Two major processes are involved in cell growth, differentiation and proliferation. Normally these two processes are well regulated but when these processes lose regulation, the normal cells turn to hyperplasia or neoplasia. Hyperplasia is still a regulated useful growth, whereas neoplasia is unregulated purposeless growth thus leading to tumor, benign or malignant. Benign will remain at the primary site with less risk and successfully treated by complete removal whereas, malignant growth has associated genetic instability thus liable to mutations which lead to malignant disease and associated with poor prognosis and short survival time because of their ability to metastasize.
Early detection of malignancy offer the best possible prognosis with treatment. The aim is to diagnose cancer when tumor is still small enough to be completely removable surgically and confined to the primary site only. Though morphological diagnosis of the tumor by the histopathologist is the mainstay in diagnosis of malignancy but efforts were being made in last several decades to identify a tumor specific marker or tumor specific epitope or any cell product like enzymes, serum proteins, metabolites and receptors associated with any event during tumor formation, proliferation, differentiation or metastasis that could be used as a tumor marker for early diagnosis.
Tumor marker is defined as any substance present in or produced by tumor itself or produced by host in response to a tumor that can be used to differentiate tumor from normal tissue, which could be detected in cells, tissue or body fluids, qualitatively or quantitatively by chemical, immunological or molecular biological methods to identify the presence of cancer (1). The clinical value of any given tumor marker will depend on the intended clinical use, specificity and sensitivity of that marker. Few markers are specific for a single individual tumor (tumor specific marker), and few are found with different tumors of the same tissue type (tumor associated marker).
The saga of tumor markers can be divided into four eras. The first era was of Bence Jones proteins, discovery of which in 1847 laid the foundation of tumor markers (2). The second era, from 1928 to 1963 which included the discovery of hormones, enzymes, isoenzymes and proteins and their use as the diagnostic tool for diagnosis of cancer (3). The advent of Alpha fetoprotein in 1963 (4), carcinoembryonic antigen in 1965 (5) and onco-developmental markers (6) marked the beginning of third era and during this phase general application of tumor markers for study of malignant diseases was actually initiated. The fourth era started in 1975, with discovery of monoclonal antibodies and their use to detect oncofetal antigen like Carbohydrate antigen CA 125, CA 15 – 3, & CA 27.29. Finally this era has advanced to the use of these marker at the molecular level e.g. advances in molecular genetics including study of oncogenes, suppressor genes and genes involved in DNA repair (7). The detection of ras oncogene in colonic cancer has advanced the diagnostic capability (8) and discovery of BRCA 1 & 2 in breast cancer have led to possibility of screening for familial breast cancer in high-risk individual (9).
The classification of tumor markers and their predominant association with individual malignant disease is given in Table-1. The tumor marker should ideally be both sensitive and specific for the given type of cancer but none of the tumor markers presently known fulfill the above criteria. Therefore the role of tumor markers in the present scenario is screening of general population, differential diagnosis of symptomatic patients, clinical staging of the disease, estimating tumor volume, prognostic indicator for disease progression, evaluating and monitoring of the therapy, detection of recurrence, radioimmunolocalisation of tumor mass and determining direction for immunotherapy. (10, 11) Deb et al in their study of breast cancer used tumor marker for clinical grading and as prognostic indicator and found that the receptor positivity declined whereas p53 mutation and c erb B-2 over expression increased with increase in tumor grade (12).
TABLE 1.
Classification of Tumor Marker and their association to type of malignancies
| Type of Tumor Marker | Major diseases | Minor diseases |
|---|---|---|
| Enzymes: | ||
| Alkaline phosphatase | Bone Liver and Placenta | Leukemia, Sarcoma, Lymphoma |
| Creatine kinase | Prostate, Lung (SCC) | Breast, colon, ovary, stomach |
| Lactate dehydrogenase | Liver, Lymphoma, Leukemia | Breast, colon, stomach, lung |
| Neuron Specific Enolase | Lung (SCC), Neuroblastoma | Pheochromocytoma, Carcinoid |
| Prostatic Acid Phosphatase (PAP) | Prostate Cancer | Oesteogenic sarcoma, Multiple myeloma, Bone Metastasis |
| Prostatic specific antigen (PSA) | Prostatic cancer | BPH |
| Hormones: | ||
| Adrenocorticotrophic Hormone (ACTH) | Lung (Small cell carcinoma) | Pancreatic, Breast, Gastric, colon |
| Calcitonin | Medullary carcinoma thyroid | Carcinoid, Breast, lung |
| Human chorionic gonadotrophin | Choriocarcinoma | Testicular tumor, Trophoblastic tumor |
| Oncofetal antigens | ||
| α-Fetoprotein | Primary hepatocellular carcinoma | Teratoblastoma of ovary and testis |
| Carcinoembryonic Antigen (CEA) | Colorectal carcinoma | Gastrointestinal, Pancreatic, lung, breast |
| Tissue polypeptide Antigen | Breasr, colon, ovary | Choriocarcinoma (TPA+), Hepatocellular (TPA-) |
| Sq cell ca antigen | Cervical, lung, skin | Gastrointestinal, ovaries, urogenital |
| Carbohydrate antigen | ||
| Episialin | ||
| CA 15-3 | Breast | Pancreatic, ovaries, lung, colorectal |
| CA 549 | Breast | Metastatic ovarian, prostate, lung |
| CA 27.29 | Breast (Recurrent) | — |
| Mucin like carcinoma associated antigen (MCA) | Breast | Ovaries, cervical, endometrial |
| CA – 125 | Ovaries & Endometrial | Pancreatic, lung, breast, Gastrointestinal |
| Du – PAN – 2 | Pancreatic | Biliary, hepatocellular, Gastrointestinal |
| Blood group antigen | ||
| CA 19 – 9 | Colorectal, Pancreatic | Gastrointestinal, Hepatic |
| CA 50 | Pancreatic & Colorectal | Gastrointestinal, Hepatic |
| CA 72 – 4 | Gastrointestinal, ovary | Breast, Colon |
| CA 242 | Pancreatic & Colorectal | Gastric carcinoma |
| Receptors and other marker | ||
| Estrogen & Progesterone | Breast carcinoma | — |
| Catecholamines Metabol | Neuroblastoma, Pheochromocytoma | — |
| Hydroxyproline Proteins | Bone metastasis (breast), Multiple myeloma | — |
| Immunoglobulins | Multiple myeloma, Lymphoma | Waldenstrom macroglobinaemia |
| Microglobulin | Multiple myeloma, B cell Lymph | Waldenstrom macroglobinaemia |
| C-peptide | Insulinoma | — |
| Bladder tumor associated antigen | Urinary bladder tumor | — |
| Nuclear matrix protein | TCC of urinary bladder | — |
| (NMP 22) | ||
| Genetic markers | ||
| Oncogenes | ||
| N-ras mutation | Neuroblastoma, Myeloid leukemia | — |
| K-ras mutation | Pancreatic, Leukemia, Lymphoma | Colon, Lung, Bladder |
| c-erb B-2 amplification | Breast | Ovarian & Gastrointestinal |
| c-myc translocation | B&T cell lymphoma | Lung (SCC) |
| Suppressor genes | ||
| Retinoblastoma gene | Retinoblastoma | Oesteogenic sarcoma, Lung (SCC) |
| P53 gene | Breast, colon | Liver, Renal cell, Bladder, Sarcoma |
| APC gene | Colorectal | — |
| Neurofibromatosis ty 1 | Neurofibromatosis | Colon, Melanoma, Neuroblastoma |
| BRCA 1 & 2 | Breast | Neurofibromatosis, Melanoma |
| WT 1 | Wilm's tumor | — |
Increase of enzymes, isoenzymes and hormones is not specific or sensitive enough to identify the type of cancer with exception of PSA (13). Oncofetal antigen, the protein produced during fetal life and whose concentration increase in certain cancers do play some role in diagnosis of small group of cancers (Table 1). Carbohydrate markers are new generation of markers and tend to be more specific than naturally secreted markers like enzymes and hormones (14). Amongst the genetic markers, oncogenes (cell activation gene) code for proteins that function at some stage of activation of cells for proliferation. These are associated with hematological malignancies. The other class of tumor gene, the suppressor gene (recognition and repair of damaged DNA) is associated with solid tumors and cause and effect is due to the loss of gene rather than activation.
References
- 1.Sell S. Serological cancer markers. Totowa, New Jersey: The Humana Press. 1992 [Google Scholar]
- 2.Bence-Jones H. Pathology Papers on Chemical Lecture III. Lancet. 1847;2:269–272. [Google Scholar]
- 3.Sell S, Cancer Markers. In. In: Moossa AR, Schempff SC, Robson MC, editors. Comprehensive Text book on Oncology. Williams and Wilkins; Baltimore: 1991. pp. 225–238. [Google Scholar]
- 4.Abelev G I, Perova S D, Khramkova N I. Production of embryonal alpha – globulins by transplantable mouse hepatomas. Transplantation. 1963;1:174–180. doi: 10.1097/00007890-196301020-00004. [DOI] [PubMed] [Google Scholar]
- 5.Gold P, Freeman SO. Demonstration of tumor specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques. J Exp Med. 1965;121:439–462. doi: 10.1084/jem.121.3.439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Fishman WH, Sell S. Onco-developmental gene expression: A preview. In: Fishman WH, Sell S, editors. Onco-Developmental Gene Expression. Academic Press Inc; New York: 1976. [Google Scholar]
- 7.Knudson Jr A G. Hereditary cancer, oncogenes, and antioncogene. Cancer Res. 1985;45:1437–1481. [PubMed] [Google Scholar]
- 8.Sidransky D, Tokino T, Hamilton SR. Identification of ras oncogene mutations in the stool of patients with curable colorectal tumor. Science. 1992;256:102–105. doi: 10.1126/science.1566048. [DOI] [PubMed] [Google Scholar]
- 9.Petty E M, Killeen AA. BRCA – mutation testing, controversies and challenges. Clin Chem. 1997;43:6–8. [PubMed] [Google Scholar]
- 10.Chan D W, Sell S. Markers Tumor. In: Burtis Ashwood A C, editor. Tietz Text Book of Clinical chemistry 3rd ed. Harcourt Brace & Company Asia PTE Ltd; Singapore: 1999. pp. 722–749. [Google Scholar]
- 11.Wu J T. Diagnosis and management of cancer using serological tumot markers. In: Henry J B, editor. Clinical Diagnosis and Management by Laboratory Methods. W B Saunders; New York: 1996. pp. 1064–1080. [Google Scholar]
- 12.Deb P, Deshpande G U, Rai R. Correlation of hormone receptor status, p53 mutation and c erb B-2 over expression with nuclear grading in breast cancer. MJAFI. 2000;56:4. doi: 10.1016/S0377-1237(17)30215-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Chu T M. Prostate Specific Antigen. In: Sell S, editor. Serological Cancer Marker. The Humana Press; Totowa, New Jersey: 1992. pp. 99–115. [Google Scholar]
- 14.Hlkens J. Disease biochemistry and function of mucin in malignant. Cancer Rev. 1988:24–54. [Google Scholar]