Chronology of oncology in fish, amphibians and invertebrates 1/24_06… · · 2015-05-22Chronology of oncology in fish, amphibians and invertebrates ... creatures subject to any

Bull. Eur. Ass. Fish Pathol., 24(1) 2004, 62

Chronology of oncology in fish,amphibians and invertebrates

John C. Harshbarger

Department of Pathology, George Washington University Medical Center; 2300 I Street, NW; Wash-ington DC 20037

IntroductionFish, frogs, other poikilothermic vertebrates and invertebrates are victims, models, sentinels,and bioassay subjects in regard to cancer. Lesions consistent with bone neoplasms have beenseen on Mesozoic dinosaurs. Nucleotide sequences of some mammalian tumour genes havebeen recognized in sponges and yeast. Though rarely credited, new carcinogens have beendiscovered in fish, an oncogenic virus was discovered in frogs and new tumour genes have beendiscovered in both invertebrates and fish. Some epizootic fish and mollusc cancers are correlatedwith high human cancer mortality consistent with a common environmental etiology. Otherepizootic neoplasms are communicable due to a known or suspected oncogenic virus.The aims of this paper are 1) give a working definition of several terms, 2) chronicle milestonesin oncology with emphasia on fish, invertebrates and other cold-blooded animals and 3) providereferences that will be useful for further literature search. To conform to the limits of the originaloral presentation, experimental and physiological studies were largely excluded and regrettablysome worthy milestones of oncology may have been inadvertently omitted.

DefinitionsOncology is the study of neoplasia. Neoplasmand tumour are interchangeable terms incurrent medical usage. The same workingdefinition applies to tumours of fish andinvertebrates as to mammals. A neoplasm isa heritably altered, relatively autonomous,dysplastic growth of tissue detrimental to thehost. In other words a neoplasm is aninharmonious, purposeless, overgrowth of agenetically abnormal cell type that continuesto multiply even after the initiating mutagensare no longer present. Oncogenic mutagensinclude certain chemicals, ionizing radiation,ultraviolet radiation, and some viruses. Thereis no threshhold for tumourigenic mutagens.As mutations accumulate among neoplasticcells by natural selection, neoplasms

progressively lose the ability for differentiation(anaplasia) concomitant with more aggressivebehaviour. Aggressive neoplasms containcells capable of invading and destroyingnormal tissues and are called cancers.Cancers can spread by direct extension intoadjacent normal tissues and sometimes cellsfrom a primary cancer metastasize throughbody fluids to establish secondary cancers inremote locations.

Neoplasia is the opposite of toxicity in thesense that the autonomous proliferation ofcells in neoplasia contrasts to the cessationof cellular proliferation in toxicity. Toxin derivesfrom the latin word toxicum meaning poison.A toxin kills cells, usually by the production offree radicals that interfere with intercellular


mechanisms, whereas neoplasia increasesgrowth. Toxins have a threshholdconcentration. Below the lethal toxic thresh-hold some chemicals can be carcinogenic.

Proliferation of normal cells surviving thetoxicity can regenerate the necrotic tissues,such as replacing epidermal cells killed bysunburn. This process is regenerative hyper-plasia. Hyperplasia differs from neoplasiabecause the regenerating cells are normalrather than heritably altered and proliferationceases once the stimulus is removed. Othertypes of hyperplasia include compensatoryhyperplasia that occurs after the removal ofone kidney and the other kidney grows largerto compensate and physiologic hyperplasiathat occurs when adipose tissue increases toaccommodate the storage of excess dietaryfat or when goiters develops in response toiodine deficiency.

ChronologyCancer is the Latin word for crab. Itsuperseded the Greek word for crab,“karkinos”, introduced into medical usage byHippocrates (460-335 BC) for advancedbreast cancer, which had a visual similarity tothe hard body and bluish tentacles of a crab.“Cancer” remains a valid crab genus.

An early fish tumour was the seasonallylimited, communicable, epitheliomapapulosum of common carp, Cyprinus carpio.It has been a problem in fish culture from atleast the 16th century AD (Hofer, 1896).Epithelioma papillosum, sometimes referredto by the misnomer “carp pox”, is caused bytemperature sensitive Herpesvirus cyprinae(Sano et al., 1993). Susceptibility and severityare strain dependent.

The observation by Sir Percivall Pott (1775)that boys used as chimney sweeps developedscrotal cancer was one of the earlierindications of a chemical etiology for cancer.Bathing reduced incidence (Butlin 1892).

Bell (1793) reported multiple, osteomas onvertebral spines of butterflyfish, Chaetodonsp., and similar familial bone tumours are nowknown in about 60 fish species.

The Edinburgh Medical Committee of theSociety for Investigating the Nature and Cureof Cancer in 1802 questioned, “are brutecreatures subject to any disease resemblingcancer in the human body. It is not at presentknown whether brute creatures are subject tocancer, though some of their diseases have avery suspicious appearance…” (Baillie et al.,1806).

Kirby and Spence (1826) discussed tumour,malformations, parasitism and other diseasesin insects.

Formulation of the concept that all plant andanimal tissues are composed of cells (the celltheory) is attributed to Matthias JacobSchleiden – a botanist (1838) and FriedrichTheodore Schwann – a medical physiologistand anatomist (1838). Both were graduatestudents in the Department of Anatomy andPhysiology, Friederick Wilhelm Universityunder Johannes Mueller. Muller (1838) thendemonstrated the cellular composition ofcancer.

Crown gall neoplasm of plants was discoveredin 1853 according to Mani (1964). Crown galltumor is caused by the bacterium,Agrobacterium tumefaciens (Smith andTownsend, 1907) and the tumor cells continue


their autonomous growth after the bacteriumis removed. The transforming agent is aplasmid transported by the bacterium. Thetransforming plasmid becomes incorporatedin a plant cell genome and is passed tosuccessive tumour cells (Braun 1977).

The same year that Crown Gall was dis-covered, Deslongchamps (cited by Thomas1931) gave the first report of neoplasia in achrondrichthyan, a fibroma in a thornbackskate, Raja clavata.

Nineteen years after the cell theory wasformulated Rudolph Virchow (1858)introduced the doctrine of cellular pathologyand described the pathology of a number oftumour types.

Contemporarily, Charles Robert Darwin andAlfred Russell Wallace (1858) co-announcedtheir independent discovery of the concept ofnatural selection. Darwin (1859) expoundedthat announcement in his book, “On the Originof Species by Means of Natural Selection, orthe Preservation of Favored Races in theStruggle for Life”.

Gervais (1886) reported a huge fibrous tumourin the body cavity of a carp, Cyprinus carpio,reminiscent of gonad neoplasms seen in manycarp and carp hybrids since then.

A pericardial neoplasm, presumably amesothelioma, was reported in an oyster,Crassostrea virginica, (Ryder, 1887) andtumours in freshwater mussels, Anodontacygnoea, were reported by Collinge (1890)and by Williams (1890).

Julius Cohnheim (1839-1884) lectured thattumours cannot grow beyond the size of a

pinhead unless the host supplies bloodvessels. That concept was comfirmed byJudah Folkman and associates bytransplanting malignant cancer cells to theanterior chamber of a rabbits eye. Tumoursremained dormant while floating but grew16000 times in 3 days when they weremanually held against the iris and becamevascularized (Gimbrone et al., 1972;Gimbrone et al., 1974). Folkman is one ofthe most pre-eminent cancer investigators inthe world today for his extensive research oncancer inhibition via antiangiogenesis(Folkman, 1995). One tissue that containsaniogenesis inhibitors is cartilage (Brem et al.,1975) including shark cartilage (Lee andLanger, 1983). This has led to the marketingof shark cartilage for the treatment of cancerin humans but its effectiveness in that role hasbeen refuted in clinical trials (Miller et al.,1998).

David von Hansemann (1890) noted that asgrowth proceeds neoplasms become lessdifferentiated and more primitive, i.e. hedeveloped the concept of anaplasia. He alsonoted that anaplastic tumour cells frequentlyhad unequal numbers of chromosomes,variable amounts of chromatin andasymmetric mitoses.

Epizootic lymphoma in northern pike, Esoxlucius, was reported in the United States byA. P. Ohlmacher (1898), in Ireland by Maire F.Mulcahy (1963) and in the Baltic Sea by OlleLjungberg (1976). Studies by Mulcahy andO’Leary (1970), Eric R. Brown (1974), RonaldA. Sonstegard (1976) and others support aviral etiology. James S. Thompson andKostiala (1990) reported that the cell of originis the tissue macrophage based on studies in


Finnish pike. If Ohlmacher had continuedstudying pike lymphoma he might have beenthe one to discover viral oncogenicity insteadof Peyton Rous (1911) who discovered it infowls.

By 1900 approximately 30 scientific papershad reported neoplasms in reptilia, amphibia,osteichthyes, chondrichthyes, mollusca andarthropoda.

McFarland (1901) described epidermalpapillomas on a white catfish, Ameiurus catus,from Pennsylvania.

In 1902 Theodor Boveri (1929) observedunequal development and death of sea urchinembryos initiated by polyspermic fertilization.Building on the observations of vanHansemann (1890), Boveri popularized theidea that cancer cells, like aberrant sea urchinembryos, result from an unequal distributionof genome material.

Orocutaneous papillomatosis (cauliflowerdisease) in Atlantic Eels, Anguilla anguilla, wasnoticed on the German coast of the Baltic in1910. It had spread to Bornholm, Sweden andthe Jutland peninsula by 1944 and Denmarkby 1946 according to M. Christiansen and A.Jensen (1950). It reached The Netherlandsin 1956 or 1957 followed by Belgium (B.F.Deys 1976).

Peyton Rous (1911) transmitted a solidsarcoma in Plymouth Rock chickens, Gallusdomesticus, with a cell free tumour filtrateindicitative of a viral etiology. His report wasmet with intense skepticism but the work waseventually confirmed and the agent wasshown to be a retrovirus. Rous received aNobel Prize in 1966.

Goiters, often misinterpreted as neoplasms,were a significant problem in cultured fish inthe early 1900’s, especially in rainbow trout,Oncorhynchus mykiss . To address thisproblem, Harvey R. Gaylord and M.C. Marsh(1912) held a meeting entitled “Carcinoma ofthe thyroid in fish”One outcome was to preventor reverse goiter formation in cultured fish byincreasing Potassium iodide. Though thyroidhyperplasia is most often seen in cultured fisha dramatic exception is a 100% prevalence insalmon in the great lakes probably due tofactors other than iodine levels (Leatherland1994).

Since bony fish thyroid tissue is un-encapsulated it can easily migrate and it iscommonly ectopically dispersed in somespecies. Thyroid hyperplasia can bemodulated by many factors includingpotassium iodide levels, temperature, diet,contaminants, crowding, and UV radiation asreviewed by Hoover (1984). Due to thesecharacteristics and sensitivities, hyperplasticthyroid can readily develop and might be seenin the heart, spleen, kidney, gills, post orbitallyand elsewhere. It can destroy cartilage, boneand other tissues. Hyperplastic thyroid cantake on a papillary cystic morphology or anafollicular, colloid free morphology either ofwhich can resemble neoplasia. The complexnature of fish thyroid physiology (Leatherland,1994) adds to the probability that most thyroidproliferations in bony fish, and sharks (Crowet al., 2002), are hyperplastic rather thanneoplastic. Definitive studies on whatconstitutes thyroid cancer in fish will have tocombine experimental regimens, molecularanalyses, electron microscopy, behaviormorphology and physiology. Especially they


will have to distinguish physiologicalhyperplasia from genetic transformation.

Yamagiwa and Ichikawa (1915) experimentallyconfirmed the carcinogenicity of coal tar (soot)by painting tar on the ears of rabbits two orthree times a week for a year. Papillomasdeveloped at the exposure site followed bymetastatic carcinoma. Benzo(a)pyrene wasthe first of many carcinogenic compoundsisolated from tar by Ernest Kenneway andassociates (Kenneway, 1955).

Twenty percent of European Smelt, Osmeruseperlanus, from the Baltic had epitheliomas(Breslauer, 1916).

Gene dependent cancer was discovered inlarvae of a mutant strain of Drosophiliamelanogaster homozygous for the lethal 7gene (Bridges 1916). Mary Stark (1937), thena student in Calvin Bridges’ laboratory, studiedthe strain until it was lost in a laboratoryaccident in 1939. The same mutant tumourstrain, now called l (2) gl, was rediscoveredand a neuroblastoma developed after adefective gene failed to suppress the activityof a growth gene (Gateff and Schneiderman,1969). Elizabeth Gateff was honoured on thecover of Cancer Research (Colburn, 1989) asone of the first individuals to recognize the roleof suppressor genes in cancer development.The human homologue of the l (2) gl genecodes for a cytoskeletal protein (Strand et al.,1995).

The 2nd inherited neoplasm to be discoveredwas a melanoma that consistently arosespontaneously in certain Xiphophorus hybrids(Haeussler 1928) . The genetics of thismelanoma’s tumourigenesis was indepen-dently investigated by Kurt Kosswig (1931)

and by Myron Gordon (1948, 1959). In the1960’s, Fritz Anders et al., (1984) showedtumours result from the expression of anactivated tumour gene (his tu gene is nowcalled oncogene) following the elimination orinactivation of its regulating genes (suppressorgenes). Anders, his wife and colleagueAnnarose Anders, Kurt Kosswig and MyronGordon were honoured on a cover of CancerResearch (Weisburger, 1990). TheXiphophorus model continues to have anactive role in the study of cancer genetics(Woodhead and Chen, 2001).

From 1900 to 1950 approximately 500 paperswere published on tumours in invertebratesand cold-blodded vertebrates. Investigatorsbeyond those already named who reportedtumours in fish included E.F. Bashford, JamesJohnstone, Mariann Plehn, Otto Pflugfelder,Ross Nigrelli, and J.A. Thomas. K. Takahashi(1929) reviewed fish tumours in Japan.Schlumberger and Lucke (1948) thoroughlyreviewed reports of tumors in fish, amphibiansand reptiles. Invertebrate tumours werereviewed by Scharrer and Lockhead (1950)and an invertebrate tumour bibliography waspublished by Cantwell et al., (1968).

Beginning about 1935 the world production ofsynthetic organic chemicals acceleratedsharply. On average production has doubledabout every 8 years, from one hundred millionkg to well over on hundred billion kg.Simultaneously epizootic tumours in wild fishhave increased every decade.

Early fish tumours possibly related toenvironmental carcinogens weretransplantable, epidermal papillomas onbrown bullhead, Ameiurus nebulosus, from theDeleware and Schuykill Rivers near the


industrial city of Philadelphia (Lucke andSchlumberger 1941). Papillomas were stillpresent in brown bullhead from the DelawareRiver north of Philadelphia in the 1980’s andhepatocellular neoplasms were also reported(Harshbarger and Clark ,1990).

Hans Georg Schlumberger who enthusiasticlyapplied his medical pathology knowledge andpresteige to the study of cancer in reptiles,amphibians, fish and invertebrates had a largeinfluence on comparative oncology in the mid20th century (Dawe and Walls, 1989). Hisuntimely death following an automobileaccident, and 10 years in a coma, was a greatloss to the field He described polycystickidney in goldfish, Carassius auratus(Schlumberger 1950), peripheral nerve sheathneoplasms in goldfish (Schlumberger 1952),ameloblastoma in chinook salmon,Oncorhynchus tshawytscha (Schlumbergerand Katz, 1956) and reviewed the field(Schlumberger and Lucke, 1948; Schlum-berger 1957). He was interested in all typesof pathology in all types of animals and washonored on the cover of cancer research forhis contributions to comparative pathology(Anonymous 1970).

The first evidence a herpesvirus can beoncogenic was the visualization of herpesvirusparticles (Fawcett, 1956) in epizootic, renalcarcinoma in northern leopard frog, Ranapipiens, described by Lucke (1934 a., b.).This northern leopard frog renal carcinomaalso upset the dogma that cancer isirreversible. Cancer nuclei were transplantedto activated enucleated but unfertilized ovafrom normal frogs (King and Mckinnell, 1960).Surprisingly, normal tadpoles developed. Thisshowed that the genetic components required

to form a normal embryo were still present inan adult cancer nucleus and were still able tofunction. It further showed that the cytoplasmcan have a controlling influence on geneexpression. Ramifications and extensions ofthis work have been discussed by McKinnell(1985).

White croakers, Genyonemus lineatus, at aCalifornia sewage outfall had oral papillomaswhile white croakers in relatively pristine waterwere tumour free (Russell and Kotin, 1957).The authors thought the papillomas were dueto carcinogens in the sewage effluent and thatappears to have been the case. After thesewage plant was upgraded no morepapillomas have been reported from whitecroaker near that outfall pipe.

Panzootic, primary, metastatic liver cancerwas occurring in up to 90% of 3 years oldhatchery rainbow trout, around 1960.Researchers linked the cancer to trout feedand discovered that aflatoxin, produced byAspergillus flavus growing on the feed grain,is a potent carcinogen. Papers from the 1965research conference assembled by JohnHalver and Ian Mitchell (1967) show themethods and progress in solving the problem.Knowledge that aflatoxin is carcinogenic hassaved the lives of countless humans and otheranimals. Key researchers were honoured fortheir work on the cover of Cancer Research(Anonymous, 1973). Rainbow trout have beenused extensively for testing potentialcarcinogens, promoters, inhibitors andtherapeutics as well as for studyingmechanisms of tumourigenesis.

Wilhelm Hueper (1963) made a persuasivecase for environmental carcinogenesis in an


original symposium on the epizootiology ofcancer in animals. He used photographs ofrainbow trout hepatoms and softshell clampapillomas to show that wild animal tumoursare important counterparts for experimentalstudies on hepatogenesis in laboratorymammals. He discussed and tabulated thevarious types of environmental contaminantspossibly related to tumourigenesis including:Aromatic amino-, nitro-, and azo-compounds,Coal tars and derivitives, Petroleum andderivitives, Arsenicals, Radioactive chemicals,Ultraviolet radiation, Lead, Selenium,Chlorinated hydrocarbons and otherpesticides and herbicides, Goiterogens,Hormones and others. His status at theNational Cancer Institute and thethoroughness of his presentation enhancedthe level of research interest and funding.inthis field.

C.J. Dawe, M.F. Stanton and F.J. Swartz(1964) reported that white sucker, Catostomuscommersoni, from Deep Creek Lake,Maryland, USA, heavily polluted with minewaste, motor boat exhaust, pesticides,agricultural runoff and domestic input, hadepidermal papillomas and liver neoplasms.

Mearl F. Stanton (1965) performed the firstexperimental carcinogenicity study with asmall fish and introduced the zebrafish , Daniorerio, as a test animal. Seventeen of 65 zebradaneos developed liver neoplasms in the 10-30 weeks following 8 weeks of exposure to10-100 ppm diethylnitrosamine dissolved inthe aquarium water.

Cancer transmission by bloodsuckingarthropods was demonstrated. Five of 50mosquitos, Aedes aegypta , feeding on

hamsters with a transplantable, leukemic,reticulum cells sarcoma, in a cagedexperiment, transmitted the neoplasm tohealthy recipient hampsters in 23 days.Histology and chromosome studies verifiedthe transmission (Banfield et al., 1965).

Abnormal coralites, lacking evidence of injuryor parasitism, but with developmentalsequences preserved in the skeletonsuggestive of neoplasia were described in adried specimen of Madrepora karaiensis bySquires (1965). Histology on the soft tissuesof irregular skeletal protrusions on livingelkhorn coral, Acropora palmata “revealedproliferation of gastrovascular canals andassociated calicoblastic epidermis, with lossof normal polyp structures and zooxanthellae”(Peters et al 1986). The protrusions wereinterpreted as neoplasms and diagnosed ascalicoblastic epitheliomas.

Clyde Johnson Dawe started a Registry ofTumors in Lower Animals in 1965 to facilitatecomparative oncology (Harshbarger 1969).The Registry was directed by George E.Cantwell, 1966-1967 and by John C.Harshbarger 1967-2002. Present operatorsare Marilyn Wolfe and Jeffrey Wolf. For theirrole in this work Dawe and Harshbarger werefeatured on the cover of Cancer Research(Shimkin, 1980).

S.F. Snieszko, R.F. Nigrelli and K. Wolf (1965)chaired a symposium on virus diseases inpoikilothermic vertebrates. The symposiumbrought together amphibian and fishvirologists for possible synergy. Topicscovered included long known virus diseasesof fish such as lymphocystis, more recent fishdiseases such as infectious pancreatic


necrosis and viral hemorrhagic septicemia andviral neoplasia such as the renal carcinomaof leopard frogs. The meeting reinforced theimportance of cell culture for studying virusesand of host immunity for establishingresistence.

C.J. Dawe and J.C.Harshbarger (1969)organized and edited the symposium,“Neoplasms and related disorders ofinvertebrates and lower vertebrate animals,”Amphibian tumours were not includedbecause of Mizell’s symposium that followsand reptile tumours were not included becauseno one in the world was working on them.Among highlights of the meeting the firsthematopoietic neoplasms in molluscs werereported in the eastern oyster, Crassostraevirginica (Couch, 1969) and (Farley, 1969) andepizootic mantle papillomas. in the rock oyster,Saccostrae commercialis from Australia (Wolf1969).

M. Mizell (1969) hosted a symposium on thebiology of amphibian tumors. While many ofthe presentations concerned the leopard frogrenal adenocarcinoma, Delanney and Blackler(1969) reported an interesting study of atransplantable lymphoma that had arisenspontaneously in a colony of Mexican axolotls,Ambystoma mexicanum. Tumor cells trans-planted to a limb of a normal histocompatablerecipient could grow rapidly, metastasize andkill the host. However if the leg containing theimplant was amputated before the tumour hadspread the host would survive and would neverbe susceptable to another tumour graft.Obviously a tumour specific immunity haddeveloped as a result of a non-overwhelmingshort-term exposure.

C.J. Dawe (1970) organized a Committee onComparative Oncology, under theCommission on Epidemiology of the UnionInternationale Contra Cancer (UICC), in agrass roots effort to grow the field. Theorganizational meeting was held 15-16 Oct1970 at the Fogarty Center, National Institutesof Health, Bethesda MD USA. The 12attendees (Figure 1) seated left to right: MaireMulcahy (Ireland), Clyde J. Dawe (USA-Chairman), William U. Gardner (USA -President UICC) and Gregory T. O’Conor(USA-Head, UICC Commission onEpidemiology). Standing l to r: Lionell E.Mawdesley-Thomas (England), John C.Harshbarger (USA), Bob F. Deys (TheNetherlands), Yohei Ito (Japan), Peter H. Wolf(Australia), C. Austin Farley (USA-guest ofAaron Rosenfield), Aaron Rosenfield (USA)and Edgar Lee (USA). Not present Sefton R.Wellings (USA). The 10 original Committeemembers each chose a research project andrecruited 2-3 people for his or her work group.The committee was directly active for nearlya decade and most of the work groups wereimpressively productive during that time.Some workgroup members made comparativeoncology with lower animals their life career.

The guppy, Poecilia reticulata, was introducedfor carcinogenicity testing by Khudoley (1971).Diethyl- and dimethylnitrosamine dissolved inthe aquarium water in doses of 13.3 to 100ppm induced hepatocellular adenoma,hepatocellular carcinoma and cholangioma in23 per cent of the guppies after 7-8 weeks ofexposure.

Lionel E. Mawdesley-Thomas (1972) reviewedsome tumours of fish in a 1971 symposium


he hosted and edited on diseases of fish.David Bucke assisted.

Eric R. Brown, et al., (1973) reportedneoplasms in multiple fish species from thepolluted Fox River west of Chicago comparedto almost none in the same species frompristine Canadian lakes.

Medaka, Oryzias latipes, a Southeast Asia ricepatty fish, was introduced as a useful smallfish for carcinogen bioassay by TakatoshiIshikawa et al. (1975). Liver neoplasms ofseveral histiotypes were induced in 66 % offish treated by by the addition of 15-135 ppmdiethylnitrosamine to the aquarium water for8 weeks followed a 5 week holding period.

A symposium on tumors in aquatic animalswas hosted in Ireland in 1974 by Maire F.Mulcahy (Dawe et al., 1976). Epizooticepidermal paapillomas, melanomas and atype of fibrous tumour in neotenic tigersalamanders, Ambystoma tigrinum living in atreated sewage pond on an Air Force Basewere reported by Frances Rose (1976).Subsequent metachromatic stains of thefibrous tumours combined with electronmicroscopy of similar cutaneous fibroustumours in the related neotenic axolotl,Ambystoma mexicanum demonstratedcharacteristics of mastocytomas for the firsttime in cold-blooded animals (Harshbarger etal.,1999).

The symposium in Ireland led directly to a1976 symposium on aquatic pollutants andbiological effects with emphasis on neoplasiaorganized and edited by H.F. Kraybill et al.,(1977). Informally at that meeting but moreformally later, Bruce McCain (1977) reported

liver cancer in English sole, Parophrys vetula,in a heavily polluted tributary of Puget Sound.Subsequent fish surveys and analyses at 49sites in Puget Sound and vicinity that directlyrelated liver neoplasms and precursor lesionsto polycyclic aromatic hydrocarbons in thesediment (Landahl, 1990).

Hepatocellular carcinoma was reported inAtlantic tomcod, Microgadus tomcod, from theHudson River, NY heavily polluted by PCB’sand PAH’s (Smith et al .,1979).

In 1979 Baumann found brown bullhead, A.nebulosus, with squamous cell carcinoma,hepatocellular carcinoma and cholangio-carcinoma at a coking plant outfall in the BalckRiver Ohio (Baumann et al., 1982;Harshbarger et al., 1984). Long term studieshave shown a direct correlation of liver cancerwith polynuclear hydrocarbons in the sediment(Baumann and Harshbarger, 1998). Thecoking plant was closed in 1982. By 1987polynuclear aromatic hydrocarbons in thesediment had plummeted, liver cancer inbrown bullheads had dropped 75% and lifespan of the fish had increased two years. Thiswas the first study using fish cancer as an endpoint that confirmed that remediation canoccur naturally when the source ofcontamination is eliminated (Baumann andHarsbarger, 1995).

The Princess Takamatsu Cancer ResearchFund, Tokyo, sponsored the symposium,Phyletic approaches to cancer (Dawe et al.,1981). One highlight of the meeting wasconfirmation that the problematic X-cell lesionknown since the 1920’s and prevalent in manyfish genera is parasitic rather than neoplastic(Dawe, 1981). While X-cell lesions super-


ficially resemble cutaneous papillomas orpseudobranch adenomas, the principal celldoes not look or behave like any known fishcell, hence X-cell. By tissue imprints, histology,cytochemistry and electron microscopy it wasshown that unlike fish cells, X-cells havemultiple, minute, synchorously dividing nucleicontaining much less DNA than fish cell nuclei.The quantity of DNA is consistent with someunicellular organisms. The X-cells were shownto be strikingly similar in appearance and lifecycle to amebae in the familyHartmonellidae.which form multinucleateplasmodia and displays synchronus mitoses.X-cells are enveloped by fish epithelial cells,which protect them from the immune reaction.

A rapidly growing, invasive neuroblastomawith tripolar mitotic figures was reported in atrematode, Otodistomum plunketi from a shark(Harshbarger and Gibson, 1982). This is themost clear cut case of cancer in an animalthis primitive. The case was thoroughlyreviewed by Sparks (1985) along with tumorsand tumorlike lesions in Coral, Planaria,Annelid worms, Sipunculids, Shrimp, Snails,Bivalve mollusks and Echinoderms.

Liver cancer was reported in sauger,Stizostedion canadense and walleye, S.vitreum, from Torch Lake MI contaminated bycopper mine tailings and chemicals used toextract copper (Black et al., 1982).

Six species of fish from the Niagara River, NYhad neoplasms of skin, liver and/or peripheralnerve origin (Black, 1983).

Hematopoietic neoplasia first discovered in thecommon cockle, Cerastoderma edule , inIreland (Twomey and Mulcahy, 1984) has

been transmitted by cell free extractsconsistent with a viral etiology (Collins andMulcahy, 2003).

A CNN TV series of reports on fish cancer inpolluted waterways including Torch Lake MI,Black River OH, Hudson River NY and PugetSound WA in 1982-1983 generated a hugeunexpected global response. The responseincluded a hearing by the US Congress onthe causes of reported epidemics of cancerin fish and the relationship between theseoccurrences and environmental quality andhuman health. John C. Harshbarger (1984)gave the lead testimony.

K. Hoover (1984) organized and edited a 1982symposium on the use of small fish incarcinogenicity testing that evaluated over adozen species including, top minnows,Poeciliopsis lucida and P. monacha, rivulus,Rivulus marmaratus, medaka, Oryzias latipes,Amazon molly, Poecilia formosa, zebra danio,Danio rerio, guppy, Poecilia reticulata,sheepshead minnow, Cyprinodon variegatus,mummichog, Fundulus heteroclitus, gulfkillifish, F. grandus, central mudminnow,Umbra limi and eastern mudminnow, U.pygmaea , , fathead minnow, Pimephalespromelas, Xiphophorus sp. rainbow trout,Oncorhynchus mykiss, and nibe croaker,Nibea mitsukurii. Data were summarized in aconsensus report (Couch et al., 1984).

Nifurpirinol is the second chemical found tobe carcinogenic by fish (nibe croaker)bioassay, the first being aflatoxin, (Ikuo Kimuraet al., 1984).

The discovery of epizootic liver cancer inWinter flounder, Pleuronectes americanus,


from the Deer Island sewage outfall in BostonHarbor (Murchelano and Wolke, 1985) led toa major upgrade of sewage treatment resultingin disappearance of winter flounder livercancer.

Skin painting of extracts of sediment fromBlack River OH and Buffalo River NYproduced cancer at that location on brownbullheads and mice (Black, 1983, Black etal.1985). Thus the epzootiologic associationof neoplasms with contaminated sediment wasexperimentally verified in fish and mammals.

Cellular (myc) oncogene was isolated inrainbow trout, O. mykiss (Van Beneden et al.,1986).

The homology between the ras gene clonedfrom goldfish liver and human ras was reportedto be 96% for k-ras, 87% for h-ras and 88%for N-ras (Nemoto et al., 1986).

Neurofibromatosis in the bicolor damselfish,Stegastes partitus, from the Florida reefs wassuggested as a model for von Recklinghausenneurofibromatosis in humans (Schmale et al.,1986). Schmale et al., (2002) believes anunusual virus is the etiologic agent.

Bowfin, Amia calva, liver cancer was reportedand reconfirmed from the Detroit River(Maccubbin et al., 1987, Maccubbin andErsing, 1991).

Liver neoplasms were reported inChesapeake Bay white perch, Moroneamericana (May et al., 1987).

Brown bullhead liver cancer was reported inthe Cuyahoga River, Cleveland, Ohio(Baumann and Mac, 1988). This is the riverthat was once so polluted it caught on fire.

Oral papillomas and liver neoplasms in whitesucker reported from polluted sites on LakeOntario. (Smith and Zajdlik, 1987; Cairns andFitzsimons, 1988). Extracts of thecontaminated sediments injected into rainbowtrout, Oncorhynchus mykiss ova, induced livercancer (Metcalfe et al., 1988).

Oyster toadfish developed pancreas and liverneoplasms in the York River Virginia near apetroleum refinery (Thiyagarajah and Bender,1988).

Mummichog liver cancer was highly prevalentadjacent to an old creosote plant in theElizabeth River, Virginia (Vogelbein et al.,1990).

Is it safe to eat fish from contaminatedenvironments? To address this commonquestion, Dawe and Stegeman (1991) held asymposium on chemically contaminatedaquatic food resources and human cancerrisk. A key suggestion by attendees to feedfish from contaminated waterways to rodentsusing the standard rodent bioassay protocolwas unacceptable to bioassay personnel.

However, the hypothesis that chemicalcarcinogens move up the food chain wasconfirmed by the experimental trophic transferof carcinogens to winter flounder fed bluemussels contaminated with carcinogencontaining sediment from the Central LongIsland Sound dump (Gardner et al., 1991).

Striated muscle develops in nephroblastomain Japanese eels, Anguilla japonica (PrinceMasahito et al. 1992) which is similar to Wilms’tumour in humans. Striated muscle alsodevelops in nephroblastoma of American eel,Anguilla rostrata, but in no other fish genera


or nephroblastoms of any non-humanmammalian species. This suggests that eelsmight be the most useful surrogates to studyWilms’ tumor.

Further, the Wilms’ tumor gene, wt, is highlyconserved in the Japanese eel (Nakatsuru etal., 1992).

The Prince Hitachi Prize for ComparativeOncology was established in 1996 by TheJapanese Foundation for Cancer Research inhonour of HIH Prince Masahito Hitachi whohas published extensively on cancer in loweranimals, especially fish and amphibians.Recipients of the Prince Hitachi prize haveincluded John C. Harshbarger, Fritz Anders,Robert G. McKinnell, Elisabeth Gateff, ShozoTakayama, Takatoshi Ishikawa, MakotoAsashima, George S. Bailey and Jerry D.Hendricks

Rossi, et al. (1997) organized and edited thefirst world congress on spontaneous animaltumors: a survey.

Nearly 5% of lake whitefish, Coregonusclupeaformis, from the St Lawrence River nearQuebec had liver cancer (Mikaelian et al.,1998). This was the first epizootic liver cancerreported in wild salmonids even thoughhatchery rainbow trout have long been knownto be susceptible to dietary hepatocarcinogensand liver cancer has been experimentallyinduced in several salmon species.

Consistent with many other contaminatedsites, epidermal papilloma of white sucker,Catostomus commersoni was also reportedfrom the St Lawrence River (Mikaelian et al.,2000).

The first suprasellar germinomas originatingin fish were reported in three lake whitefish,Coregonus clupeaformis (Mikaelian et al.,2000).

Brown bullhead, Ameiurus nebulosus, haveliver and skin cancer closely correlated withcarcinogenic polynuclear aromatichydrocarbons in the sediment from severallocations in the Potomac and Anacostia Riversystem in the Washington D.C., Virginia andMaryland area (Pinkney et al., 2001).

The 2nd edition of the BSAVA (British SmallAnimal Veterinary Association) Manuel ofOrnamental fish, edited by William W.Wildgoose included an illustrated chapter, onneoplasia and developmental anomalies(Harshbarger, 2001).

ConclusionsFish amphibians and invertebrates have had,and should continue to have, an important rolein oncology. In fish, for example, neoplasmshave been reported in several hundred diversespecies. All organ systems and many celltypes are represented. The same classes ofcarcinogenic chemicals and families ofoncogenic viruses active in mammals andbirds have caused fish tumours. At least somehuman oncogenes are present in fish with ahigh level of homology. Due to the diversity offish, some fish tumours might make idealsurrogates for the study of a mammaliantumour counterpart.

A score of fish species have been evaluatedfor chemical testing covering the gamut fromlarge to tiny, oviparous to viviparous togynogenetic, cold water to tropical andfreshwater to brackish by a variety of


procedures. These different characteristicsallow test procedures to be optimizedregarding route of exposure, formulation,dose, endpoint and period of post exposure.Fish bioassay is useful to evaluate thecarcinogenic potential of chemicals incommon usage. It is also useful to evaluatemixtures of chemicals discharged into theenvironment such as oxygen scavengers andnitrosamines from nuclear power plants,

aromatic hydrocarbons from industrial effluentpipes, pesticides, drugs and cosmetics frommunicipal sewers and solvent extracts ofsmoke filters on or near smoke stacks.

Some wild fish, especially bottom feeders, areexcellent sentinels for environmentalcarcinogens. Liver cancer rates in somebottom feeding wild fish are high in the USAwhere human cancer rates are also high.

COMMITTEE ON COMPARATIVE ONCOLOGY – COMMISSION ON EPIDEMIOLOGY, UICC, Bethesda,Md. October 15-16, 1970

Back row (l to r): Dr. Lionel Mawdesley-Thomas, Dr. John C. Harshbarger, Dr. Bob F. Deys, Dr. Yohei Ito, Mr..Peter H. Wolf, Mr. Austin Farley, Dr. Aaron Rosenfield, Dr. L. Edgar Lee.Front row (l to r): Dr. Maire F. Mulcahy, Dr. Clyde J. Dawe, Dr. William U. Gardner, Dr. Gregory T. O’Conor.


Epizootic neoplasms discovered in wild fishhave increased dramatically from less than 10in 1960 to over 200 today. This is partly dueto an increased awareness and more surveysbut it coincides closely with the increase inproduction of synthetic organic hydrocarbons,which has increased almost geometricallysince World War II. Liver is the primary organfor metabolizing indirect acting carcinogensand therefore liver cancer is most stronglyrelated to carcinogen exposure in pollutedenvironment as well as in experimentalstudies. The next organ of importance is skin.

Finally, fish , amphibians and invertebrates arevaluable human resources for food, medicine,science, agriculture, recreation andcompanionship. They merit protection fromneoplasms, developmental anomalies andinfectious diseases.

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