The Cancer Journal - Volume 10, Number 3 (May-June 1997)
Tumor-specific antigens do not exist - Cancer is generally regarded as a parasite encroaching on an indolent host. Yet, unlike other parasites that have qualities other than those of the host, the tumor does not differ qualitatively from its host, rather it differs quantitatively. This unusual feature is somewhat disappointing, since a qualitative difference is essential for an efficient anti-parasitic treatment, e.g. immunotherapy. Like all other life-forms, parasites carry unique antigens that differ from antigens of other life-forms. The tumor, on the other hand, does not carry any antigen that is not also present in its host. Despite an intensive search for unique tumor antigens, none have been discovered. Several antigens that were thought to be tumor-specific were also found in normal tissues, such as pancreatic onco-fetal antigen, carcino-embryonic antigen, or alpha-feto protein. The names reveal the disappointment of researchers who thought that they had discovered a "carcino" antigen, until realizing that the antigen is a normal embryonic product, elevated in cancer.
Tumor-associated antigens are tissue-specific antigens - Since tumor antigens remain elusive, substitutes have been adopted: tissue-, or tumor-associated antigens, with the hope that these can be applied to tumor treatment, but with no success. The therapeutic margin of these antigens is too narrow. In other words, antibodies formed against tumor-associated antigens, damage "good" as well as "bad" cells. This observation can now be generalized; there is nothing in a tumor that does not also exist in the host. Tumor and host differ only quantitatively. Any so-called "tumor-specific markers", are amplified normal constituents. This is also the stumbling block of chemotherapy. While antibiotic treatment exploits qualitative differences between host and parasite, none were found in tumor cells. Chemotherapy exploits merely quantitative differences, the therapeutic margin is narrow and declines with every treatment, since tumors become resistant to chemotherapy. Still, chemotherapy remains valuable as a palliative treatment.
We may thus distinguish between two kinds of parasites, those which differ qualitatively from their host, and those which do not. All known parasites belong to the first category, while the second is occupied solely by the tumor. Yet since the tumor differs from all known parasites, shouldn't we replace this poor metaphor by a better one?
One tumor hallmark, chromosomal translocations, seemed to be tumor-specific, and might serve as qualitative marker. It had not been observed in normal cells. On the other hand, hardly anybody had searched for it in non cancerous pathologies, e.g., chronic granulation tissue, or granuloma, which display increased cell and protein turnover like cancer. This has now changed: new and refined technology, e.g. PCR, has revealed translocations in normal B-cells (1).
B-cells of healthy individuals have the t(14;18)(q32;q21) translocation. Lymphocytes in most follicular lymphoma patients carry a typical translocation: t(14;18)(q32;q21) involving bcl2. The authors report that : "We and others independently proved that t(14;18) breakpoints are regularly detected outside the setting of follicular lymphoma and even in healthy individuals. Recent data from another laboratory show that the t(8;14) associated with Burkitt's lymphoma is detectable in normal individuals as well (2)." These chromosomal breakpoints were detected by the PCR method. When testing lymphoma patients, the authors used hyperplastic tonsils of young children as controls. "Unexpectedly, our experiments on tonsils and lymph nodes with follicular hyperplasia yielded positive results indicating a t(14;18). Other control tissues were consistently negative." The authors cite research demonstrating that 2% of normal individuals harbor the Burkitt's lymphoma-associated translocation t(8;14) in their blood cells. "Analysis of stored blood samples showed that in one individual the same breakpoint had persisted over a period of 9 years."
"The frequency of t(14;18) breakpoints in normal individuals is extremely high. At least half of all normal [Dutch] individuals harbor numerous B cells with a translocation" while the incidence of lymphoma in the Netherlands is 3/100,000/year. Many individuals carry multiple clones with unrelated breakpoints. These startling observations lead to the following conclusions: chromosomal translocation is a physiological process which was hitherto detected only when amplified, e.g. in cancer. Sensitive PCR techniques reveal it in healthy cells as well. Since it is ubiquitous, it cannot be regarded as pre-malignant. This would be like saying that life is pre-malignant. Neither can it be regarded as a random mutation. It has to be controlled by the organism (3). It is mobilized in children's disease, and amplified in cancer.
Rene Leriche has pointed out that, although the normal state precedes disease, knowledge of the normal is triggered by disease. "At every moment there lie within us many more physiological possibilities than physiology would tell us about. However, it takes disease to reveal them." Or, as Canguilhem puts it: "Disease reveals normal functions to us at the precise moment when it deprives us of their exercise." (4)(5). It now remains to find out what is the normal function of the t(14;18)(q32;q21) translocation or, better, what do we gain by creating a Philadelphia chromosome (3)?
1. Kluin PM, Schuring E. Chromosomal translocations in B cells of normal individuals: Preneoplasia ordormancy? in Premalignancy and Tumor Dormancy (E Yefenof and RH Scheuermann eds.); Springer-Verlag, Heidelberg, Germany, 1996.
2. Muller JR, Janz S, Goedett JJ, et al. Persistence of immunoglobulin heavy chain/C-MYC recombination-positive lymphocyte clones in the blood of human immunodefficiency virus-infected homosexual men. Proc.Natl Acad.Sci 92, 6577-6581, 1995.
3. Zajicek G. Controlled mutation in cancer. The Cancer J 8, 88-89,1995.
4. Canguilhem G. Le normal et le Pathologique. Translated into English by Fawcett CR, Cohen RS. Zone Books, New York, 1991.
5. Zajicek G. The Normal and the pathological. Cancer J 7, 48-49, 1994.