tumors in the invertebrates: a reviewtumors in the invertebrates: a review...

Tumors in the Invertebrates: A ReviewBERTASCHARRER*ANDMARGARETSZABÃ“LOCHHEAD

(From the Department of Anatomy, University of Colorado School of Medicine, the Department of ZniHogy, ?'nirer.tity of

Vermont, and the Marine Biological Laboratory, Woods Hole, Massachusetts)

INTRODUCTIONTumors are the result of abnormal cell prolifera

tion. Therefore, the study of tissue growth, normaland abnormal, constitutes the central problem oftumor research which thus becomes essentially abiological problem. When approached from thisbroader point of view, an analysis of tumorousgrowth should include representatives from allgroups of living organisms. It has been recognizedthat the study of plant tumors yields significantresults. Within the animal kingdom comparativepathology has concerned itself largely with neoplasms in various groups of vertebrates (74, 10!),112, 124), while invertebrates have been all butneglected. As a matter of fact, until fairly recentlyinvertebrate tissues were often considered incapable of developing tumorous growths.

Teutschlaender (144) believed that tumors cannot occur in animals at a phylogenetic level lowerthan the fishes. Engel (25) elaborated extensivelyon the reasons why invertebrates are unable todevelop cancer. Emphasizing anatomical differences between invertebrates and vertebrates hediscussed chiefly three points. The first two concern differences in the nervous and vascular systems; the third deals with the embryonal theory oftumor growth. Believing that invertebrate cells, onaccount of their considerable regenerative power,are embryonic in character, Engel concluded thatthey cannot revert to the embryonic stage andproduce tumors. In the light of modern biologicalconcepts these views are obsolete, not only withregard to anatomical considerations, but also he-cause they are based on inadequate material.

Actually, during the past .50 years a considerable literature on spontaneous and experimentallyinduced tumors in invertebrates has grown. Inaddition, numerous observations exist concerningvarious tissue reactions that may be more or lessclosely related to tumorous growth. These data arescattered and often not easily accessible. The only

* Special Research Fellow, I'.S. Public Health Service. Re

search grantÂ»from the American Cancer Society and The AnnaKuller Ktiiul are gratefully acknowledged.

Received for publication, April 14, 1950.

papers in which invertebrate tumors are reviewedto some extent are two in French (13, 148) andone in Russian (30).

A. critical survey of the present status of theproblem of invertebrate tumors encounters seriousdifficulties. For one thing, the Â«latain the literatureare often controversial, and many of the descriptions are inadequate or hard to evaluate. Patholo-gists specializing in tumor research are not, as arule, familiar with invertebrate material. On theother hand, zoologists, versed in the intricacies ofinvertebrate anatomy and taxonomy, are usuallyinexperienced in the diagnosis of tumor growth.Furthermore, the terminology developed almostexclusively for use in mammalian pathologyshould not be applied to invertebrate animals,until the analogies between vertebrate and invertebrate tissues are more thoroughly understood.

In spite of such difficulties two facts stand outas the result of this survey: invertebrate tissues arecapable of tumorous change, and they offer an opportunity to approach the study of tumors in new-

ways.TUMORS IN VARIOUS GROUPS

OF INVERTEBRATESThe first question one may ask is : In which types

of invertebrates have tumors or cellular reactionscomparable to tumorous growth been observed?The information available refers to almost all themajor invertebrate phyla. Tumors are said to occur in annelids, sipunculids, arthropods, molluscs,and ascidians. Even among the most primitivemetazoansâ€”dicyemids (91)â€”and among the protozoans (82) nuclear anomalies have been observedwhich are comparable to atypical mitoses as foundin certain mammalian neoplasms. The best knowngroup and the most interesting from the point ofview of comparative oncology are the insects.

VARIOUS TISSUE REACTIONS ANDTUMORLIKE GROWTHS

Great caution is indicated in an evaluation ofthe types of tumors occurring in invertebrate animals. For one thing, the difficulty of arriving at a

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404 Cancer Research

satisfactory classification, which exists even inmammalian pathology, is multiplied in invertebrates. Furthermore, in a number of instances avariety of formations in invertebrates which cannot be considered as true tumors have been designated as such. Among these are cysts, often theresult of what is called an "inflammatory process."It would be preferable to call such processes "injury reaction" or "repair hyperplasia," since ac

cording to Menkin (78) the term inflammation,which implies vascular response, should be restricted to vertebrates. A frequently observed situation is the following (e.g., 8, 11, 24, 81, 54, 56, 59,60, 61, 64, 68, 69, 80, 83, 98): almost any disturbing factor (foreign body, parasite, tissue implantwith or without bacterial contamination, degenerating organ, hereditary tissue anomaly, sterileagar or celloidin, or irritant, such as croton oil) willcause an accumulation of lymphocytes in the affected area. In many invertebrates certain bloodcells may change from free-moving to sessile elements and vice versa under various conditions (27,28, 73, 163). When they accumulate, often in impressive numbers in the vicinity of irritants,phagocytosis and encapsulation of the center ofdisturbance take place. In the cysts thus formedthe cells making up the capsule may undergochanges, sometimes of a degenerative nature. Suchtissue responses resulting in well defined "growths"

may easily be mistaken for tumorous processes. Inmost cases they merely indicate an injury reaction, but it is not unlikely that under certain conditions such cysts may eventually give rise totumor-like growths or real tumors.

Various abnormal growths, with or without ulcÃ©ration, have been observed on the body wall ofmolluscs collected in nature or reared in the laboratory. The causes of these growths are unknown.In each case the histolÃ³gica! picture showed thepresence of an injury reaction with repair hyperplasia, characterized by densely packed nuclei ofconnective tissue cells, fibroblasta, and numerousmigrating cells. Tissue reactions experimentallyproduced by burning and by strong acid were essentially the same as these natural growths (139,141, 142).

Another type of cellular response in invertebrates which in itself should not be considered astumorous growth manifests itself in the hypertrophy of cells due to the action of parasites. For example, in the intestinal epithelium of certainmarine worms gregarines may cause up to a tenfold increase in cellular size accompanied bychanges in the appearance of nuclei and cytoplasm(9, 10, 102, 136, 145).

Somewhat more significant in connection with

tumorous changes is the effect of certain parasiteson the so-called fat body of insects, a type of connective tissue which stores reserve materials and,in certain species at least, shows no sign of cellular proliferation after metamorphosis. Under theinfluence of the parasites these adipose cells havebeen observed to hypertrophy and to resume mi-totic activity in the adult stage. Many of thesemitotic figures are abnormal (67, 79, 106). Theresult is a hyptrplasia of the fat body of these insects (16, 17, 18, 23, 99).

Another instance where caution in the u.se ofterms is indicated is that of the insect "myce-tomes" (structures caused by intracellular sym-

biotes). The practice of Mahdihassan (75, 76) ofconsidering these biologically useful structures ofbacterial origin as tumors is not in keeping withcommonly accepted views (135, chapters 4 and (i:137, chapter 5). Likewise, parasitic structures suchas those described by Mclntosh (77) in the caudalregion of Sagitta (Chaetognatha) are not tumorsin the strict sense of the word.

Many of these pathological formations are evidently not true tumors but may show certain resemblances to neoplastic growth. Thus, it is obvious that in many instances the decision as towhether or not a reported structure is to be classified as a neoplasm meets with considerable dif-culty. A great deal of further observation is necessary before an opinion can be formulated. Just ascertain tumors in vertebrates are considered to beon the borderline between hyperplasia and benigntumors, some of the formations reported here inthe invertebrates might prove to be borderlinecases.

Nevertheless, so far as can be judged from theavailable evidence, cases of true tumors, both benign and malignant, appear to occur among invertebrates. These cases are discussed in the following section, in which the term "tumor" will be

freely used wherever the balance of evidence seemsto suggest a true neoplastic growth. Also discussedin this section will be certain experimental work ofrelevant interest, including cases in which no neoplastic growth was obtained.

CAUSES OF INVERTEBRATE TUMORS ANDTUMOR-LIKE STRUCTURES

Spontaneous occurrence.â€”A number of cases reported in the literature concern incidental observations of so-called spontaneous tumors. It is perhaps more accurate to classify them as tumorswhose cause is unknown. Among the earliest observations is one on a lobster (Homarus) by Mclntosh who "many years ago, described a tumourwhich originated in the wall of the grinding storn-



SCHARRERAND LOCHHEADâ€”Tumors in Invertebrate* 405

ach and pushed its way through the carapace behind the eyes. The tumour enlarged and finally resulted in the death of the lobster, which was a verylarge and old specimen."1

KolosvÃ¡ry (65) found a tumor on the prosomaof an arachnid, Phalangium opilio L. The chitinousbody wall produced an overlapping fold over thetumor; the latter was so large that it pushed theinternal organs to one side. The author suggestedthat this tumor might have started during embryonic development. No histolÃ³gica!study of thetumor was made.

Additional chance observations among arthropods concern insects. The earliest reference to insect "tumors" seems to be in a treatise on insect

diseases by Kirby and Spence in 1826 (quotedfrom 137). Figure 1, taken from a monograph byIlalazuc (4), shows a large tumor in the prothoraxof a beetle (Phytodecta variabilis) of which no his-tological analysis is available. White (152) founda fibroma-like structure in the thorax of one honeybee among a large number of dissected specimens.The tumor appeared as a mulberry-like mass whichdisplaced adjacent structures and seemed connected with the mesothoracic ganglion. However,the microscopic picture indicated that the tumorwas derived from connective tissue rather thanfrom ganglionic elements.

Likewise unknown was the cause of tumor-likestructures which Ã–rÃ¶si-Pal(92) described in thehindgut of old winter bees. They consisted of cystsformed by fusion of vacuolated giant cells whosenuclei did not seem diffÃ©rentfrom those of normalhindgut epithelium.

A rather unique finding of a brain tumor in anant (Formica pratensi*) was described by Brun (6).The specimen, a worker, showed motor disturbances (continuous circular movements to the right )which suggested a cerebral lesion. On microscopicexamination a compact tumor was found on theupper left side of the protocerebrum, taking theplace of the corpora peduncolata. It consisted ofvery small, densely arranged cells, presumablyproliferated glia elements. A differential diagnosisbetween tumor and brain abscess was, however,not possible on the basis of the available material.

A "unicellular tumor" was described by Palm

(IMS)in one corpus allatum of a male nymph of(Â¡ryllotalpa (Orthoptera). Among the small cellelements of this endocrine organ giant cells oc-

' The quotation is from Prince (108). In spite of considerableeffort, in which the assistance of Dr. S. VV.Smith (I'niversity

of Colorado School of Medicine) and of Dr. J. M. Dodd ((Ã¬attyMarine Laboratory, St. Andrews I'niversity, Scotland) was ob

tained and greatly appreciated, the original source of this information could not lie located. Dr. Dodd kindly supplied us withreference (77).

cur which are derived from several smallercells by cytoplasmic, and subsequently nuclear,fusion (20). In the case reported such a round,giant cell, which was clearly separated from thesurrounding tissue, showed distinct signs of kary-orrhexis. The nuclear membrane had disappeared,and numerous chromatin granules and nucleolarremnants were freely distributed in the cytoplasm.The cytoplasm appeared dense and homogeneous,exhibit ing signs of hyaline degeneration. No visibleinfluence of this condition on the health of the hostcould be detected. Although this pathologicalstructure, whose diameter was 65 p, took up aboutone-third of the total longitudinal diameter of thecorpus allatum, it seems debatable whether or notit should be classified as a tumor.

Another case reported by Palm (!)7) concernsthe pharyngeal glands of the bumble-bee, Bombos.One of the male specimens examined showed "tumor formation" in the gland of one side. Normally

consisting of unicellular units equipped with separate canals leading to a common duct, the diseasedgland appeared as a displaced, rather large, compact structure containing an abundance of connective tissue. There was no connection to the common duct; numerous aberrant small secretioncanals ended blindly. The abnormally large glandular elements showed signs of hypersÃ©crÃ©tionanddegeneration. Karyorrhexis occurred among thenuclei.

Among molluscs, several tumors have been reported. Williams (155) and Collinge (14) found,among about one thousand examined specimens ofthe freshwater mussel (Anodonta cygnaea, var.zellensis), three with tumors. These growths wereapparently derived from the tissues of the mantleand, in their microscopic structure, resembledadenomyomas. There was evidence that these tumors had seriously interfered with the physiologyof the afflicted animals.

In the oyster (O.ttrea rirginica) G. M. Smith(127) observed, as had Ryder (118) before him, abenign tumor of mesenchymal character whichhad its origin in the pericardium. The pediculatedstructure, whose largest diameter was 14 inches,showed a nodular, polypoid appearance (Fig. 2).A single layer of ciliated columnar cells surroundedthe mass. The tumor cells were large and oval-shaped with relatively small nuclei. Finely dispersed lipoid granules and probably also glycogenwere present in the cytoplasm. Figures 3 and 4show the vacuolated appearance of this tumor.

A benign tumor of epithelial origin was described in the slug, Limaxftavus L., by SzabÃ³andSzabÃ³ (140). In an almost 4-year-old laboratoryspecimen this whitish, lobated tumor, connected



Fio. 1.â€”Largetumor in prothorax of a beetle(Phytodecta). X12.5. From Balazuc (4).

Fio. 2.â€”Oyster (Ostrea) with benign tumor.(a) Location of tumor (A) in pericardia! region.(6) Tumor (A) lifted up, showing pedicle (P) andadductor muscle (M). (c) Cross section throughturnor (A), showing underlying pericardium (X)and heart (H). From G. M. Smith (127).

Fio. 3.â€”Sectionthrough oyster tumor showingmesenchymal cells and blood vessels (A). FromG. M. Smith (127).

FIG. 4.â€”Sametumor as in Figure 3 at highermagnification. Note large, vacuolated tumor cellswith small nuclei. X75. From G. M. Smith (127).

FIG. 5.â€”Slug (Limax) showing location of alarge spontaneous tumor (T). About life size. Redrawn from SzabÃ³and SzabÃ³(140).

FIG. 6.â€”Crosssection of two lobes which fell offfrom the tumor shown in Figure 5. Note atypicalarrangement of epithelial cells with connectivetissue filling each lobe of the tumor. Redrawn fromSzabÃ³and SzabÃ³(140).

FIG. 7.â€”Highpower photomicrograph of sametumor as shown in Figure 6. Cuboidal epithelialcells forming alveolar tumor tissue; spaces containing some mucus and necrotic cell particles. FromSzabÃ³and SzabÃ³(140).



SCHARRERAND LOCHHEADâ€”Tumors in Inrertebratex 407

with the border of the iimntle by a pedicle (Fig. 5),periodically fell off and grew again. Its maximumsize was 1Ã“X8X3 mm. Histologically, the epithelial tissue constituting the tumor (Figs. 6, 7) differed from the tissue in normal specimens in thatits arrangement was similar to that in alveolar ortubular glands. The center of the tumor mass wasfilled with dense, richly nucleated connective tissue, whose presence was considered secondary bythe authors. The interpretation of this structure asa true tumor is supported by the abnormal his-tological appearance which set it off from surrounding normal tissues, the tendency for unlimited growth, and the absence of signs of an injuryreaction.

Ladreyt (71, 72) found what he considered amalignant growth in a Sipunculus. This abnormalstructure had developed in one of the two vasculartubes ("hearts," canals of Poli) which extend along

the esophagus of this annelid. Under normal conditions the epithelial lining of these tubes gives riseto various types of blood elements. In the diseasedspecimen the endo- and perithelium showed extensive cellular proliferation by means of (frequentlymultipolar) amitoses and nuclear fragmentation.The tumor cells had undergone changes in appearance; they had become fusiform orepithelioid withlarge, often irregular nuclei. They formed layersaround the lumen of the tube which became obstructed in places. Some tumor cells degeneratedat the original site, others were disseminated in theblood stream. Musculature, nervous system, andncphridia showed signs of degeneration. The evidence for a diagnosis of malignancy in this casewas not considered sufficient by other authors (13,148). The lack of illustrations in Ladreyt's report

further adds to the difficulty of arriving at a conclusive interpretation.

Hereditary factors.â€”Inview of the fact that certain chromosomal deficiencies are known to causecytological abnormalities which lead to severemorphogenetic disturbances in Drosophila (107),it is not surprising that hereditary "tumors" have

been described in this insect. Stark (130), using astrain discovered by Bridges, was the first to callattention to the significance of such tumors inDrosophila. Since then, a number of investigatorshave worked on Drosophila tumors occurring invarious strains. Many important questions concerning the morphology and physiology of thesepathological formations are still unanswered, andthe fact that not all the investigators were dealingwith identical material increases the difficulty ofevaluating the descriptions.

According to Stark (130-134) multiple geneticfactors in Drosophila larvae of the strain "lethal 7"

bring about lethal tumors (Figs. 8and!)) which occuronly in males, and which are comparable to certainvertebrate tumors (melanoepithelioma, lymphosar-coma). These sex-linked tumors arise for the mostpart in groups of embryonic cells (imaginai discs)which normally give rise to adult organs, but whichin this strain become prematurely active (cf. embryonal theory of the origin of tumors). They mayalso originate in the epithelium of the integumentor gut and in "sites of blood formation." As many

as fifteen tumors may be observed in one larva;some may grow to one-fourth the size of the host.Excessive amounts of melanin are deposited in thetumors (for chemical tests see 53). They are said toproliferate rapidly, to infiltrate surrounding tissues, to metastasize, and to show mitotic abnormalities. Extirpation of the tumors from larvaeprolongs their life but does not permit pupationto occur. Tumor implants in normal larvae causedeath of the host before pupation. Larval tumorcell suspensions when injected into adult Drosophila give rise to lethal growths in some specimens. There is evidence that the tumors are notdue to the presence of a microorganism.

In addition to this "malignant" type of tumor.

Stark described in a mutation of the same strain ofDrosophila a nonlethal hereditary tumor, implantsof which in normal hosts do not prevent metamorphosis and are carried over into the adult fly. Thisbenign tumor is not sex-linked. It develops at alater larval stage from embryonic cells whose pro-liferative potency is consequently decreased. Thesetumors are more limited in growth and becomenecrotic after being encapsulated by connectivetissue elements.

Some authors, such as N'eedham (88), seem satisfied that Stark's "lethal strain" tumors were indeed malignant. However, many of Stark's inter

pretations do not appear to be supported by conclusive evidence and have, therefore, met withcriticism. The criteria for malignancy seem insufficient (13, 84, 115, 116, 148). Furthermore, Russell (116) claimed that the death of the larvae wascaused by an abnormal and extensive disintegration of the midgut cells, permitting the escape offood and thus causing starvation. This abnormality appears a few hours before the first tumors appear. Russell further pointed out that the tumorsdo not really seem to arise from or be a part of anyorgan. Whether they are free in the hemocoel orconnected with some organ, they look alike and insize most closely resemble groups of amebocytes orof imaginai disc cells. Russell also could find no difference between the malignant and the benigntypes of tumors. The prolifÃ©rÃ¢tivegrowth of tumors and of tumor transplants has not been dem-



MESENCHYMAL

TUMOR .. ..â€ž.

TISSUE

CROSS

SECTION OF

EXOSKELETON

OF FOOT

12FIG. 8.â€”Portions of Drosophila larvae with

lethal tumors. Dorsal (1 and 6), ventral (2, 3, and4) and lateral (5) views. From Stark (130).

FIG. 9.â€”High power photomicrograph of alongitudinal section of a portion of a Drosophilalarva showing tumor (T) attached to the wall ofthe stomach (S). The tumor consists of uniformpolygonal cells and contains pigment. From Stark(132).

Flu. 10.â€”Tumor in the abdominal foot of a

lepidopterous larva (Pygaera). From Fedorley(29).

Fio. 11.â€”Insecthost (ephemerid nymph) withectoparasitic insect larva (chironornid) causing irritation and subsequent tumor formation; bt. =Region of mesothoracic blood sinus pierced bysucking parasite. From Codreanu (13).

FIG. 12.â€”Syncytialtumor of ephemerid nymphderived from macronucleocytes, developing during"local phase" of proliferative process. Xote nu

merous mitotic figures (nit). From Codreanu (13).



SCHARRERAND LOCHHEADâ€”Tumors in Inrertehnite.f 40!)

oust rated beyond doubt either by Stark or byRussell.

I. T. Wilson (156) studied two Drosophila tumors, similarly melanotic and dependent on multiple hereditary factors as were those of Stark. Inone of the two strains as many as a hundred smalltumors were scattered throughout the body, displacing normal tissues. Pigmentation increasedwith the age of the tumor. In the few survivors thetumor cells disappeared during pupation. The tumors of the second strain were small in number andfar less destructive. Histologically, these structures consisted of a center of polygonal cells surrounded by spindle-shaped cells and fibrous non-cellular elements which may have originated fromblood cells.

In regard to these growths described by Wilsonand also those originally described by Stark, thepossibility exists that they arc encapsulations byblood cells of small tissue fragments, cell agglutinations, or foreign bodies. Such an interpretation issupported by a close study of the published figures(peripheral melanization of the nodules; see 27).The growths described by W7ilson were possibly

the result of parasitic intrusion from infectedfood, since tumor incidence was highest in bottlescontaining relatively few larvae, in which was seenthe greatest contamination of the medium by bacteria and fungi.

Morgan, Schultz, and Curry (85, 86) interpreted as "melanotic necrosis" tumor-like abnor

malities in the fat body of hybrids of Drosophilamelanogaster with Drosophila simulons, which theyattributed to imbalance of heterochromatin between the two species.

The melanotic lesions observed by Gowen (44)in adult Drosophila are different from but showcertain parallelisms with the structures reportedby Stark.

Tumors of the type originally described byStark have been studied in regard to relationshipsbetween environmental conditions and tumor incidence. Ardashnikov (1) and Russell (117) foundthe appearance of tumors in Drosophila culturesinversely proportional to the degree of crowding.Temperature is a factor which may modify tumorincidence. According to HÃ¤rtung (50-52) its effect

may be direct (acting on the ontogenetic process)or indirect (affecting other environmental conditions). In general, high temperatures tend to decrease tumor incidence, while lower ones increaseit in the three Drosophila strains tested. However,this general statement does not seem to hold for alltumor strains investigated so far. HÃ¤rtung himself(51) reported an increase in incidence with risingtemperature in one of his strains. Similarly, Gard

ner and Woolf (41) found a rise in incidence fromabout 76 per cent at 22Â°('. to about 93 per cent at30Â°C. in the growth abnormality "tnmorous-head." The first 24 hours of development were de

termined as a temperature-effective period modifying only one of the two chromosomal factorsinvolved.

Prolongation of the larval period by 2,4-dinitro-phenol, or inhibition of larval growth by certainamino acids in high concentration, delay tumor appearance (157; see also 149). 0.1 M arginine addedto the basal diet containing sterile brewer's yeast

significantly increases the tumor incidence; orni-thine does not show this effect (158).

In experiments by Zivin (164) the feeding ofthymonucleic acid failed to inhibit the development of Drosophila tumors; the substance had nomutagenic effect in Drosophila melanogaster.

The genetic background for the manifestation ofthese tumors was further discussed by Jones (58)and Russell (117). The tumor incidence may be100 per cent or less depending on the genetic constitution.

Extensive work is being conducted in the genetics laboratory of the University of Utah (seeGardner, Newby, Dearden, Ratty, and Woolf)2 ona growth abnormality ("tumorous-head") in Dro

sophila melanogaster. These growths appear on anypart of the head derived from the head primordiaand are usually external, less frequently internal,and associated with the hypodermis. They are irregular in shape and size, and they seem to be different from the tumors described by Stark. Thistrait is inherited through the action of a recessive(or slightly dominant) sex-linked gene which produces a maternal effect in the egg and of a semi-dominant third chromosome gene.

The effect of x-ray treatment on the growth ofDrosophila tumors has been studied by several authors with varying results. While Stark (130) noticed no effect, Enzmann and Haskins (26) observed a decrease in the percentage of developingtumors when larvae 18 24 hours of age were exposed to x-rays. Finally, HÃ¤rtung (49) pointed outthat the result depends on the dosage. In a certainstrain the hereditary incidence of 15 per cent couldbe stepped up to 48.3 percent with 1,500 r. On t In-other hand, the incidence fell below the controlvalue when 5,000 r were administered. In this connection it is of interest that Pogossiants (105) produced pigmented "tumors" in Drosophila by

means of x-rays (4,000 r) which, with respect tomorphology and location, resembled the known

1We are grateful to Drs. E. J. Gardner and W. W. Newby,University of Ctah, for permitting us to report these data whilesome of the papers were in press.



410 Cancer Research

hereditary types. His results, which he interpretedas "melanotic necrosis (86) give no evidence of

malignancy. The structures were not transmittedto later generations (see also 63; for further information on Drosophila tumors see 7, 42).

The hereditary tumors just described are notrestricted to Drosophila. In a lepidopterous larva(Pygaera pigra, Notodontidae; Fig. 10) similarsex-linked tumors, affecting only the males in thecolony while the females are carriers, were observed by Federley (29). To account for this typeof inheritance, Federley advanced the interestinghypothesis that the tumors develop from the threepolar bodies, which in the male would contain sexchromosomes X, Y, and Y, respectively; in thiscombination the expression of a recessive gene repeated on each of the Y chromosomes would not besuppressed by the single homologous gene on the Xchromosome. Continued division of polar body nuclei is a phenomenon well known in insects.

The tumors which Federley described were ofseveral types. Large numbers of one type floatedfreely in the hemocoel. Other types were located invarious organs, such as hindgut, testes, ganglia,hypodermis, glands, tracheae, and musculature.Vacuolated and giant cells with multipolar divisions, flattened elements, and necrotic structuresoccurred in some of these tumors. As in the case ofthe Drosophila tumors, it is uncertain whetherthese growths in Lepidoptera are true tumors.Since giant cells and multipolar divisions areknown to occur normally in the intestinal cells ofcertain insect larvae (45, 153), and in wound healing (154), more cytological and histological criteria would be necessary for a definite diagnosis ofneoplasia in these insects.

In summary, there exist in insects pathologicalformations which have certain characteristics ofhereditary tumors. But despite the relatively largeamount of study these growths have received,there is considerable doubt as to their correct interpretation. Various factors contribute to the difficulty. Pigment deposition in the growths proceeds so rapidly that only in the earliest stages canthe cells be examined in detail; even there difficulties are encountered in securing adequate fixation(HÃ¤rtung, personal communication). Therefore,no satisfactory figures or descriptions of the histology of these tumors have been published. Nodirect evidence has been presented of cell proliferation in the "tumorous" tissue. Comparison with

normal or injured tissues is hampered by inadequate knowledge concerning the normal histo-physiology of the insect organism. Even in a genuswhich has received as wide attention as Drosophila, the normal functional relationships of adi

pose tissue, "lymphocytic tissue," imaginai discs,

and free blood cells have been only insufficientlystudied (114). In the metamorphosing insect thesetissues undergo radical changes which are adequately understood in relatively few species. Inview of all these facts it would seem evident thatfurther work must be done before the real nature ofthese hereditary "tumors" can be clearly estab

lished.Parasitic origin.â€”Viruses, fungi, microsporidi-

ans, and insects parasitizing certain invertebrateshave been made responsible for "tumorousgrowths" observed in their hosts.

In a recent study Bird (5) observed insect tumors associated with a virus infection. The abnormal growths occur in the midgut of the European spruce sawfly, Gilpinia hercyniae (Htg.), afterinfection of the epithelium by the virus. As a resultof the infection, polyhedral bodies are formed inthe nuclei of the digestive cells of the midgut. Inthe vicinity of the regenerative nidi abnormal cellproliferations occur which project into the bodycavity or, less frequently, infiltrate the cytoplasmof the digestive cells. If larvae become infected justbefore the last larval molt, i.e., at a time when cellular activity in connection with metamorphosis isat a peak, large tumors develop. Such tumors contain a necrotic, pigmented center, a layer of greatly enlarged infected cells, and an outer region ofproliferating cells. During metamorphosis some ofthese tumors disappear from the gut, either bybeing pushed into the body cavity or possibly bycoming under the influence of digestive juices. Thetumor cells do not invade other organs of the infected insects. All available evidence seems to indicate a nonmalignant character of these tumors.

As pointed out earlier, not all abnormal accumulations of cells are tumors. Thus, the prolifer-ative tissue reactions in the fat body of certain insects (Lepidoptera) caused by virus infections (94,95) probably were the result of an injury reaction(13). Similarly, the "tumeur mycÃ©lienne"found

by de Boissezon (19) in the abdomen of an adultfemale of Culex may have been merely a 2-mm.cyst formed of dense fibrous tissue to isolate thefungus present; however, the author stated thatthe intestinal epithelium in its proximity had undergone morphological changes as a consequenceof the presence of the fungus.

Cellular reactions of interest in connection withcertain features of tumorous growth have been reported in an ascidian, Ciona, parasitized by thegregarine Monocystis (125, 126). As a rule, almostthe entire development of the parasite is intracel-lular, causing the intestinal cells of the host to react conspicuously. They become enlarged up to 20



SCHARRERAND LOCHHEADâ€”¿�TumorÂ»in Invertebrate* 411

times their original size and show a vacuolatedcytoplasm. The nuclei hypertrophy and laterbreak down and disintegrate with the rest of thecell. There is evidence that this influence of a foreign organism on the individual host cell is chemical in nature. Up to this point, the observationswould seem to indicate cellular hypertrophy dueto parasitism, as discussed before. In some cases,however, Siedlecki also noted a reaction in neighboring cells; the epithelium proliferated, and evenconnective tissue elements became involved in theresulting abnormal growth. These tumor-like structures, in which the original cause, i.e. the parasite,is often no longer found, were compared by the author with mammalian liver adenomas.

Papilloma-like structures, of mesoderma] origin,have been described in the annelid worm Pota miliatorelli by Mesnil and Oaullery (81) as caused byanother sporozoan parasite. They grow rather intensely, ramify, and protrude into the coelom,which is filled with parasites. In these growths thenuclei continue to divide amitotically, even afterthe parasites have disappeared. It is difficult todecide whether or not these structures should beclassified as tumors, or whether they are simplyhyperplastic formations.

Several authors have studied the effect of insectparasites on insect hosts (98, 99), but the most informative results are those of Codreanu (12, 13).An ectoparasitic larva, the chironomid Symbio-cladius, feeds on the blood of certain insect hosts,i.e. ephemerid nymphs of the genera Heptagenia,Kithrogena, etc. (Fig. 11). When so doing theparasite causes the following progressive reactionsin the host. Aside from an injury reaction due to irritation, a proliferative process takes place whichconsists of two phases. During the "local phase" a

syncytial tumor derived from macronucleocytesbut gradually changing in its histological appearance (increasing cytoplasm, vacuolization, changeof nuclear and nucleolar size, abnormal mitoses)appears near the site of the parasite (Fig. 12). Inthe "generalized phase" which follows, free macro

nucleocytes accumulate in the circulation (leukemia), infiltrate organs of the host, and form smallnests, for instance in the vicinity of the ovariantubes. The formation of these tumors whichCodreanu compares with a leucosarcoma, andwhich in all probability are malignant, continueseven when the ectoparasite is removed at an earlystage. The host invariably dies before the completion of its development with tissues depleted andprematurely "aged."

Experimental work.â€”In the investigation ofvertebrate and invertebrate tumors alike the mostuseful material is that in which neoplastic growth

can be produced experimentally. Various attemptshave been made to induce tumors in invertebratesin which either the customary ways of approach,such as the administration of carcinogenic hydrocarbons, or essentially new methods have beenused. The effects of chemicals, of bacteria, of endocrine and of nervous factors have been studied.

Hammett and his associates conducted extensive investigations in an attempt to elucidategrowth mechanisms relative to neoplasia. Experiments with various invertebrates, as well as withplants, mice, and humans led these authors topostulate that cell proliferation with consequentgrowth is stimulated and regulated by certainchemical compounds containing the sulfhydrylgroup. In the course of regeneration experimentson t lie hermit crab, Pagurm longicarpus, accidental injuries often occurred at the site of a regenerating chela and between segments of the new chelawhere the chitin was thinnest (47). Aberrantgrowths developed from such lesions in controls aswell as in animals treated with Â¿Â»-thiocresol.However, in the experimental group all lesions resultedin growths, whereas only 7o per cent of the controlsproduced growths. Furthermore, the growths inthe group treated with the chemical were alwaysconsiderably larger. In a few instances, and onlyafter treatment with p-thiocresol, crabs developedan aberrant growth on the tip of the regeneratingchela in the absence of a lesion. Histologically suchaberrant growths consisted of normal tissues in ahighly unorganized arrangement showing no resemblance to any organ. In the opinion of the authors, these pathological overgrowths can be compared with malignant tumors. Figure 21, p. 348, ofthe paper by Hammett and Hammett (47) mayserve as an example. It shows a section through agrowth which had developed "spontaneously," i.e.without injury, after p-thiocresol treatment at asite which is normally an intensely proliferatingcenter. It is described as consisting of epithelialcells without chitin formation and is interpreted asa wildly disorganized proliferation analogous tocertain types of malignancy. The magnification atwhich the photograph is reproduced does not permit the distinction of cell types, and further details about the histology of this growth and theultimate fate of similar structures are not given.From a study of the material presented one getsthe impression of an injury reaction at a ratherearly stage. More information would seem necessary for an evaluation of the possible malignantpotencies of this and similar structures.

Bacterium tumefaciens, known to cause tumorsin plants and in fishes, was inoculated into themarine annelid Nereis by Thomas (145-148). The



412 Cancer Research

conditions under which tumorous growth tookplace in these experiments are of interest because,in addition to the bacterial action, an ecologie factor is involved. The author found that in a givenhabitat, characterized by a certain salt content ofthe water, the oÃ¶cytesof the worms degeneratedand gave rise to granulomas (88). Only specimensthus affected responded to the stimulus of bacterial

FOREGUT

SALIVAR* GLANDS

RECURRENT NERVE

SALIVARY RESERVOIR

- M1DGUT

13

FIG. 13.â€”Diagram of I/eucophaea, showing sites of tumorformation, i.e., anterior portion of alimentary canal (foregutand midgut) and salivary organs (salivary reservoir andglands), and their innervation by branches of the recurrentnerve, a, l>.c, three locations where nerve has been cut. X2.Orig.

infection with abnormal growth of the connectivetissue, appearance of giant nuclei, atypical mitoses, whorl formation, etc. The resulting tumorswere characterized by fast growth and invasive-ness. They were fatal to the worm and were "sar-comatous" in appearance. Thomas, therefore, con

sidered them as malignant or close to malignantgrowths, an interpretation which was subsequently questioned by Codreanu (13).

Earlier attempts to cause tumors in caterpillarsof Galleria mellnnella by inoculation of Bacteriumfinnefaciens emulsions were unsuccessful (66).

Another approach to induce tumor growth ininvertebrates, chosen by several investigators,

consisted of the introduction of foreign bodies, irritants, etc., into experimental animals (p. 404).Implants of this kind frequently caused injury reaction and cyst formation by fibroblasts. In the experiments of LabbÃ©(70) who used celloidin soakedin coal tar in the marine snail Doris, tumor-likestructures subsequently developed. Their cells,being fibroblastic in origin, became giant, plurinuclear, their growth pattern invasive. WhileLabbÃ©himself took these criteria as signs of a cancer-like behavior, Thomas (147, 148) could notproduce comparable effects in Nereis, Ascidia, andother forms and, therefore, expressed a certainskepticism with regard to LabbÃ©'sconclusions.

During the last decade, newer methods wereadopted in the application of carcinogenic compounds. The carcinogens used in invertebrateswere the common ones, methyleholanthrene,1,2,5,6-dibenzanthracene, benzpyrene, etc. Theywere administered by mouth, as implants of crystals, as aerosols in the surrounding atmosphere, ordissolved in aqueous media, etc.

A. response most closely approaching those observed in mammals due to the action of carcinogenic hydrocarbons was elicited in cephalopods(Sepia) with 1,2,5,6-dibenzanthracene (57). Within a few days after the subcutaneous administration of a pellet of this compound a whitish tumor,several cm. in diameter, could be observed. His-tologically, the epithelium and subcutaneous connective tissue appeared replaced by numerous diffusely infiltrating histiocyte-like cells whichshowed signs of degeneration (autolysis; homogeneous, pyknotic nuclei). There was no indicationthat the tumor was attacked by the defense mechanisms available to the host. This type of lesiondiffers essentially from the injury reaction observed earlier in the same species, as well as inOctopus and Eledone, as a consequence of traumaor irritants (59 61) or of subcutaneous coal tarinjections (62).

The tolerance for carcinogenic azo dyes in thecockroach, Blattella, is much higher than in therat or mouse. After administration of 0.2 per centof three of these dyes in the diet nodular formations were observed in these insects, whose tumorous nature could, however, not be established (90).3

Based on the hypothesis that cancerous growthmay be correlated with mutations occurring insomatic cells, the effect of carcinogens on the mutation rate of Drosophila was studied. While

3The effect of benzpyrene on insects is currently beingstudied by M. I'. Boulet, MusÃ©ezoologique, UniversitÃ©deStrasbourg, France, to whom we are indebted for this information.



SCHARRERAND LOCHHEAD-Tumorx in Inreriebmles 41!5

Auerbach (2) had negative results, Demerec (21,22), using a different technic, was able to producegene mutations (considerable increase in lethalimitations) with four carcinogenic hydrocarbons,as well as with a nitrogen mustard (3). The muta-genie effect of these compounds, especially of di-benzanthracene, on Drosopbila is very similar tothat of x-rays, ultraviolet light, and neutronsâ€”all

agents whose carcinogenic capacity is well known.Phenol has a positive effect on the mutation

rate of Drosophila (46), an observation which isof interest in view of clinical evidence that thiscompound may produce skin cancer (138, p. 16,5).

The early phase of growth, but not cell differentiation, was stimulated in the marine hydroidObelia by 1,2,5,6-diben/aiithracene and by metli-ylcholanthrenc in experiments by Hammettand Reimann (48) and Reimann and Hammett(113). Since cell proliferation is one of the primarymanifestations of cancer, these results have somebearing on the problem of neoplastic growth.

Regeneration in planaria!) worms was .stimulated by the presence of carcinogenic compoundswithout effect on the histolÃ³gica! appearance ofthe tissues (93).

Tchakhotine (143) exposed sea urchin eggs tosodium monobromo- or monoiodoacetate with theresult that atypical tissue proliferation took place.The mesenchyme became "wild," filling up the

blastulae and thus preventing gastrulation. Theoutcome was fatal in the early sea urchin stages.

In a study involving a number of chemical substances Rapaport (110) found that arsenic andboron compounds caused melanotic tumors inDrosophila larvae, similar to the hereditary typesalready discussed.

The effect of carcinogenic hydrocarbons on protozoans has been studied by several authors. Tit-tier (150), using pure cultures of a ciliate (Tetra-hymena) was unable to detect mutagenic effectswit h l ,2,5,6-diben/ant hracene, 3,4-benzpyrene,and iiK'thylcholanthrene in concentrations ranging from 1:50,000 to 1:200,000. This observationis in contrast to the positive results in Paranieciumreported in earlier papers (87, 129, 151, 160). Theeffects observed in these experiments (polymorphism, increased growth rate, enhanced vital functions) may have been indirect, i.e. they may havebeen brought about via the bacteria, present inthe cultures on which Paraniecium feeds. Thisinterpretation suggested by Tittler would seemplausible, because carcinogenic hydrocarbons areknown to increase the rate of reproduction of bacteria, such as Escherichia (43,55). However, beforea more definii e stai einen t can be made, experiments

with bacteria-free cultures should be extended toinclude other ciliates, especially paramecia.

In view of the known connection between endocrines and tumor growth in mammals it is significant that abnormal tissue reactions similar tocertain vertebrate tumors could be elicited in the

x-v,'---;*ifvâ€¢¿�sijA-. f â€¢¿� . Â«k'.-\ /-..*â€¢.*.'â€¢â€¢¿�'utâ€¢¿�â€¢"â€¢'-y-

\** v,**>\*i* ' Â¿:Ãir>

15

FIG. 14.â€”Midgut tumor of Leucoptiaea. The large tumor

mass, replacing the normally thin gut wall incorporÃ¢tes partsof the intestinal caeca (<â€¢),and the hindgut (/i), m, lumen of

inidgut with debris. About X24. Orig.FIG. 15.â€”Same tumor as in Figure 14 at higher magnifica

tion. The tumor cells differ greatly from the cells normally composing the midgut wall. X.'iliO. Orig.

insect Carausius (Dixippus, walking stick) byPflugfelder (100, 103, 104) by means of an experimentally induced disturbance of the hormone balance in early nymphal stages. This effect, as wellas degenerative processes, was brought about bythe removal of the corpora aliata. RÃ©implantÃ¢tionof these endocrine glands prevented the abnormaltissae reactions. Implants of supernumerary corpora aliata also caused abnormal growths. Theatypical growths were observed in certain locations, especially in mesoderma] structures. A.mitot-ic divisions were noted in the proliferating part of



414 Cancer Research

the gut at the place of origin of the Malpighianvessels. The wall of the oviduct and the corporacardiaca showed similar changes with occasionalgiant nuclei.

Atypical new growths could also be producedwhen embryonic tissue of the same insect specieswas transplanted into the head capsule of nymphsor adults whose own corpora aliata had either been

17

FIG. 16.â€”Tumor in wall of foregut of Leucophaea. To theleft and right of the tumor the wall is normal, consisting of amuscularis and a chitin-covered epithelium facing the lumen(above). Note stratification of the tumor. About X24. Orig.

FIG. 17.â€”Tumortissue of Figure 16 at transition of layersat higher magnification. The types of tissue shown do not normally occur in the foregut wall. X360. Orig.

extirpated or which had received supernumeraryiillatuin implants (101, 103). The abnormal growthof the embryonic tissue, taking place in part by mi-totic division, in part by nuclear fragmentation(atypical amitoses), involved all three germ layers.Certain neuroblasts, for example, developed noaxons, became giant elements, while their nucleidivided amitotically. Glia cells surrounded suchpathological elements and proliferated to formcystlike structures or large cell aggregates. Theprospective midgut (entoderm) showed profoundabnormalities with cell proliferation by means of

niitotic and amitotic nuclear division. The embryonic mesoderm displayed a tendency to invasivegrowth which affected particularly the muscles ofthe host. No pathological growths of this kindwere observed in embryonic implants which hadbeen transferred to normal hosts serving as controls. Spemann (128) has discussed the productionof tumors by embryonic tissue implants in vertebrate hosts. It is difficult to state at this point towhat extent the abnormal growths in Carausiusare comparable to true neoplasms, but the factthat they are definitely due to an endocrine imbalance should make them interesting objects forfurther study.

An essentially new way of inducing tumors wasfound in Leucophaea, a large roach which offersmany advantages for experimentation (Ili), 120,122). In this insect the severance of a nerve (recurrent nerve) causes tumors to develop in organswhich are innervated by this nerve. The organsconcerned are the anterior portion of the alimentary canal (foregut and anterior midgut) and thesalivary organs (salivary reservoir and salivaryglands). Figure 13 shows the topography of theseorgans and their innervation by branches from therecurrent nerve. Three possible locations for nervetransection are indicated; all three types of operation were carried out with essentially the same results. The tumors developing in a large proportion(75-80 per cent) of the operated adults andnymphs after varying periods of time were, as arule, conspicuous structures. Histologically, theyconsist of layers of cells which in the course of development apparently became progressively moreabnormal and finally necrotic. Few, if any, mitoticfigures were observed, a fact which, in view of theoften rapid growth of the tumors, may be explained by assuming that the mitoses are completed within a very short time or that cell divisionis mainly by amitosis. Giant cells, not normally observed in the organs in question, are not infrequentin the tumors.

The most commonly affected organ is the anterior portion of the midgut (stomach). Normallyconsisting of an almost transparent columnarepithelium and muscularis, the mucosa increasesin width many times after nerve section and becomes opaque or brown (Figs. 14, 15). Severe tumors of this kind usually lead to the death of theanimal. A foregut tumor, sarcoma-like in its microscopic structure, is shown in Figures 16 and 17.The conspicuous tumors of the salivary reservoir(Figs. 18, 19), which is normally a thin transparentmembrane, suggest epithelial tumors. Their sizemay become impressive (diameter up to 10 mm.).



SCHARRERAND LOCHHEADâ€”Tumors in Invertebrates 415

The tumors of a certain number of operated insects showed signs of malignancy (121). Tissuesnear the original tumor site were invaded andsometimes incorporated in a large mass of tumortissue. In a few cases this process led to the perforation of the chitinous body wall.

The primary (possibly degenerative) effect ofseverance of the recurrent nerve on the tissueswhich it innervates, and the early phases of thepathological growth process which this operationbrings about, are not yet fully understood. Thepossible role of connective tissue and blood elements in this process need further study. Insectsare capable of producing large masses of connective tissue at sites of injury. The tumors in Leuco-phaea, which develop at locations distant fromthe injury caused by the operation, do not resemble such connective tissue masses. Controloperations with equal or greater injury at the samesite, but without nerve severance, do not lead totumors. The tumors due to nerve severance do notshow melanization. (Ã¬iantcells occur in certaininsects normally, or during wound healing, butthe ones mentioned in the Leucophaea tumors areevidently not involved in the healing process, aredifferent from those observed in cases of injury reaction, and are normally not found in the corresponding tissues of nonturnorous specimens. ThehistolÃ³gica]appearance of the tumors developingin organs whose innervation has been disturbedby severance of the recurrent nerve differs to suchan extent from the normal histology of the organsin question that these tumors cannot be lookedupon merely as the result of tissue hyperplasia.Against their interpretation as ulcerative processesspeak the lack of necrosis and the maintenance ofsurface continuity in the earlier phases of their development.

Following severance of the recurrent nerve inLeucophaea early death from the resulting tumorsis more frequent in females than in males. In animals which have been gonadectomized severalweeks previous to nerve severance this sex-linkeddifference in mortality is no longer observed. Thesurvival rates in tumor-bearing castrates of eithersex are approximately equal and represent valuesintermediate between those of males and femalesin which only the nerve has been cut (123). Thesedifferences may perhaps be based on sex differences in metabolism, in that the greater lability inthe metabolic pattern of the reproducing femalesmay account for their lower resistance to tumorgrowth. In an attempt to substantiate these possible correlations, the fat content, in relation tototal dry matter and body weight, of whole nor

mal, castrate, and tumor-bearing animals wascompared (159). The content in body fat of thetumor-bearing males (with nerve severance only,or with nerve severance after castration) was below normal and close to starvation levels. The corresponding values for females with nerve severanceranged from starvation to normal levels. Theamount of fat in ovariectomiwd females with tumors ranged from the low values found in starva-

!

gÃ¬*M .

19

FIG. 18.â€”-Tumor in the wall of the salivary reservoir of

Leucophaea, filling part of the lumen. About X24. Orig.FIG. 19.â€”Salivary reservoir tumor of Leucophaea at higher

magnification. X.'ÃŽCO.Orig.

tion to the above average amounts characteristicof castration. These data seem to indicate essentialdifferences between males and females. In at leastsome of the analyzed females death cannot be attributed to starvation in connection with tumorouschanges in the alimentary canal, since it occurredat a time when the fat reserves were not yetdiminished.

SUMMARYPhenomena related to neoplastic growth have

been studied in a number of invertebrate phyla,and tumors of either epithelial or connective tissueorigin have been reported in annelids, sipunculids,arthropods, molluscs, and ascidians. Evidence ofthe true neoplastic character of such alleged tu-



Cancer Research

mors is often scanty; reasonably convincing signsof malignancy are found only in a small number ofreported cases.

A number of tumors described in representatives from various invertebrate groups may beclassified as spontaneous growths, since their causeis unknown. In insects certain of the alleged tumors are known to be hereditary. Other factorsreported to cause tumors or abnormal growths ininvertebrates are parasites, endocrine imbalance,and disturbance of innervation. Carcinogens havebeen tried on a variety of invertebrates and havebeen reported to cause tumors only in molluscs.X-rays in suitable dosage are known to causetumor-like growths or increase their incidence ininsects (Drosophila).

REFERENCES1. AHDASHNIKOV, S. N. Malignant Tumors in Drosophila

melanogaxter. Influence of the Left End of the Sex Chromosome on the Development of Tumors. Compt. rend.Acad. d. se. t RSS, 30:344-46, 1941.

2. Al'ERBACH, C. Tests of Carcinogenic Substances in Rela

tion to the Production of Mutations in Dromphilamelanoga.iter. Proc. Roy. Soc. Edinburgh, 60:164-73,

1939/40.3. Al'ERBACH, C., and ROBSON, J. M. Production of Muta

tions by Allyl Isothiocyanate. Nature, 164:81, 1944.4. BALAZUC,J. La tÃ©ratologie des colÃ©optÃ¨reset expÃ©riences

de transplantation sur Tenebria molitor L. Mein. Mus.Nat. Hist. Nat., ILS. 26: 1-293, 1948.

5. BiHi), F. T. Tumours associated with a Virus Infection inan Insect. Nature, 163:777-78, 1949.

6. BRVN, R. Ein Fall von Hirntumor bei der Ameise.Schweiz. Arch. Neural, u. Psychiat., 16:86-99, 1925.

7. BrHDETTE, W. J. Studies on Drosophila tumors. CancerResearch, 10:209, 1950.

8. CAMERON, G. R. Inflammation in Earthworms. J. Path.&Bact., 36:933-72, 1932.

9. CAVLLERY, M., and MESNIL, F. Le parasitisme intracellulaire et la multiplication asexuÃ©edes grÃ©garines. Compt.rend. Acad. d. se., 132:220-23, 1901.

10. â€”¿�â€”¿�.Le parasitisme intracellulaire et la multiplicationasexuÃ©edes grÃ©garines. Compt. rend. Soc. de biol., 53:84-87, 1901.

11. CHEN, H. T. Reactions of f'tenocephalidex feus to Dipyli-dium caninnm. Ztschr. Parasitenk., 6:603-37, 1934.

12. CODREANT, R. Neoplasie maligne dans l'hÃ©mocoele desÃ©phÃ©mÃ¨ressous l'action de Symbiocladiux rithrogenae,

< hiroimmide ectoparasite. Compt. rend. Acad. d. se.,201:102-4, 1935.

13. â€”¿�â€”¿�.Recherches biologiques sur un chironomide,Symbiocladiux rithrogenae (Zavr.), ectoparasite "cancÃ©rigÃ¨ne"des Ã©phÃ©mÃ¨restorrenticoles. Arch. /noi. ExpÃ©r.

Gen., 81:1-283, 1939.14. ('OLLINGE, W. E. N'ote on a Tumour in AnoJonta cygnaea

Linn. J. Anal. Physiol. Norm. & Path., 26:154, 1891.15. DEAHDEN, I). M. Genetic Modifiers of Tmnorous Head in

Drosophila melanogaxter. Proc. Itali Acad. Se. (in press).1<>.DEBAISIEI'X, P. Microsporidies parasites des larves de

Simulimi! (Thclohania rarian.i). Cellule (Louvain), 30:47-79, 1919/20.

17. â€”¿�â€”¿�.Ã‰tudessur les microsporidies. IV. Glugea anomala Monz. Ibid., pp. 215-45, 1919/20.

18. DEBAISIEUX, P., and GASTALDI, L. I-es microsporidiesparasites des larves de Simulimi!. IL Cellule (Ixnivain),30:185-214, 1919/20.

19. DE BOISSEZON, P. Contribution Ã l'Ã©tudede la biologie etde l'histophysiologie de l'idei pipienx L. Arch. Zool.

ExpÃ©r.GÃ©n.,70:281-431, 1930.

20. DE LERMA, B. Osservazioni sui corpora aliata del Grillotalpa. Arch. Zool. Ital., 17:417-33, 1932.

21. DEMEHEC, M. Mutations in Drosophila Induced by aCarcinogen. Nature, 169:604, 1947.

22. â€”¿�â€”¿�.Production of Mutations in Drosophila by Treat

ment with some Carcinogens. Science, 106:634, 1947.23. DE SINÃ‰TY,II. Recherches sur la biologie et l'anatomie

des phasmes. Cellule (Louvain), 19:117-278, 1901.

24. DREW, G. IL, and DE MORGAN, W. The Origin and Formation of Fibrous Tissue Produced as a Reaction to Injury in PectÃ©n maximiis, as a Type of the Lainelli-branchiata. Quart. .J. Micr. Sc., 56:595-610, 1910.

25. ENGEL, C. S. Warum erkranken wirbellose Tiere nicht anKrebs? Ztschr. f. Krebsforsch., 32:531-43, 1930.

26. ENZMANN, E. V., and HASKINS, C. P. MorphogenesisStudies by Means of X-llays. II. Note on an InheritedCuticular Tumor in Drosophila. Arch. f. Entwcklngs-mechn. d. Organ., 138:159-60, 1938.

27. ERMIN, R. I'eber Bau und Funktion der Lymphocyteii

bei Insekten (Periplaneta americana L.), /tschr. f. /ellforsch, u. mikr. Anat., 29:613-69, 1939.

28. FAURÃ‰-FRÃ‰MIET,E. Les amibocytes des invertÃ©brÃ©sÃ l'Ã©tatquiescent et Ã l'Ã©tatactif. Arch, aiiat. micr., 23:99-

173, 1927.29. FEDERLEY, H. Sex-limited Hereditary Cancer in Lepidop-

terous Larvae. Hereditas (Lundi, 22:193-216, 1936/37.

30. FINKELSTEIN, A. Tumor Growth in Invertebrates andLower Vertebrates, l'sp. sovrem. biol., 17:320-48, 1944.

SI. FISCHER, E. Association chez le crabe d'un tissu parasiteet d'une trame conjonctive analogue Ã certains processustumoraux. Bull. Assoc. franc, p. l'Ã©tude du cancer, 17:

468-70, 1928.32. (Â¡ARDNER,E. J. A Case of Genetically Controlled Cyto-

plasmic Influence in Dromphila melanogaxter. DIS (Drosophila Information Service), 22:70, 1948.

33. â€”¿�â€”¿�.Genetic Analysis of Tumorous Head in Dromphilamelanogaxter. Ree. Genet. Soc. Am., 18:87-88. 1949.

34. â€”¿�â€”¿�.Head Tumors in Dromphila melanoga.iter. Proc.t'tali Acad. Sc. (in press).

35. â€”¿�â€”¿�.Inheritance of Tumorous Head in Drosophilamelanoyaxter. Ibid, (in press).

36. â€”¿�â€”¿�.The significance of the Genetic Analysis of Tu

morous Head in Dromphila melanogaxter. Ibid, (in press).37. GARDNER, E. .J., and DEARDE.N, D. M. Genetic Modifiers

of Tumorous Head. Genetics (in press).38. GARDNER, E. J., and RATTY, F. J. PenetraneÂ« and Expres

sivity of Tumorous Head and Viability of Flies WhichCarry It. Genetics (in press).

39. (Â¡ARDNER,E. J., and STOTT, G. Genes Producing a Maternal Effect on Tumorous Head Found in "Wild"

Populations of D. melanogaxter. DIS (Drosophila Information Service), 23:89, 1949.

40. (Â¡ARDNER,E. J., and WOOLK, C. M. Maternal Effect Involved in the Inheritance of Abnormal Growth in theHead Region of Droxopliila melanm/axter. Genetics, 34:573-85, 1949.

41. - â€”¿�.The Influence of High and Low Temperatures

upon the Expression of Tumorous Head in Dromphilamelanogaxter. Genetics, 35:44-55, 1950.

42. (ÃŒHELELOVITCH,S. l'ne nouvelle tumeur hÃ©rÃ©ditairechez

la Drosophile (Droxophila melanogaxter Meig.). Compt.rend. Acad. se., 230:1002-4, 1950.



SCHARRER AND LOCHHEADâ€”Tnmorn in Invertebrates 417

4:Ã¬.(ÃŒOLDSTEIN,S. A Microbiological Test for CarcinogenicHydrocarbons. Science, 86:176-77, 1937.

44. GOWEN,J. W. The Inheritance of Focal Melanosis inDrosophila. Arch. Path., 17:638-47, 1934.

45. GRELL, SISTERMARY.Cytological Studies in Culex. I.Somatic Reduction Divisions. Genetics, 31:60-76, 1946.

4(>. HAOORN,E., and NICOLI H. Mutations in Drosophilaafter Chemical Treatment of Gonads in Vitro. Nature,167:168-63, 1946.

47. HAMMETT,F. S., and HAMMETT,D. W. The Influence ofSulfhydryl on the Formation of Aberrant DisorganizedOvergrowths in the Regenerating Right Chela of the Hermit Crab (Pagiirnnlongicarpiin). Protoplasma, 17:321-58,1932/33.

48. HAMMETT,F. S., and REIMANN,S. P. Effect of Methyl-eholaiithrene on Developmental Growth of Obelia geni-culata. Am. J. Cancer, 25:807-8, 1935.

t!>. HÃ„RTUNG,E. W. The Ktfects of Roentgen Radiation onTumor Incidence in Dro.mphila melanogaster. Cancer Research, 2:837-40, 1942.

50. â€”¿�â€”¿�.Some Effects of Temperature on Tumor Incidence in Several Strains of Droaophila melanogaxter. J.Kxper. Zool., 106:223-32, 1947.

51. â€”¿�â€”¿�.Some Observations on the Larval Growth Rateand Viability of Two Tumor Strains of Dronophiiamdanogaater. Science, 107:296-97, 1948.

52. â€”¿�â€”¿�.Some Factors Influencing Tumor Incidence inDro.mphila melanogaxter.Anat. Ree., 106:4!)S, 1949.

53. HÃ„RTUNG,E. W., and TILLINGHAST,M. G. The Nature ofthe Piginented Sheath in Drosophila Tumors. Science,109:505-66, 1949.

54. HÃ‰RUBEL,M. Sur une tumeur chez un invertÃ©brÃ©(Sipvncuhu nudua). Coinpt. rend. Acad. d. se., 143:979-81, 1906.

55. HOPPER,S. H., and ('LAPP,1). B. Effect of Carcinogenic

and Other Hydrocarbons on the Growth of Kucherirhiacommunior. J. Bact., 38:13-23, 1939.

56. IWASAKI,Y. Sur quelques phÃ©nomÃ¨nesprovoquÃ©schez leschenilles de papillons par Tint roduction de corps Ã©trangers.Arch. anat. micr., 23:319-46, 1927.

57. JAQUEMAIN,R.; JULLIEN,A.; and NOEL,R. Sur l'action

de certains corps cancÃ©rigÃ¨neschez les cÃ©phalopodes.Compt. rend. Acad. d. se., 225:441-43, 1947.

58. JONES,D. F. Tumors in Dromphiia melanogaxter Resulting from Somatic Segregation. Science, 84:135, 1936.

59. .liiiii-., A. De certaines tumeurs et inflammations dumanteau de la seiche. Arch. /ool. ExpÃ©r.(Â¡en.,67:139-58,1928.

60. â€”¿�â€”¿�.Sur la transformation des cellules sanguines de laseiche au cours des rÃ©actionsinflammatoires aseptiques.Compt. rend. Acad. d. se., 186:526-29, 1928.

61. â€”¿�â€”¿�.Sur la signification des granulations Ã©osinophilesdes cellules sanguines de la seiche (Sepia officinalia L.).Ibid., pp. 644-45, 1928.

62. â€”¿�â€”¿�.Sur les rÃ©actionsdes mollusques cÃ©phalopodesauxinjections de goudron. Ibid., 210:608-10, 1940.

63. KAVETHKI,K. E. ExpÃ©rimentalCancer Research in thÃ©I'SSR. (Address delivered at the 3rd aim. meet. Am.Soviet Med. Soc.) Am. Rev. Soviet Med., 4:322-27,1946/47.

64. KEDROWSKY,B. Reaktive Veraenderungeii in den Geweben der Tcichimiscliel (Anodonta sp.) bei Einfuehrnngvon sterilem Celloidin. Virchows Arch. f. path. Anat.,267:815-45, 1925.

65. KOLOSVÃ•RY,G. VON. Neue Weberknecht-Studien. I.BeitrÃ¤gezur Teratologie d. l'Ã¬ialangiumopiÃ¬ioL. Actabiol., 3:1-10, 1934.

66. KOSTHITZKY,M.; TOUMANOFF,M.; and METALNIKOW,S.

Bacterium tumefacieiis chez la chenille de (Â¿allertamei-lancila. Compt. rend. Acad. d. se., 179:225-27, 1924.

67. KOWALSKI,J. CiÃ±esesatypiques dans les cellules adipeuses de larves de Pi/rrhocarix apierna L. avec quelquesremarques sur le centrosome. Cellule (Louvain), 30:H1-118, 1919/20.

68. LABBÃ‰,A. Production expÃ©rimentalede tissu conjonctifpar les amoebocytes chez Doria Inberrulata L. Coinpt.rend. Acad. d. se., 187:1073-75, 1928.

69. - â€”¿�.RÃ©actionsexpÃ©rimentalesdes mollusques Ã l'in

troduction de stylets de celloldine. Compt. rend. Soc. debiol., 100:166-68, 1929.

70. â€”¿�â€”¿�.RÃ©actiondu tissu conjonctif au goudron chez unmollusque: Doris tiiberculata Cuvier. Ibid., 103:20-22,1930.

71. LADREYT,F. Sur une tumeur cancÃ©reusedu siponcle(ÃŸijntncuhmnudua L.). Bull. inst. OcÃ©anogr.(Monaco),405: 1-8, 1922.

72. â€”¿�â€”¿�.UnicitÃ©Ã©volutiveet pluralitÃ©Ã©tiologiquedestumeurs cancÃ©reuseschez quelques animaux marins(roussettes, raies, tortues, siponcles). Faits et thÃ©ories.Ibid., no. 414: 1-16, 1922.

73. LAZARENKO,T. Beitraege zur vergleichenden Histologiedes Blutes und des Bindegewebes. II. Die morphologischeBedeutung der Blut- und Bindegewebeelemente derInsekten. Xtschr. f. mikr.-anat. Forsch., 3:409-99, 1925.

74. LÃœCKE,B., and SCHLUMBERGER,H. Neoplasia in Coldblooded Vertebrates, Physiol. Rev., 29:91-126, 1949.

75. MAHDIHASSAN,S. Insect Tumours of Bacterial Origin.TheDeccan Med..I. (Hyderabad, Deccan),pp. 1-19,1941.

76. â€”¿�â€”¿�.Cicadella riridi.t. Its Symbiotes and Their Function. Curr. Sc., 16:58-59, 1947.

77. MclNTOSH,\V. C. On a Parasitic Growth on the Tail ofSagitta and in a Cirrus of Hermadion from the "Challenger." Ann. & Mag. Nat. Hist., ser. 9, 20:1, 1927.

78. MENKIN,V. The Biochemistry of Cell Injury as Manifested in Inflammation. Proc. 6th Internat. Congr. exp.Cytol., Stockholm, 1947. Exp. Cell Res. Suppl. 1, Stockholm 1949, pp. 511-16.

79. MERCIER,L. Neoplasie du tissu adipeux chez des Blattes(Periplaneta Orientalin L.) parasitÃ©espar une micro-sporidie. Arch. f. Protistenk., 11:372-81, 1908.

80. MERCIER,L., and POISSON,R. l'ne haplosporidie, Haplo-

sporiditim Caullery nov. sp., parasite de Nercilepasfucata Sav. Compt. rend. Acad. d. se., 174:1205-7, 1922.

81. MESNIL,F., and CAULLERY,M. NÃ©oformationspapillo-mateuses chez une annÃ©lide(Palomilla torelli), duesprobablement Ã l'influence de parasites (Haplosporidieset levure). Bull. Sc. France Belg., 45:89-105, 1911.

82. METCALF,M. M. Cancer (?) in Certain Protozoa. Am. J.Trop. Med., 8:545-57, 1928.

83. METSCHNIKOFF,E. l'eber eine Sprosspilzkrankheit der

Daphnien. Beitrag zur Lehre lieber den Kampf derPhagocyten gegen Krankheitserreger. Virchows Arch. f.path. Anat., 96:177-95, 1884.

84. MORGAN,T. H.; BRIDGES,C. B.; and STURTEVANT,H. H.The Genetics of Drosophila. Bibliogr. genetica, 2:1-262,1925.

85. MORGAN,T. H.; SCHULTE,J.; and CURRY,V. Investigations on the Constitution of the Germinal Material inRelation to Heredity. Carnegie Inst. Wash. Yearbook,40:282-87, 1940/41.

86. MORGAN,T. H., and SCHULTZ,J. Investigations on theConstitution of the Germinal Material in Relation toHeredity. Carnegie Inst. Wash. Yearbook, 41:242-45,1941/42.

87. MOTTRAM,J. C. 3,4-Benzpyreiie, Paramecium and theProduction of Tumors. Nature, 145:184-85, 1940.



418 Cancer Research

88. NEEDHAM,J. Biochemistry and Morphogenesis. Cambridge: Univ. Press, 1942.

89. NEWBY, W. \V. Abnormal Growths on the Head ofDroxophila melanogaster. J. Morphol., 86:177-90, 1949.

90. NOLANO,J. L., and BACMANN,C. A. Effects of CertainAzo Dyes upon the Cockroach, Blattella germanica. Proc.Soc. Exper. Biol. & Med., 71:365-68, 1949.

91. NOUVEL,H. Les DicyÃ©mides.2e partie: Infusoriforme,tÃ©ratologie,spÃ©cificitÃ©du parasitisme, affinitÃ©s.Arch.Biol., 69:147-223, 1948.

94. Ã–RÃ–8I-PAL,Z. Pathologische VerÃ¤nderungen ("Ge-schwUlste") im DÃ¼nndarmder Honigbiene. Zentralbl.Bakter. H, 96:338-40, 1937.

93. OWEN,S. E.; WEISS,H. A.; and PRINCE,L. H. Carcinogens and Planarian Tissue Regeneration. Am. J. Cancer,35:424-26, 1939.

94. PAILLOT,A. Nouvel ultravirus parasite d'Agrotis segetum

provoquant une prolifÃ©ration(les tissus infectÃ©s.Compt.rend. Acad. d. se., 201:1062-64, 1935.

95. â€”¿�â€”¿�.Contribution Ã l'Ã©tudedes maladies Ã ultravirusdes insectes (2Â°mÃ©moire).Ann. Ã‰piphyt.PhytogÃ©nÃ©t.(Paris) n. sÃ©r.,2:341-79, 1936.

96. PALM,N. B. Notes on thÃ©Structure of the CorporaAliata in (Ã¬ryllotalpa.Kgl. Fysiogr. Saells. Foerhandl.,17: no. 13, 1-11, 1948.

97. - â€”¿�.The Pharyngeal Gland in Bombus LATRand Psithyrus LEI", with a Description of a Case ofPathological Development of the Pharyngeal Gland-Opuscul. entomol. (Lund), 14:27-47, 1949.

98. PANTEL,J. Recherches sur les diptÃ¨res Ã larves en-tomobies. 1. CaractÃ¨res parasitiques aux points de vuebiologique, Ã©thologiqueet histologique. Cellule (Lou-vain), 26:25-216, 1910.

99. . Recherches sur les diptÃ¨resÃ larves entomobies .II. Les enveloppes de l'oeuf avec leurs dÃ©pendances,lesdÃ©gÃ¢tsindirects du parasitism. Ibid., 29:5-289, 1913.

100. PKLUGFELDER,O. Weitere experimentelle Untersuchungen ueber die Funktion der Corpora aliata von Dixippusmorosas Br. Ztschr. wiss. Zool., 161:149-91, 1938.

101. â€”¿�â€”¿�.Geschwulstartige Wucherungen embryonalerTransplantate Â¡nCarausius (Dixippus) morosus, nachexperimenteller Stoerung des Hormonhaushalts. Biol.Zentralbl., 66:170-79, 1947.

102. â€”¿�â€”¿�.Haplosporidienwucherungen (Sporozoa) in Asel-lus aauaticus L. (Wasserassel) nach Extirpation tier rudi-mentaeren Antennennephridien. Zentralbl. Bakt. L,162:519-26, 1948.

103. â€”¿�â€”¿�.Atypische Gewebsdifferenzierungen bei Stabheuschrecken nach experimenteller Stoerung der innerenSekretion. Ztschr. Krebsforsch., 56:107-20, 1948.

104. â€”¿�â€”¿�.Mechanismus der Amitose und Pseudoamitosebei experimentellen Geschwulstbildungen und nachGiftwirkung. Verband!, deutsch. Zool. Kiel, pp. 49-58,1948.

105. POGOSSIANTS,H. E. On the Problem of the So-calledTumours in Drosophila. Compt. rend. Acad. d. sc.URSS, 62:255-58, 1946.

106. POISSON,R. Sur une infection Ã microsporidie chez lanÃ¨pecendrÃ©e(HÃ©miptÃ¨re-HÃ©tÃ©roptÃ¨re).La rÃ©actiondestissus de l'hÃ´tevis-Ã -visdu parasite. Arch. Zool. ExpÃ©r.GÃ©n.,67:129-37, 1928.

107. POULSON,D. F. Chromosomal Control of Embryogenesisin Drosophila. Am. Naturalist, 79:340-63, 1945.

108. PRINCE,E. E. Special Report on the Natural History ofthe Lobster. 29th Ann. Rep. Dept. Marine & Fish.Canada suppl. 1, I-IV, 1-36, 1897.

109. PURR, A. Tumoren bei Mensch, Tier und Pflanze. Tab.Biol., 15:154-206, 1937/38.

110. RAPAPORT,J. A. Specific Morphoses in Drosophila Induced by Chemical Compounds. Bull. Biol. et MÃ©d.ExpÃ©r.URSS, 7:415-16, 1939.

111. RATTY,F. J. The Effects on Viability of Tumorous Headin Drosophila melanogaster. Proc. Utah Acad. Sc. (inpress).

112. REIMANN,S. P. Significant Trends in Cancer Research.J.A.M.A., 136:87-88, 1947.

113. REIMANN,S. P., and HAMMETT,F. S. The ProliferationStimulating Action of 1,2,5,6-dibenzantliracene on Olieliageniculata. Am. J. Cancer, 23:343-49, 1935.

114. ROBERTSON,C. W. The Metamorphosis of Drosophilamelanngaster,Including an Accurately Timed Account ofthe Principal Morphological Changes. J. Morphol., 69:351-99, 1936.

115. ROUSSY,G., and WOLF,M. Le cancer chez les animaux.Ann. de mÃ©d.,8:462-92, 1920.

116. RUSSELL,E. S. A Comparison of Benign and "Malignant" Tumors in Droxophila melanogaaler. J. Exper.Zool., 84:363-85, 1940.

117. â€”¿� . The Inheritance of Tumors in Drosophila melana-gaxler,with Special Reference to an Isogenic Strain of st srTumor 36 a. Genetics, 27:612-18, 1942.

118. RYDER,J. A. On a Tumor in the Oyster. Proc. Nat. Acad.Sc., 44:25-27, 1887.

119. SCHARRER,B. Experimental Tumors in an Insect. Science,102:102, 1945.

120. â€”¿�â€”¿�.Experimental Tumors after Nerve Section in anInsect. Proc. Soc. Exper. Biol. & Med., 60:184-89, 1945.

121. â€”¿�â€”¿�.Malignant Characteristics of Experimentally Induced Tumors in the Insect, Leucophaea maderae (Orthop-tera). Anat. Ree., 100:774-75, 1948.

122. â€”¿�â€”¿�.Gastric Cancer Experimentally Induced in Insects by Nerve Severance. J. Nat. Cancer Inst., 10:375-76, 1949.

123. â€”¿�â€”¿�.Tumor Mortality and Sex in Leucophaea maderae(Orthoptera). Anat. Ree", 106:624, 1949.

124. SCHLUMBERGER,H. G., and LÃœCKE,B. Tumors of Fishes,Amphibians, and Reptiles. Cancer Research, 8:657-753,1948.

125. SIEDLECKI,M. Sur les rapports des grÃ©garineset del'Ã©pithÃ©liumintestinal. Compt. rend. Acad. d. se., 132:218-20, 1901.

126. â€”¿� . Sur les rapports des grÃ©garinesavec l'Ã©pithÃ©liumintestinal. Compt. rend. Soc. de biol., 63:81-83, 1901.

127. SMITH, G. M. A Mesenchymal Tumor in an Oyster(Ostrea rirginica). Am. J. Cancer, 22:838-41, 1934.

128. SPEMANN,H. Ueber das Verhalten embryonalen Gewebesim erwachsenen Organismus. Arch. Entwcklngsmechn. d.Organ., 141:693-769, 1942.

129. SPENCER,R. R., and MELROY,M. B. Effect of Carcinogens on Small Free-living Organisms. II. Survival Valueof Methylcholanthrene-adapted Paramecium. J. Nat.Cancer Inst., 1:343-48, 1940/41.

130. STARK,M. B. An Hereditary Tumor in the Fruit Fly,Drosophila. J. Cane. Res., 3:279-301, 1918.

130a. - â€”¿�.An Hereditary Tumor. J. Exper. Zool., 27:509-29, 1919.

131. â€”¿�â€”¿�.A Benign Tumor That is Hereditary in Droso-phila. Proc. Nat. Acad. Sc., 6:573-80, 1919.

132. â€”¿�â€”¿�.The Origin of Certain Hereditary Tumors inDrosophila. Am. .1. Cancer, 31:253-67, 1937.

133. STARK,M. B., and BRIDGES,C. B. The Linkage Relationsof a Benign Tumor in Drosophila. Genetics, 11:249-66,1926.

134. STARK,M. B., and MARSHALL,A. K. The Blood-formingOrgan of the Larva of Drosophila melanogaxter. J. Am.Inst. Homeop., 23:1204-6, 1930.



SCHARRERANDLOCHIIEADâ€”Tumor*in Invertebrates 419

135. STEINHAUS, E. A. Insect Microbiology. Ithaca, N.Y:Comstock, 1946.

186. â€”¿�â€”¿�.A New Disease of the Variegated Cutworm,PerÃdromo margaritona (Haw.). Science, 106:323, 19-17.

137. â€”¿�â€”¿�.Principles of Insect Pathology. New York: McGraw-Hill, 1949.

138. STERN, K., and WILLHEIM, R. The Biochemistry ofMalignant Tumors. Brooklyn, N.Y.: Reference Press,1943.

139. SZABÃ“,I., and SZABÃ“,M. Altersveraenderungen undpathologische Erscheinungen in der Koerpenvand vonLima* flams L. Biol. /!>!., 51:695-701, 1931.

140. â€”¿� . Epitheliale Geschwulstbildung bei einem wirbel

losen Tier Limax flams L. Ztschr. f. Krebsforsch., 40:540-45, 1934.

141. SZABÃ“,M. KÃ³rns elvÃ¡ltozÃ¡sok csigÃ¡kon. AllÃ¢t. Koezl.,32:132-35, 1935.

142. â€”¿�â€”¿�.Todesursachen und pathologische Erscheinungenbei Pulmonaten. IV. Arch. Molluskenk., 68:199-204,

1936.143. TCHAKHOTINE, S. CaiicÃ©risation expÃ©rimentale des Ã©lÃ©

ments embryonnaires, obtenue sur des larves d'oursins.

Compt. rend. Soc. de biol., 127:1195-97, 1938.

144. TEITSCHLAENDEH, O. Beitraege zur vergleichendenOnkologie mit Beriiecksichtigung der Ideiititaetsfrage.Ztschr. f. Krebsforsch., 17:285-407, 1920.

145. THOMAS, .1. A. Ã‰tuded'un processus nÃ©oplasique chez

Nereis dirersicolor O.K.M. dÃ» Ã la dÃ©gÃ©nÃ©rescencedesoocytes et quelquefois des soies. Arch. anal, micr., 26:251-333, 1930.

146. â€”¿�â€”¿�.Sur la rÃ©partition, aux environs de Roscoff, d'une

neoplasie de Nereis dirersicolor (). F. M. (Essai Ã©cologique). Bull. biol. France Belg., 64:332-54, 1930.

147. . Contribution Ã l'Ã©tudedes rÃ©actionsde quelquesinvertÃ©brÃ©sÃ l'inoculation de substances Ã propriÃ©tÃ©s

cancÃ©rigÃ¨neset du bacterium tumefaciens Sm. et Town.Ann. Inst. Pasteur, 49:234-74, 1932.

148. â€”¿�â€”¿�.Les rÃ©actions tumorales des invertÃ©brÃ©s.RevuegÃ©nÃ©rale.Bull. Soc. Philomath., 116:70-88, 1932.

149. THORNTON, D. The Effect of 2,4-Dinitrophenol on theLarval Growth of Drosophila melanogaster. Growth,11:51-60, 1947.

150. TITTLER, l. A. An Investigation of the Effects of Carcinogens on Tetrahymena geleii. J. Exper. Zool., 108:309-

25, 1948.151. TITTLER, 1. A., and KOBRIN, M. Effects of Carcinogenic

Agents on Paramecitnn caudatum. Proc. Soc. Exper. Biol.& Med., 60:95-96, 1942.

152. WHITE, P. B. Note on a Case of Fibroma in a Honey-Bee.J. Path. & Bact, 24:138-39, 1921.

153. WHITE, M. J. 1). Animal Cytology and Evolution. Cambridge: Univ. Press, 1945.

154. WIGGLESWORTH, V. B. Wound Healing in an Insect(Rhodnivs prolixus, Hemiptera). .[. Exper. Biol., 14:364-

77, 1937.155. WILLIAMS, J. W. A Tumour in the Fresh-Water Mussel

(Anodnnta cyynea Linn.). J. Anat. Physiol. Norm, andPathol., 24:307-8, 1890.

156. WILSON, I. T. Two New Hereditary Tumors in Drosophila. Genetics, 9:343-62, 1924.

157. WILSON, L. P. Effect of Dinitrophenol and Excess AminoAcids upon Melanotic Growths in Drosophila. Anat.Ree., 99:600, 1947.

158. â€”¿�â€”¿�.Increased Incidence of a Tumor of Drosophila in

the Presence of High Concentrations of Arginine. Anat.Kec., 106:627-28, 1949.

159. WILSON, V. T., and SCHARRER, B. Fat Metabolism inTumor Bearing Insects (Leucophaea maderae, Orthop-tera). Anat. Ree., 106:625, 1949.

160. WOLMAN, M. A Proliferative Effect of Carcinogenic Hydrocarbons upon Multiplication of Paramecia. Growth,3:387-96, 1939.

161. WOOLF, C. M. Temperature Effects on Head Tumors inDrosophila melanogaster. Proc. Utah Acad. Sc. (in press).

162. . The Effect of Temperature Treatments on anEarly Developmental Period of Tumorous Head inDrosophila melanogaster. Ibid, (in press).

163. ZAWARZIN,A. Beitraege zur vergleichenden Histologie desBlutes und des Bindegewebes. IV. Ueber die entzuend-liche Neubildung von Bindegewebe bei der Teichmuschel(Anodonta anatina L.). Ztschr. f. mikr.-anat. Forsch.,6:508-625, 1926.

164. XIVIN, M. O. Influence of Thymonucleic Acid uponDrosophila melanogaster. Compt. rend. Acad. Sc. l'RSS,

62:263-64, 1946.



1950;10:403-419. Cancer Res Berta Scharrer and Margaret Szabó Lochhead

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