Precurser stages in cancer

Daniel Roth, M D

There are two facets to the searc-. for precursor stages in cancer. One is turned toward the attempt to learn how ma- lignancy is caused, the other, perhaps of greater immediacy, toward the need for recognizing cases of clinical cancer while they are still at a curable stage.

Modern surgery has come about as far as one can hope toward the goal of achieving a high rate of cure by ablation of malignant tissue. Localized cancer, arising at almost any site, can presently be attacked surgically with low morbidity. This view certainly ap- plies to the major, lethal cancers (head and neck, breast, lung, bowel, and uterus). Yet the overall cure rate is not satisfactory. This is, in too many

Daniel Roth, MD, i s ossociote professor of pathology at the New York University Medical Center. He is o graduate of the New York Medical College and has been in the practice of clinical and surgical path- ology since 1951. In addition to instructing path- ology to the house staff and students, Dr. Roth has done research into detection of early cancer, biochem- ical changes during carcinogenesis and repair of mu- tagenic damage in cells as related to carcinagenesis. Fig 1 in this article was previously published in

Cancer, 24611. 1969, and i s reprinted with their permission.

cases, because of the remote dissemina- tion or inoperable extension of the dis- ease at the time the diagnosis is made. By the time the patient comes to sur- gery, the favorable period for cura- bility has all too often been passed.

In addition, cancer detection centers, which proliferated in the period follow- ing the Second World War, promised early detection, and this has not been significantly realized. While a modest degree of success most certainly can be attributed to these facilities, a national lessening of cancer mortality has some- how been prevented. The high cost of case-finding, apathy - of the public, and all too often, the profession as well - and, most important, limited capa- bility for recognizing cancer in its early stages, have conspired to prevent this sweeping reduction.

There is clearly an urgent need for practical means of recognizing the in- dividual with curable or incipient can- cer. Spotty progress in this direction has been made, with a few spectacular ad- vances.

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Foremost of these must be the field of exfoliative cytology, introduced by George Papanicolaou, MD. Cancer of the cervix has been made controllable by this technic. Yet; for a number of reasons, extension of the technic to other anatomical sites has not been very successful. It is possible that, as ob- stacles are overcome, a more generalized usefulness of cytodiagnosis of cancer may emerge.

Other approaches should also be taken. Because it would be impossible to foresee which direction has the greatest potential for progress, these can cover the entire breadth of activity in the biological sciences, and can range from a straightforward statistical epi- demiological approach to one slanted toward the most advanced areas of the physical sciences.

Good examples of the former are to be seen in the sporadic but perhaps significant outbreaks af acute leukemia in “clusters;” the complete pedigreeing of multiple cancer families; positive cor- relations which involve only one or a few parameters such as that between heavy smoking and respiratory tract can- cer; and more complex associations such as the increased risk of colon cancer among obese, constipated, urban females with familial diabetes. High risk groups can thus be selected for more intensive, expensive follow-up. Further leads into possible causative factors can be antici- pated from such studies.

Some developments in the fields of biology, biochemistry, and biophysics possess unusual promise, and may be worth describing. Such a listing cannot begin to be complete, and one is always hauntingly frustrated at the knowledge that, sitting somewhere on a library shelf, there may be a work from which potential for direct application to cancer

detection is unsuspected, even by its author.

This real problem of seizing exploit- able breakthroughs is a constant chal- lenge to those medical workers who can bridge the gulf between the clinic and the research laboratory. For, increasingly and unavoidably, basic research is leav- ing the physician-directed arena and localizing in some remote, unlikely places ( military arsenals, space-age in- dustries, electronics laboratories, ocean- ographic expeditions), and the scientists working in such places may not always be able to envisage possible clinical uses or needs for their discoveries.

Those of us in laboratory-based medi- cal practice have the obligation of keep- ing pace with progress in these places, in order to recognize and exploit new knowledge as early as possible.

Nieburgs and others have reported and documented a series of visible changes occurring ubiquitously among accessible normal cells of humans (blood cells, buccal epithelium) suffering from deepseated or even occult cancer. This knowledge has already been put to use in screening populations for asympto- matic cancer. Even if some benign con- ditions can also produce these changes, their value in selecting the few, high risk subjects for more intensive study, may become established.

Possibly related to these so-called “ma- lignancy associated changes” (MAC) in cells far from the real tumor, is the re- port of Bendich and coworkers that transforming DNA inoculated intra- peritoneally into susceptible animals, is carried by the blood to all parts of the animal and can be incorporated into cells everywhere before it is destroyed by nucleases of the blood. Such foreign DNA, if absorbed in sufficient quantities by cells, would be able to alter their straining properties in the direction of

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the “MAC” changes. Thus, a link be- tween a clinical test and one form of experimental carcinogensis may be dis- cerned.

The potentially exploitable cytological abnormalities known to be associated with cancer cover a broad spectrum. At one end, for example, is the frequent occurrence of increased numbers of eosinophils in the finger-tip blood smear of individuals who, only years later, may develop myelogenous leukemia.

At the opposite end of the spectrum, in terms of the exotic, can be mentioned aberrations of the karyotype of cells in individuals who are predisposed to future development of leukemia; these include the additional chromosome found among Mongoloids; the so-called “Philadelphia” abnormaliy associated with myelogenous leukemia; the aber- rations produced by x-rays, and those associated with disorders of “self-recog- nition” or “autoimmunity.”

New approaches to chromosome map- ping, such as automated microdensi- tometry and fluorescence-labelling of specific sites in chromosomes, are open- ing up pathways for ultimately being able to anticipate probable cases of leukemia and other malignancies in their precursor stages.

Abnormalities of the DNA molecule and its gene content are being studied on a massive scale. Among the promis- ing developments here are technics for identifying very small amounts of ex- ogenous (viral) DNA integrated into the genome of the host by RNA-DNA hybridization.

Thus, if certain viruses prove to be capable of initiating some cancers in humans, it may become possible to identify their presence in blood cells or other accessible cells of subjects infected with these agents at a very early stage of cancer development. The presence of

oncogenic viral genes may also become recognizable through new refinements of classical immunological technics such as complement-fixation, immunofluores- cence, and neutralization methods.

Of great potential also are enzymo- logical approaches to cancer diagnosis. Some are already proving of clinical value; the diminished alkaline phospho- tase activity in normal leukocytes can help to identify the patient suffering from preclinical stages of chronic mye- logenous leukemia. Deficiencies of other, essential metabolic enzymes, such as cytochrome and alpha-glycerophosphate dehydrogenase, may soon be utilized clinically in one form or another to identify the cell undergoing malignan- tization.

The cells of patients suffering from a hereditary disease, xeroderma pigmen- tosum, which leads to early onset of fatal skin cancers, have been found to be defective in enzymes required for “re- pairing” damage to their DNA structure inflicted by environmental mutagens.

Heightened malignant “transforma- biIity” of cells from certain individuals with another genetic disorder predis- posing them to early cancer, Fanconi syndrome, has been demonstrated.

In other cases, such as heavy smok- ing, from which predisposition to cancer may be acquired, there apparently is sufficient incorporated exogenous DNA in the cells that it competes with in- trinsic DNA for the normal repair sub- stances available to each cell. It thereby leaves them susceptible to any future encounter with carcinogenic mutagens. (Fig 1 shows rates of recovery from experimental ultraviolet irradiation dam- age in desquamated buccal cells from two normal subjects, a smoker, and a patient who had been cured previously of cancer of the oral mucosa. Indicated is a pre-existing deficiency in the avail-

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0 10 20 30 40 TIME CMIN)

ability of cellular DNA to “repair” mechanisms).

The technics for measuring these ab- normalities are not difficult, and may find clinical applications in the near fu- ture. The circulating plasma may also indicate the cancerous state by yielding changes in enzyme levels. These could reflect simple leakage of normal en- zymes into the plasma from abnormally fragile cancer cells, or the appearance of abnormal enzymes which are pro- duced only by cancer cells.

The presence of particulate material typical of cancer may be found in the blood of some patients, thus serving

to permit screening by examination of the blood. At present, the “ C type par- ticles are thought to be a specific index of infection by leukemogenic viruses.

Finally, antibodies against known car- cinogenic viruses such as adenovirus type XII, and SV40, may be found in the serum of individuals in the process of cancer development. Antibodies against abnormal enzymes secreted by cancer cells may soon be a reality.

A continuing, aggressive exploration of potential tools is required in this search, for one must expect far more failures than successes. 0

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