some aspects of the developmental biology of neoplasia1...essential problem of developmental...

[CANCER RESEARCH 2S, 1880-1887,September 1968)

Some Aspects of the Developmental Biology of Neoplasia1

Henry C. Pitot2

The McArdle Laboratory and Department oj Pathology, The Medical School, University o} Wisconsin, Madison, Wisconsin

INTRODUCTION

The major goal of the new hybrid science of developmentalbiology is an understanding in molecular terms of the processesinvolved in the development of a fertilized ovum to a mature individual organism. In the initial session of this symposium several aspects of this topic were discussed, utilizing the unicellularorganism as a model and applying knowledge gained thereinto an understanding of the development of multicellular or-ganismal systems. A key term utilized by the developmentalbiologist is that of "differentiation." However, when one at

tempts to obtain a succinct definition of this term, one is metwith some degree of frustration. As our knowledge expands inthe area of molecular biology, the definition of differentiation,a uniquely biologic term, must take on a rather general character. Such a definition has been proposed by Mayer (19), whostated that differentiation is ''development of something homo

geneous and chaotic into something heterogeneous and patterned." A corollary to any definition of differentiation is that

the key to its mechanism is control ; control of DN A synthesis,control of cell division, control of cell structural modification,control of enzyme levels in cells, and control of specific metabolic functions. Although it is presumed that all cells of anorganism have an identical complement of DNA, they obviously express themselves quite differently. The mechanism forthe development of this difference in expression of genetic information in a single genetically homogeneous organism is theessential problem of developmental biology.

If the above is true, then it might be stated that the essentialproblem of abnormal developmental biology (developmentalpathology) is the problem of neoplasia, wherein cells, whichin many cases have already differentiated to their fullest degree, lose certain mechanisms controlling their genetic expression; be it that of DXA synthesis, cell division, or regulationof specific enzyme levels. We have already discussed variousmechanisms for the instigation of this major abnormality ofdevelopmental biology. Virus infections of cells may rapidly(within 24 hours) cause a transformation from a normal to amalignant cell in vitro (12, 21). In an analogous vein, virusesare known to alter normal developmental mechanisms seen inembryogenesis (43). Perhaps the most striking and patheticinstance of this is the effect of German measles infections inpregnant women resulting in dramatic deformities in the infant.

1 The original research reported in this paper was supported inpart by grants from the National Cancer Institute (CA-07175)and the American Cancer Society (P-314).

2 Career Development Awardee of the National Cancer Institute (CA-29405).

We have seen that specific neoplasms possess specific antigens,even to the point that each tumor caused by chemicals appearsto be distinctly antigenic from every other neoplasm causedby the same chemical (17, 27). An analogy to this may be seenin the organ-specific antigens present within any single organism. Finally the fact that numerous chemicals and physicalagents may rapidly or slowly induce the malignant transformation has its parallel in the teratogenic action of numerous chemicals, a number of which share both carcinogenic and teratogenicproperties (8). Thus, neoplasia presents many characteristicproblems already familiar to the developmental biologist. Thefocus of this symposium is to gain new insight into these problems by indicating relationships in apparently diverse fieldswhich had hitherto been overlooked.

THE DEVELOPMENT OF CANCER RESEARCH

The historic aspects of cancer research have been discussedat length (44, 45). In general, studies of the disease up untilseveral decades ago were centered almost exclusively around itsbiology. As has been pointed out (29), no acceptable definitionof the disease appeared to be available before 1930. Discussionsof the biologic definition of malignancy have been presentedelsewhere (28, 30). In essence, the major components of thedefinition are: (a) Cancer, as biologically defined, occurs only inmulticellular organisms; (6) increased replication of cells per seis not a sine qua non of malignancy; (c) the major biologiccharacteristic of cancer, benign or malignant, is an alterationin the control of cellular metabolism and function. The factthat increased cellular replication per se is not an absolute criterion of malignancy may come as a shock to some of the biochemically oriented investigators in oncology, but it is wellknown in the area of tumor biology. As has been pointed out(29), the abnormal regulation of growth may be considered inthe overall picture of malignancy as another example of abnormal regulatory mechanisms rather than the essence of the malignant process itself.

Regulatory Interactions in Host-Tumor Relationships

That tumor growth itself may in many instances not be theprimary cause of death of the host organism is well documentedby numerous examples in the human being. The fact that certain hormone-producing neoplasms may cause destruction ofthe host by an excess secretion of their product is exemplifiedby the insulin-secreting pancreatic tumors as well as the esoteric pheochromocytoma which produces excessive amounts ofnorepinephrine-like compounds leading to extreme hypertensionand sometimes death of the patient. The fact that many neoplasms in the human being may result in the demise of the

1880 CANCER RESEARCH VOL. 28

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Neoplasia Aspects

patient without any demonstrable anatomic cause of death hasbeen a frustration to many an autopsy prosector. The phenomenon of terminal cachexia seen in a number of human patientshas its counterpart in a number of experimental neoplasms. Therecently developed series of highly differentiated hepatocellularcarcinomas (25, 40) may be cited as primary examples of this.Although many of these tumors may be found in certain casesto metastasize, the vast majority of lesions destroy the hostwith no associated anatomic cause of death. Early studies (36)from this laboratory demonstrated that certain enzymes involved in amino acid degradation, especially serine dehydratase,may be at quite high levels in several of the neoplasms whileat the same time the host liver even on a very high protein dietexhibits quite low levels of the enzymes. A similar phenomenonhas been found with several other enzymes, including tyrosinea-ketoglutarate transaminase, ornithine S-transaminase, and inat least one instance, glutamine synthetase (53). Studies (C.Peraino, M. O'Connor, and H. C. Pitot, unpublished observa

tions) have shown that, in animals bearing neoplasms with highserine dehydratase activity, the serum level of threonine (analternate substrate for the enzyme) is about 50% that in normal rats, and these tumor-bearing animals convert threonineto carbon dioxide at rates seen in nontumor-bearing animalson a high protein diet. These data suggest that the tumoractually may act as a specific amino acid trap which is irreversibly draining the host of an essential amino acid, threonine.Most neoplasms studied in this group do not contain the enzyme glutamine synthetase. In animals bearing such neoplasms,the host liver has an exceptionally high level of this biosyn-thetic enzyme. In the one neoplasm which has been found tocontain quite high levels of the enzyme, the Morris Hepatoma7800, the liver level of the enzyme is normal or below normal(53). These data strongly suggest that the relatively uncontrolled metabolism of the neoplasm is dramatically affectingthe relatively well-regulated control mechanisms in the normalorgan from which the tumor arose. A somewhat more subtleeffect of the host on the tumor which ultimately has ramifications in the reverse direction is seen in Table 1. Herein is de

picted the effect of adrenalectomy on the high level of serinedehydratase (measured as threonine dehydrase) and tyrosinetransamjnase in the Morris 5123 hepatoma (33). It can be notedthat, although the activity of both of these enzymes in the intact tumor-bearing host is quite high, adrenalectomy of thetumor-bearing host causes a resultant drop to normal or belownormal levels in both enzymes in the neoplasm. These experiments suggest that the high, unregulated production of otherintracellular products, such as hormones by endocrine tumorsor serum factors by many neoplasms, may be altered by alteringthe endocrine balance of the host.

Development of the Biochemistry of Neoplasia

In considering the biochemistry of neoplasms several majorstudies may be cited. These studies may be divided into twogroups, those concerned with a study of neoplasms in general,and those concerned with a study of specific malignant systems.In the former case, the earliest generalization was presented byWarburg (46, 47), in which the primary biochemical defectfound in all neoplasms was an increased rate of glycolysis. Onlyrelatively recently have exceptions (2, 14) to this generalizationbeen described. It might be noted that exceptions to the generalization of increased rates of cell proliferation as characteristic of malignancy are about as rare as those exceptions tothe Warburg hypothesis. An extension of Warburg's concepts

were those of Greenstein (11), wherein the theory of convergence considered that all neoplasms were tending towards onespecific biochemical type.

The first major hypothesis resulting from studies of a specificsystem, that of liver and hepatoma, was the deletion hypothesis(23), which stated in essence that neoplasms resulted from adeletion of specific proteins by carcinogens, these proteins probably being involved in some growth-controlling process. Theexperimental basis for the deletion hypothesis has been welldocumented (38). More recent studies by Potter (39) haveextended the concept of the deletion hypothesis to includealtered mechanisms for regulating DNA synthesis and cellularreplication, these considerations giving rise to the concept of

Table 1

StimulusNo. ofanimals Host liver Hepatoma 5123

A. Tyrosine transaminaseNoneTyrosineCortisoneAdrenalectomyAdrenalectomy and

cortisone

B. Serine dehydrataseControlCasein feedingAdrenalectomyAdrenalectomy and

casein

16645

767

347 Â± 581850 Â±3141550 Â±117380 Â± 63

610 Â± 58

10 Â± 2100 Â± 50

10 Â± 2

414 Â± 80

2040 Â± 2382780 Â± 2933700 Â±1375630 Â± 87

1500 Â± 540

440 Â± 50520 Â± 75

8Â± 5

12 Â± 5

The effect of adrenalectomy on the serine dehydratase and tyrosine a-ketoglutarate transaminase activity of host liver and Hepatoma 5123. Data taken from that of Pitot et al. (33,36). See original references for experimental details.

SEPTEMBER 1968 1881



Henry C. Pilot

the "minimal deviation neoplasm," which states that there exists

a real or hypothetic intermediate cell or cellular populationwhich possesses the least number of biochemical requirementsto characterize it as a malignant cell. The deletion hypothesisappears also to be applicable to skin carcinogenesis (22). Abelland Heidelberger (l) showed that, as with liver and the carcinogenic azo dyes, carcinogenic hydrocarbons bind covalentlyto a basic protein fraction of soluble proteins in normal skin,but this fraction as well as carcinogen binding is markedly reduced in primary epidermoid carcinomas. More recently Col-burn and Boutwell (7) have studied a new skin carcinogen,y3-propiolactone, and have shown that the tumor-initiatingaction of this compound is related to its binding to DNA.

In order in part to explain how protein binding could bringabout a lasting, heritable malignant change in a cellular population, Pitot and Heidelberger (32) proposed a model whichsuggested that the deletion of cytoplasmic proteins could bethe result of altered metabolic circuitry (24) brought aboutby brief exposure to the carcinogen. An extension of this hypothesis is that of altered template stability proposed by Pitot(29), which like that of altered circuits does not necessarilyimplicate any direct genomic change as an absolute requirement for the malignant conversion.

RECENT STUDIES IN MODEL SYSTEMS

Biochemical studies in specific model systems in neoplasiahave attacked the problem from a number of different viewpoints. We have already discussed some of the earlier studiesand will herein consider the more modern aspects of the problem by again grouping the experimental work into two overallareas: those associated with studies correlating changes inbiochemistry with changes in growth rate of the neoplasms,and those changes which do not appear to be directly associatedwith DNA synthesis or cellular replication.

Biochemical Changes Correlated with Changes in GrowthRate of Neoplasms

As indicated above, both the Warburg and the Greensteinhypotheses may be considered as primarily related to thegrowth rate of the specific neoplasm in question. In a recentstudy Burk et d. (6) were able to correlate quite well the rateof glycolysis of several highly differentiated and poorly differentiated hepatomas with their rate of growth as measuredin vivo. Some of the most extensive studies correlating growthrate with biochemical changes seen in neoplasia are those ofWeber and his associates (48, 50). Since Dr. Weber will discuss these changes in more detail in a later portion of thisprogram, we will consider them only briefly here. The studiesof Weber have led to a molecular correlation concept (49, 51)of neoplasia derived from experiments which demonstrate thatalterations in certain biochemical parameters are present tosome degree in very slowly growing neoplasms and then become more pronounced as the growth rate of the tumor increases. Some of the general trends appear to be increases inglycolysis and glycolytic enzymes coupled with decreasedgluconeogenesis. As the neoplasms grow more rapidly, theytend to exhibit a decreased responsiveness to glucocorticoids.

Related studies by Bloch-Frankenthal et al. (3) have demonstrated that the capacity to oxidize fatty acids in a series oftransplantable rat hepatomas can be correlated to some extentwith the growth rate of these neoplasms. In general, the morehighly differentiated slower growing tumors possess a highercapacity to oxidize fatty acids. On the other hand, later studiesby Weinhouse (52) on several enzymes involved in carbohydrate and lipid metabolism suggest that there is no definitepattern of the presence or absence of these enzymes which canbe correlated with the "degree of differentiation" of the hepa

tomas. The correlation of biochemical changes with growth rateof tumors has also been discussed by Potter (39) in which theconcept of tumor initiation and tumor promotion may be considered (5). As tumor promotion continues and the neoplasmitself progresses to an increased rate of growth, one can expectto see further deletions of specific enzymes giving rise to a morerapid increase in growth rate.

Although earlier studies indicated that virtually all neoplasmsdemonstrated chromosomal aberrations, it has recently becomeapparent that primary neoplasms and those of a most highlydifferentiated degree may demonstrate a perfectly normalkaryotype (30). These data suggest that gross chromosomalabnormalities may well be in the class of growth-related characteristics.

In the field of developmental biology, the relationship ofgrowth rate per se and the degree of differentiation of fetalcells in vivo is difficult to assess. It is obvious that during veryrapid growth of the embryo, both structural and enzymaticdifferentiation occurs. However, it is true that at the time ofbirth many differentiated biochemical characteristics becomeapparent which because of their rapidity of appearance areprobably not related to growth rate changes per se (18, 42).

Biochemical Changes Apparently Independent of the GrowthRate of Neoplasms

As was pointed out earlier, increased cellular replication byitself is not an absolute characteristic of malignancy. It mayrather be stated that an abnormal control of DNA synthesisand cellular replication is one of the characteristics of malignancy. Furthermore, this abnormal control of growth wouldappear to be one other example of altered control mechanismsseen in neoplasia. The insulinoma mentioned earlier is a primeexample of this, wherein the major altered control mechanismaffecting the neoplasm's damage to the host is the unregulated

synthesis of insulin. One might then expect to find alteredregulatory mechanisms in many neoplasms which, taken atface value, have little to do with DNA synthesis or replicationof the tumor. These alterations, however, are primarily associated with the biologic neoplasia exhibited by the cancer cell.

At the experimental level, excellent examples of such alteredcontrol mechanisms have been found in the highly differentiatedhepatocellular carcinomas mentioned earlier (31). The alterations in mechanisms controlling the synthesis of many enzymesin these neoplasms have been reviewed several times (30, 31).In Table 2 are specific examples of both normal mechanismsseen in the control of liver enzyme synthesis and their abnormalcounterpart seen in several neoplasms. These defects appearto be independent of the growth rate of the tumor since the




Neoplasia Aspects

Table 2

Type Example Stimulus Comparison of liver and tumor

Substrate induction Tryptophan pyrrolase Tryptophan

Hormonal induction Tyrosine transaminase Cortisone

Dietary (multiple Serine dehydratase Amino acidssubstrate) induction

Product repression Hydroxymethyl glu- Cholesteroltarie CoA reductase

Glucose repression Serine dehydratase Glucoseornithine transaminase

Control systems in liver and hepatocellular carcinomas (35).

Absent in majority oftumors and in all adrenal-ectomized hosts.

Increased "sensitivity" to

hormone in tumors.Absent in most tumors. Dif

ferential actinomycin Dsensitivity in some tumors.

Absent in all tumors studied.

Absent in all tumors studied.

changes seen in the very early transplants in any particularneoplasm appear to be identical to those found in much later,more rapidly growing transplants. Furthermore, the morehighly differentiated neoplasms, even those with a normal chromosome number, exhibit a wide range of altered control mechanisms (V. R. Potter, M. Watanabe, and H. C. Pilot, unpublishedobservations). The extent of these alterations may be seen inthe data of Chart 1 taken from that of Bottomley et al. (4).In these charts the activities of two enzymes, serine dehydratase(measured as threonine dehydrase) and glucose-6-phosphatedehydrogenase, are plotted one against the other for liver (leftgraph) under varying dietary conditions and for a number ofneoplasms (right graph). Although the grafts are superficiallyquite similar, their major difference lies in the fact that by

manipulating the dietary condition of the host, any point inthe graph of normal liver may be moved anywhere along theabscissa and ordinate. In contrast, points on the graph of theneoplasms are for the most part frozen in that position. A fewexceptions are found, such as in the Morris Hepatoma 7800,wherein serine dehydratase is inducible but glucose-6-phosphatedehydrogenase is not. From these studies and other morerecent ones (30), one may suggest the generalization that inthese hepatomas most, if not all, of the mechanisms regulatingenzyme synthesis are ubiquitously abnormal when comparedwith normal liver and that each specific neoplasm appears tohave its own set of altered control mechanisms. That one isactually dealing with altered regulations of enzyme synthesismay be seen from the data of Table 3, in which the actual rate

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Chart 1. Threonine dehydrase and glucose-6-phosphate dehydrogenase levels in liver under various dietary conditions (lejt) andin a number of hepatocellular carcinomas (right). See Bottomley et al. (4) for details and symbol key.

SEPTEMBER 1968 1883



Henry C. Pilot

Table 3

Control (zerotime)12hr + aminoacid12hr + amino acid + glucoseSDH(Units/gm)190025002750SDH

(dpm/gm)321029603180Totalprotein,

(dpm/gm)64,00079,00067,500SDH(dpm/gm)Total

protein(dpm/gm)5.03.85.1

Effect of glucose and amino acids on valine-14C incorporation into serine dehydratase

(SDH) in Hepatoma 5123. The animals used in this experiment were of the Buffalo strainbearing the Morris Hepatoma 5123. Pretreatment was carried out as reported previously (34)and amino acids administered at times and in the composition described in the paper byJost et al. (15). Immunochemical titrations were carried out as described previously (15).

of serine dehydratase synthesis in the Hepatoma 5123 is measured immunochemically. From the data in the table, the control level of serine dehydratase is seen to be quite high (1900units per gram) and the amino acid incorporated into the enzyme per gram of tissue is extremely high when compared withthat incorporated into total protein of the same unit tissue.From these data it would appear that the tumor is devotingabout 4-5% of its total soluble protein synthesis into the synthesis of this enzyme. In normal liver even in the fully inducedstate the radioactivity incorporated into serine dehydrataseper gram is less than 1% of that incorporated into total solubleprotein per gram liver.

In another model system, Mclntire and Potter (20) havedemonstrated that experimental myelomas may produce abnormal globulins in very high amounts, each specific clone ofneop'.astic cells producing its own characteristic globulin. It

would appear that the products of these altered controlledmechanisms may not in fact represent abnormal proteins, butrather an abnormal regulation of the production of thesespecific globulins. Specifically, Potter and Kuff (37) proposedthat the normal differentiation of the plasma cell was interrupted with the neoplastic transformation of the cell resultingin a ''freezing" of the mechanisms regulating globulin produc

tion. A possible analogy to the data of Bottomley et al. (4)is quite reasonable.

A somewhat more subtle alteration in control mechanismshas been described by Pitot et al. (34), wherein enzyme induction, specifically that of serine dehydratase and tryptophanpyrrolase, has been found to be differentially sensitive to theeffects of actinomycin D when compared with the same mechanisms in normal liver. An example of this for the enzymeserine dehydratase is seen in Chart 2. In this chart, normalanimals and animals bearing the Reuber H-35 or Morris 5123hepatoma were given a mixture of amino acids at zero timeand the sensitivity of enzyme induction at that time and athourly or two-hourly intervals thereafter retested to see ifenzyme induction was still sensitive or resistant to the antibiotic. In normal liver, the induction of serine dehydratase becomes insensitive to actinomycin two hours after the initialamino acid administration and remains so for another six hours.In the H-35 hepatoma, at all times tested up to six hours,induction of the enzyme was found to be sensitive to the antibiotic, whereas in the 5123, even at zero time after the animalhad been on a low protein diet for a week, induction of serinedehydratase was completely resistant to the antibiotic. This

differential sensitivity of enzyme induction to actinomycin Dhas also been reported by Hilf et al. (13) in studies on highlydifferentiated mammary adenocarcinomas. The altered effectsof actinomycin on enzyme induction in neoplasms has its parallel in the process of differentiation. Rutter et al. (41) hasdemonstrated that in developing pancreas, the appearance ofthe enzyme amylase is initially sensitive to the antibiotic duringdevelopment, whereas after the establishment of the acinar cell,the antibiotic has no further effect on the increase in the levelof this enzyme. A somewhat similar effect has been noted byYaffe and Feldman (54) in the case of developing skeletalmuscle as well as in the eye (16, 55). Thus it would appear thatduring differentiation, messenger RNA templates become stabilized as an expression of the differentiation of the cell. Thuseach differentiated cell type is characterized by its own set ofcontrol mechanisms which are a reflection of its own particularset of stable messenger RNA templates. In abnormal differentiation, that of neoplasia, the stability of certain messengerRNA templates is altered, thus giving rise to a new differentiated state which is the expression of altered mechanismsfor the control of enzyme synthesis.

BIOCHEMICAL THEORIES OF NEOPLASIA

In considering the various mechanistic concepts of neoplasia, which have been discussed thus far, it is apparent thateach has a major theoretical "core". In the case of the deletion

hypothesis and the catabolic deletion hypothesis, the proteinsdeleted were considered to be those associated with the controlof growth. Thus the basic core of these concepts revolvesaround the phenomenon of tumor cell proliferation and itscontrol or lack of control. An extension of this theory in thelight of modern-day molecular biology was the conclusion thatthe deleted protein resulted from an alteration in the genomeof the cell. With the advent of the study of a number of highlydifferentiated "minimal deviation neoplasms," certain facets of

the deletion hypothesis had to be restated. Perhaps the mostcareful of these is seen in the discussion by Potter (39), whichexplained the minimal deviation concept in biochemical terms.The essence of this concept, which in the last analysis does notattempt to locate the site of the lesion whether genomic orextragenomic, is the existence of a real or hypothetically least-deviated neoplasm. A corollary to this is that all neoplasmspresently studied are extensions along the line of tumor progression and, thus, possess certain defects not critical to the malignant transformation itself.




Neoplasia Aspects

900

MORRIS HEPATOMA 5123REÃœBERHEPATOMA H-35

8 2468TIME IN HOURS

8

Chart 2. The effect of actinomycin D (Act D) administration on the induction of serine dehydratase in liver, Reuber HepatomaH-35 and Morris Hepatoma 5123. In all cases at 0 time a single dose of casein hydrolysate (C. H.) is administered by intubation toa group of rats. At intervals thereafter, designated by the completely black circles, a dose of actinomycin (1 mg/kg) is given to aportion of this group. In most cases a second dose of casein hydrolysate is also given at this time. Four hours later the level of theenzyme is seen in the animals receiving actinomycin, designated as the open circles (and dashed lines), and those receiving a seconddose of casein hydrolysate but no actinomycin, designated as a circle with a dot in the center (solid lines'). It is to be noticed that

in the case of liver the induction is stopped at 0 and 1 hours by the administration of actinomycin but not affected thereafter untilbetween the 6- and 9-hour points. This is not actually shown on the graph, but by 9 hours the system is again completely sensitiveto the antibiotic. In contrast, at all times studied, the induction of this enzyme in the H-35 is completely sensitive to the antibiotic,

whereas the induction in the 5123 is completely resistant.

The highly theoretical concepts of Pitot and Heidelberger(32) attempted to explain how the deletion of a cytoplasmicprotein (the experimental basis for the deletion hypothesis)could result in a heritable change in a cellular populationwithout any direct interaction of the carcinogen with thegenome. On the basis of metabolic regulatory circuits (24), thesuggestion was made that a short contact with a chemical couldalter a pathway in such a way that such an alteration becamepermanent. At that time it was also suggested that the pathwayaffected was somehow involved in the regulation of growth orcell proliferation. In an actual extension of this concept to amore mechanistic hypothesis, Pitot (29) advanced the theoryof altered template stability as an explanation for the defectivemechanisms regulating the control of genetic expression inneoplastic tissues. The essence of this concept is that an alteration in the structure of intracellular membranes brought aboutby a carcinogen may result in a generalized and random changein a number of functional messenger RNA templates withinthe cell. A selective growth advantage results in those cellpopulations whose templates that are involved with enzymesimportant to DNA synthesis are more stable than these in

normal cells. This concept also predicts the existence of "neoplastic" cell populations which do not have an increased replicative rate such as might be seen in certain "occult" carci

nomas in man. As originally suggested, the changes in membranestructure could result from a genomic or extragenomic lesion.However, recent studies by Munkres and Woodward (26) suggest the possibility that a single mutation in the structuralprotein of intracellular membranes might possibly result in thepleiotropic effects which are seen in the highly differentiatedhepatocellular carcinomas. In support of such biochemical alterations in membranes of hepatomas is the work of Emmelotand his associates (9, 10), who have found that the adhesivenessof and the association of enzymes with the plasma membranesof liver and hepatoma are quite different.

The analogy between the concept of altered template stability in neoplasia and the phenomenon of template stabilizationas a prerequisite to specific cellular differentiation is quitestriking. In this light a specific neoplasm (cf. Chart 1, Tumor)may be considered as a newly differentiated cell type. Bysimilar reasoning, neoplastic differentiation just as normal differentiation may occur without the necessity of a specific genetic

SEPTEMBER 1968 1885



Henry C. Pitot

alteration. The mechanism of carcinogenesis and of normal cellular differentiation may well be similar if not basically identical. An important corollary from an experimental standpointof the concept of altered template stability or neoplastia differentiation is that in neoplasia the study of mechanisms involved in the alteration of the control of genetic expression insystems not directly involved with cellular proliferation maytake us a long way in our understanding of the neoplasticprocess itself.

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SEPTEMBER 1968 1887



1968;28:1880-1887. Cancer Res Henry C. Pitot Some Aspects of the Developmental Biology of Neoplasia

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