 defined as the interval between the conclusion of mitosis and start of DNA replication S interval during which the nuclear genome is replicated G2 interval between completion of DNA replication and the onset of mitosis. M or mitosis Go fifth phase metabolic compartment of reversibly quiescent cells occupy

Cell Cycle
These components of the cell cycle are encoded by a separate category of genes that, when mutated, will not only increase genetic instability but also accelerate cellular evolution and the progression to malignancy. Tumors is result from the absence of certain cell cycle controls Defects in the cell cycle machinery may help cause cancer.

Apoptosis
A programmed cell or physiologic death It is a natural self-destruct system present in all cells Failure of cells to undergo apoptotic cell death may lead to cancer. It is the natural process the body employs for the replacement of cells and the deletion of damaged cells inherent to normal functioning of multicellular microorganism.

Apoptosis
It is a control mechanism for tissue remodeling during growth and development. Provides a way for the body to eliminate cells that have been produced in excess, that have developed improperly, or that have sustained genetic damage. Markers: p53 protein, Bcl 2, and Fas/Fas ligand
They can be both inducers and inhibitors of cell-death These markers would have tremendous potential for diagnosis, prognosis, and therapeutic application

Angiogenesis
It is a fundamental process by which new blood vessels are formed. Tumor growth and metastasis are angiogenesis-dependent. It is critical, not only for the growth of solid tumors, but also for the shedding of cells from the primary tumor and the development of metastases at distant sites. The new blood vessels embedded in a tumor provide a gateway for tumor cells to enter the circulation and to metastasize to distant sites

Angiogenesis
The degree of angiogenesis in an initial primary tumor correlates with metastatic spread and survival rates in patients Assessment of tumor angiogenesis may, therefore, prove valuable in selecting patients with early breast carcinoma for aggressive therapy. Most well known angiogenic factors:
Vascular endothelial growth factor (VEGF) Acidic and basic fibroblast growth factor (aFGF and bFGF) Transforming growth factor alpha (TGF-alpha)

Adhesion
These are specific class of transmembrane glycoprotein involved whenever cells are moving and interacting. They regulate the migration of leukocytes to sites of inflammation or into lymphatic tissue.

Adhesion
Increasing evidence has shown that the appearance of certain membrane molecules is related to metastatic potential or a sign of the conversion of normal to malignant cells. Three classes of adjesions:
Selectins Integrins Immunoglobulin family

CLINICAL UTILITIES OF TUMOR MARKERS

Screening
None of the tumor markers discovered had sufficient specificity and sensitivity for screening in the general population It is not recommended for most tumor markers, especially in an asymptomatic population

Alpha-Fetoprotein (AFP)
The screening of primary hepatoma in Asian countries is based on the measurement of serum AFP.

Prostate-Specific Antigen (PSA) and Free PSA

First tumor marker recommended for screening for prostate cancer in men older than age of 50. The purpose was to detect prostate cancer at early curable stages, when the tumor is still confined inside the organ. Two major forms: Free PSA and a PSA alpha1antichymotrypsin (PSA-ACT) Free PSA percentage of free PSA to PSA-ACT ratio may help differentiate benign prostate hyperplasia (BPH) from prostate cancer.

Susceptibility Genes
Several familial cancers are associated with germline mutations in various genes. The most prominent are genes for susceptibility to breast and ovarian cancer, such as BRCA1 and BRCA2 are now available to screen these families for the identification of carriers.

Monitoring Treatment
One of the two most useful applications of tumor markers involves their use in monitoring the course during treatment of the cancer patient. The measurement of serum tumor markers during treatment gives an indication of the effectiveness of the antitumor drug used and provides a guide for the selection of the most effective drug for each individual case.

Detection of Recurrence
Monitoring tumor markers for the detection of the recurrence following the surgical removal of the tumor markers. It is desirable to monitor the patient using a highly sensitive tumor marker test to detect recurrence as early as possible. It should be noted that the appearance of the most circulating tumor markers have a lead time of several months (3-6 months) prior to the stage at which many of the physical procedures can be used for the detection of the cancer.

Prognosis
Determination is based on the assessment of tumor aggressiveness, which, in turn, determines how a patient should be treated. Prognostic factors measured in the clinical laboratory also indicate risk and predict the length of a relapse-free, as well as overall, survival period at the time of the primary therapy. High levels of serum tumor marker measured during diagnosis would indicate the presence of a malignant or metastatic tumor associated with a poor prognosis.

Early Detection
Detecting the phenotypes in the blood circulation corresponding to early mutations of a cancer allows the detection of early neoplasm at the curable stage. It should be noted that several risk factors may lead to tumorigenesis, which can be identified and eliminated with diet adjustment and lifestyle change Measurement of all mutant phenotypes and risk factors in the circulation would help to identify individuals at risk for cancer or detect early tumors in benign state.

Target Therapy
Previously, drugs used in chemotherapy were predominantly DNA-active drugs that were considerably toxic and had limited efficacy. Inhibition of tumor cell proliferation may also be effective by introducing agents (or genes) that turn off the signaling pathway or pathways that specifically drive proliferation within a given tumor or tumor type. The prevailing new rationale is aimed at the development of target-selective smart drugs on the basis of characterized mechanisms of action. The specific defect of the tumor identified by these new tumor markers should, therefore, lead to the design of more specific drugs, including antibodies and small molecules, which inhibit growth factor receptors tyrosine kinases.

TYPES OF TUMOR MARKERS

Enzymes, Serum Proteins, and Hormones ENZYMES ASSOCIATED MALIGNANT DS. Prostatic ACP Prostate CA, late stage Lyozyme Colon CA, Monocytic and Myelomonocytic Leukemia LDH Acute leukemia, Malignant lymphoma Germ cell tumors, Metastatic colon, Breast and Lung Cancers

TYPES OF TUMOR MARKERS

ENZYMES ASSOCIATED MALIGNANT DSE.

5-Nucleotide Phosphodiesterase Siacyltransferase Fucosyltransferase Thymidine kinase

Lung CA, Liver metastasis

Non-specific Multiple malignant tumors Hodgkins lymphoma;certain Leukemias, small cell CA of lungs Lymphoblastic CA

Terminal deoxynucleotidyl transferase

Carcinoembryonic Proteins
The expression of some proteins, slated to be turned-off during normal developmental processes, may be reactivated in tumor cells.

Monoclonal Defined Tumor Markers

MONOCLONAL KIT
CA 125 Hybri-BREScan (CA 549) or CA 15-3a Hybri-CMark (CA 195) or CA 19-9a CA 72-4 Free PSA

ASSOCIATED MAJOR MALIGNANT DISEASE

Ovarian carcinoma Breast carcinoma

Pancreatic carcinoma Gastric carcinoma Differentiate between BPH and Prostatic carcinoma

Non-specific Tumor Markers

Sensitive to changes of the tumor activity Inexpensive and simple to measure, and are, therefore , useful in monitoring therapy and detecting recurrence for patients with known diagnosis.

Cell-Specific Tumor Markers

TUMOR MARKERS ASSOCIATED MALIGNANCY DS.

Squamous cell ag (SCCA) Squamous cell CA Chromogranin (CgA) Neuroendocrine cell CA Neuron-specific enolase

RECOMMENDATIONS FOR TEST ORDERING

Ordering Serial test Using the Same Kit Half-life of the tumor marker Hook effect

FREQUENTLY ORDERED TUMOR MARKERS

Individual Tumor Markers

a. - Fetoprotein - Elevated in patients with primary hepatoma carcinoma cell (HCC) and yolk-sac-derived germ cell tumors. - Most useful serum marker for diagnosis and management of HCC b. 2 Microglobulin (2M) - It is nonspecific tumor marker because it is elevated, not only in solid tumors but also in lymphoproliferative diseases and variety of inflammatory disorders including: RA, SLE, Sjogrens syndrome, and Crohns disease. - Normal serum level 0.9-2.5 mg/L

Individual Tumor Markers

c. Cancer Antigen 125 (CA 125) - Defined first by a murine monoclonal antibody OC 125 raised against a serous ovarian carcinoma cell line. - Useful for detecting ovarian tumors at an early stage and for monitoring treatments without surgical restaging. - Upper normal limit 35 U/mL.

Individual Tumor Markers

d. Cancer Antigen 15-3 (CA 15-3) - >25 U/mL are observed in patients with metastatic breast cancer - More sensitive and specific marker for monitoring the clinical course of patients with metastatic breast cancer and is more sensitive marker for metastatic breast cancer than CEA. e. Cancer Antigen 19-9 (CA 19-9) - The highest sensitivity of CA 19-9 was found in pancreatic and gastric cancers

Carcinoembryonic Antigen
Most widely used tumor marker for gastrointestinal cancer today.

Chromogranin A
It is a useful marker of exocytotic sympathoadrenal activity in patients with pheochromocytoma. a. Estrogen Receptor (ER) b. Human Chorionic Gonadotropin (hCG)

Homovanillic Acid
Above normal in tumors originating from neural crest. Useful in detection and monitoring of patients with pheochromocytoma and diagnosis of neuroblastoma in children

Lipid Associated Sialic Acid in Plasma (LASA-P)

Found elevated in various malignant diseases, such as, in the breast, GI or lungs. It is also altered in leukemia, lymphoma, Hodgkins disease, and melamona, as well as in nonmalignant infalammatory diseases.

Lipid Associated Sialic Acid in Plasma (LASA-P)

a. Neuron-Specific Enolase (NSE) - can be found in tumors originating from the neuroendocrine cell system, including glucagonomas and insulinomas. b. Progesterone receptor (pgR) - Associated with breast tumors c. Prostate-Specific Antigen (PSA) - Major protein in seminal plasma

Squamous Cell Carcinoma Antigen (SCCA)

Useful in monitoring squamous cell carcinomas of the head and neck, lung, esophagus, and anal canal.

Vanillylmandelic Acid (VMA)

Useful in detection and monitoring of patients with pheochromocytoma and diagnosis of neuroblastoma in children