Altered Template Stability: The Molecular Mask of Malignancy?

ALTERED TEMPLATE STABILITY: THE MOLECULAR MASK OF MALIGNANCY? HENRY C. PITOT* The humanfeatures and countenance . . . are sofashioned that among so many thousands ofmen there are no two in existence who cannot be distinguishedfrom one another.—Pliny the Elder. Like the human organism it mercilessly attacks, cancer is the disease ofa thousand countenances and features. No two cases are exactly alike, at the cellular as well as the clinical level. In fact, this seeming individuality is so ingrained in our thoughts that in many laboratories and hospitals each cancer or group of cancers is considered and treated as a separate disease entity. The subclassifying and individualizing so characteristic ofclinical medicine —and truly ofnecessity, since only the broadest picture is available to the physician—has made the task ofthe investigator doubly hard. Should he look at all cancers available to him or study only one at a time? Should he look at cancer in the rat or in the human? Should he forget the disease and study the cell or disregard biochemistry and study only morphology? Should he expound theories which cannot be tested by experiment or work blindlyinthelaboratory with little orno rationalplan to his research? The dilemma continues as we stumble on groping for hints, suggestions, facts, ideas, or correlations to use to attack this curse ofevolution that we call cancer. But finding facts applicable to the problem does not insure its solution. In practice, such findings may appear to make the problem more difficult. Consider the isolation ofchemicalcarcinogens byKennaway and his group in 1928. With this discovery the cure could not be far off. But today we know ofhundreds ofdifferent chemicals capable ofcausing neoplasms, and * McArdle Memorial Laboratory, The Medical School, University of Wisconsin, Madison, Wisconsin. 50 Henry C. Pitot · Altered Template Stability Perspectives in Biology and Medicine · Autumn 1064 the cure is still "not far off" The biochemical concepts ofmalignancy— those ofimpaired respiration resulting in a high rate ofglycolysis [i] and of convergence of tumor enzymes to a common pattern [2]—are today known to be only partially complete since a number of experimental tumors don't fit these concepts [3]. The reported aneuploidy oftumors [4] is not the sine qua non of neoplasia that it was once thought to be. And today the new horizon is once again the infectious etiology of cancer. Viruses may be the answer, but to date the evidence is by no means overwhelming . Only a relatively few malignant tumors in animals and none in man have been found to have a viral etiology, and no heralded cancer "vaccine" has been found to prevent a single child from dying ofleukemia. Finally, let the scientist who would rid the world ofthis scourge beware the prophetic words ofthe late Dr. Greenstein: ". . . for some odd reason, cancer research has beenthe graveyard ofmany a scientific reputation" [5]. Amidst all this uncertainty and frustration one is apt to lose sight ofhis goal as well as his foundations. Cancer research has as its goal a method of effectively combatting and ultimately curing, in the medical sense, neoplastic disease in the human patient. As its foundation, cancer research has only cancer itself. I. The Meaning of"Cancer" To paraphrase a popular song title, what is this thing called cancer? As late as 1925 a prominent physician made the statement that one could not satisfactorily define malignant disease. Absurd as such a statement may seem to some ofour readers today, this question must be given a definite answer before logical research on the cancer problem can proceed. Are there one or more biological characteristics ofneoplasia which are common to all cancers? Ifthere are, then we can presume to have a definition. During the past three decades eminent physicians have defined the neoplastic process as they saw it. To quote a few: The really essential difference between tumors and normal tissue is not the increased energy ofgrowth, but the emancipation ofthe tissue from obedience to the laws which govern the growth and maintain the organizing activity ofthe normal tissues [6]. A neoplasm is an autonomous new growth oftissue [7]. A tumour is an abnormal mass oftissue, the growth ofwhich exceeds and is uncoordinated withthat ofthe normaltissues, and persists inthe same excessive manner after...