C o n t r i b u t i o n h 1 ' 6 t u d e d u c a n c e r d e I ' i n t e s t i n c h e z I ' a n i m a l S e s r e l a t i o n s a v e c la p a t h o l o g i e h u m a i n e
Contribution to the study of intestinal cancer in animal. Its relationship with human pathology
A. V I C A R I *, A. D U P R E Z **, F. V I C A R I ***
Lyon, Nancy (France)
Un cancer qui fait chaque ann6e 50 000 morts aux Etats-Unis, plus de 15 000 en France justifie pleinement t o u t l'int6r6t que lui portent, ~ l'heure actuelle, les services de Sant6 Publique dans les pays occidentaux.
Sa pr6vention et son d6pistage passent par la d6tection des polypes que l'on peut ais6ment enle- ver.
C e p e n d a n t , l'6tiologie de ce cancer est encore tr~s peu c o n n u e et les hypoth6ses avanc6es sont tr~s nombreuses.
L'observation de cancers similaires chez l'ani- mal, et surtout l'6tude exp6rimentale animale des produits canc6rig6nes et des tumeurs qu'ils indui- sent p e r m e t t r o n t ainsi de mieux connaitre ce fl6au et peut-6tre de l'endiguer.
I. L E S C A N C E R S I N T E S T I N A U X D A N S L E C A D R E
D E L A C L I E N T t ~ L E VI~TI~RINAIRE, C A N C E R S SPONTANt~S
A . L e s a n i m a u x d e r e n t e : b o v i n s - o v i n s - p o r c i n s
C'est surtout le cancer de l'intestin gr~le des ruminants qui parait le plus interessant ~ 6tudier et ce pour plusieurs raisons :
C e - c a n c e r , assez rare dans l'ensemble, touche dans une p r o p o r t i o n importante les m o u t o n s de certains pays (Islande : 0,97 % [3], Nouvelle Z61ande 1,6 % des animaux glg6s [1].
Or, la plus grande proportion de cancers colo- rectaux h u m a i n s est observ6e en Nouvelle Z61ande [1] oil bovins et ovins f o r m e n t les deux grandes esp~ces alimentaires.
* Ecole V6t6rinaire de Lyon.
** Service d'Anatomo-pathologie C.H.U. Nancy.
*** G.R.P.D.N. Nancy.
Travail soutenu par une bourse du G . R . P . D . N .
D ' a u t r e part, il faut retenir que du fait de leur physiologic digestive, la population microbienne est pr6dominante [1] dans le rumen et l'intestin gr61e chez les ruminants, plut6t dans le gros intes- tin chez l ' h o m m e .
C'est donc le cancer de l'intestin gr61e des rumi- nants qui pr6sente le plus d'analogies avec le can- cer colo-rectal humain.
C o m m e processus d'induction du cancer, les auteurs [1] ont pens6 ~ l'activation microbienne de substances canc6rig6nes, ce qui semblerait 6tre aussi le cas des cancers humains, du moins en partie.
D ' a u t r e s 6tudes ont r6v616 :
Le caract6re pr6-canc6rig6ne des nitrosamines pr6sentes dans certains aliments concentr6s c o m m e la farine de poissons [3].
Le caract~re canc6rig~ne de substances natu- relies. On sait en effet depuis longtemps que la consommation de la foug6re grand-aigle (pteris aquilina) est h l'origine de tumeurs b6nignes ou malignes, parfois colo-rectales, chez le b6tail [4, 19] : tumeurs de la vessie des bovins, de l'intestin et de la vessie des moutons.
L a pr6sence de parasites associ6s aux polypes colo-rectaux [5]. Mais il semblerait que le parasite trouve dans le polype un site de multiplication id6al et n'induise en aucun cas la formation du polype, donc potentiellement celle d ' u n e t u m e u r maligne.
L ' 6 t u d e des cancers de l'intestin chez les animaux de rente est encore tr6s superficielle. Elle nous permet c e p e n d a n t de rapprocher les cancers de l'intestin gr61e chez les ruminants et les cancers colo-rectaux humains, ce qui prouverait le r61e de la flore bact6rienne associ6e ~ des substances ali- mentaires pr6-canc6rig6nes dans l'6tiologie de ces cancers.
Tir6s ~t p a r t : F. V I C A R I , 127, rue Saint-Dizier, 54000
Nancy (France). M o t s - c l d s : cancer colorectal.
K e y - w o r d s : colorectal cancer.
A c t a E n d o s c o p i c a V o l u m e 1 7 N ~ 2 - 1 9 8 7 67
B. Les a n i m a u x familiers
La seule esp~ce v6ritablement 6tudi6e en clien- tele est le chien.
Le chien d6veloppe rarement des polypes colo- rectaux, on fait surtout mention de cas isol6s, touchant pr6f6rentiellement les races Collie et Airedale [6, 7]. Dans la plupart des cas, ces polypes sont b6nins [8, 9, 10], mais on les enl~ve car ils entrainent souvent une coprostase [9].
Les symptomes les plus communs de ces polypes canins sont des selles liquides contenant du sang, comme pour les polypes humains, mais ce n'est pas toujours le cas [6].
L'observation comparative de nombreux cas a permis d'6tablir une classification histopatologique de ces polypes [7]:
- Polype hyperplasique - Ad6nome papillaire - Ad6nome tubulaire - Autres.
Les cas de polypes canc6reux chez le chien sont encore plus rares [11].
Parfois, les polypes canins de plus d'un centim6- tre de diam~tre d6g6n~rent en tumeur maligne. Ce sont les ad6nomes papillo-tubulaires qui r6v~lent des atypies 6pith61iales comme des carcinomes. Le passage du polype b6nin h l'ad6nocarcinome est bien connu chez l'animal et certains auteurs pro- posent des classifications parall61es h celle de I'O.M.S. [12].
Des observations comportant des m6tastases ganglionnaires, pulmonaires, h6patiques, et m6me de la paroi intestinale ~ partir de polypes ont 6t6 d6crites [12].
On connait peu de choses sur l'6tiologie des polypes et cancers colorectaux chez le chien. On sait que le chien les d6veloppe beaucoup moins fr6quemment que l'homme dans les pays occiden- taux industrialis6s malgr6 un r6gime alimentaire assez proche. On a pens6 [7] que le chien, vivant beaucoup moins longtemps que l'homme, serait, par cons6quent, soumis moins longtemps ~t d'6ven- tuelles substances canc6rig~nes alimentaires, mais cette hypoth~se reste bien discutable car elle sup- pose d'une part que le cancer est d'origine alimen- taire, ce qui est soup~onn6, mais non prouv6, et d'autre part, l'existence d'une sorte de processus accumulatif, ce qui ne rendrait pas compte des cancers chez le jeune.
En ce qui concerne les polypes et cancers colo- rectaux du chien, par cons6quent, leur 6tude n'a 6t6 jusqu'~ pr6sent que tr~s descriptive en clien- t61e v6t6rinaire. C'est parce qu'elle cherche surtout 6tablir une classification histopathologique des tumeurs et des techniques chirurgicales d'ex6r~se.
Des 6tudes 6tiologiques plus approfondies sont souhait6es mais restent peu concevables actuelle- ment car il s'agit d'une pathologie canine peu r6pandue et dont la th6rapeutique s'av~rerait cofi- teuse.
II. LES C A N C E R S C O L O - R E C T A U X ET L'EXPI~RIMENTATION A N I M A L E A. Le mod/fle a n i m a l d ' e x p ~ r i m e n t a t i o n
Le petit rongeur (rat, souris, hamster) est l'ani- real de choix pour l'exp6rimentation parce qu'il est 6conomique, se reproduit rapidement et s'61~ve facilement en populations nombreuses qui permet- tent des 6valuations statistiques. Les r6sultats sont alors comparables d'une exp6rience ~t l'autre.
D'autre part, ces rongeurs pr6sentent tr~s rare- ment des cancers spontan6s du colon [13], mais les cancers induits par certains porduits chimiques, comme la 1,2 dimethylydrazine (D.M.H.) sont semblables aux tumeurs colo-rectales spontan6es chez l'homme.
Grace h l'utilisation de substances carcinog6nes ou h l'observation de l'effet de tel ou tel facteur du milieu (conditions du milieu, bact6ries, virus), le mod61e animal permet d'6tudier l'6volution du cancer depuis la modification initiale de I'ADN de la cellule 6pith61iale jusqu'au d6veloppement d'un ad6nocarcinome envahissant. Grglce ~ de nom- breuses exp6rimentations, on parvient actuellement connaitre les modifications pr6coces du m6tabo- lisme cellulaire, ce qui permettrait d'6tablir un test de diagnostic ~ ce stade et des th6rapeutiques plus pr6cises. Les animaux de laboratoire sont la voie obligatoire entre la d6couverte de techniques th6- rapeutiques nouvelles (immunoth6rapie, chimioth6- rapie, etc...) et leur application au cancer humain.
B. Les substances canc~rig/~nes utilis~es
c h e z l'animal et le m ~ c a n i s m e de ia canc~rog~n/~se exp~rimentale.
1) L e s s u b s t a n c e s c a n c ~ r i g d n e s
Elles peuvent induire des cancers du colon, mais aussi d'autres organes : rein, foie, conduit auditif [13,14].
On les a class6es en cinq families [13]
* Chloranth6nes
~ C H 2 m e t h y l c h l o r a n t h 6 n e Leur structure est similaire ~ celle des sels biliaires et du cholest6rol. Ils peuvent ~tre pro- duits par le m6tabolisme st6roidien de la flore intestinale.
* Amines aromatiques
C H 3 CH3
~
NH22',3 dimethyl-4-aminobiphenyl
68 Volume 17 - N ~ 2 - 1987 Acta Endoscopica
Ces compos6s sont secr6t6s activement dans la bile et se retrouvent ainsi au niveau des cellules cibles.
* D6riv6s de l'hydrazine
CH3 - NH - NH - CH3
1,2 dimethyl hydrazine Laqueur, en 1963, a isol6 la cycasine, canc6ri- g~ne de la plante cycas circinalis (iles de Guam).
I1 s'agit d'un glucoside hydrosoluble de m6thyl oxymethanol [13].
Druckey's, en 1967, a d6couvert que la 1,2 D M H 6tait tr~s proche de la cycasine [13]. La D M H est la substance canc6rig~ne le plus efficace et la plus sp6cifique pour le colon.
L'activation m6tabolique de ces compos6s donne un agent d'alkylation (le methydizonium) capable d'engendrer un ion carbonium tr~s r6actif, m6thy- lant prot6ines et acides nucl6iques.
* Alkylnitrosamides
/ CHz
N ~ ' N O
N methyl - N'nitro - N nitrosoguanidine = MNNG
La M.N.N.G. provoque l'apparition de polypes ad6nomateux et de cancers dans le colon distal, on l'administre par installation intra-rectale.
* Autres
I1 faut citer l'aflatoxine, m6tabolite du champi- gnon Aspergillus flavus. I1 induit des tumeurs du colon, en faible nombre, chez des rats d6ficients en vitamine A.
o o
Aflatoxine B 1 On a aussi beaucoup 6tudi6 les effets des extraits de la foug~re grand-aigle (Pteris aquilina), sans isoler la substance canc6rig~ne. Les effets cancerig~nes de cette foug~re sont bien connus en pathologie bovine, ils sont associ6s au syndr6me du pt6ridisme [4].
2) L a p a t h o g d n i e d ' u n e s u b s t a n c e canc~rigdne m a j e u r e : la D . M . H .
* - Le mode d'action
Des exp6riences [13] ont montr6 que la D . M . H . et ses m6tabolites peuvent 6tre transport6s jus-
qu'aux cellules 6pith61iales du colon par la circula- tion sanguine; la majorit6 de ses m6tabolites est excr6t6e par le rein et le poumon.
I1 n'y a donc pas n6cessit6 de secr6tion biliaire pour que la D.M.H. induise des tumeurs. Son action n'est pas luminale. In situ, par m6thylation de I'A.D.N., la D.M.H. va modifier le g6nome et donc le ph6notype des cellules cibles, c'est l'6tape clef de la canc6rog6n~se reconnue universelle- ment : un effet direct au niveau des g6nes. I1 y a alors d6diff6renciation, prolif6ration anormale, envahissement.
Les auteurs [13] remarquent que les tumeurs du colon induites par la D . M . H . ont une incidence plus grande que les tumeurs du foie ou du rein, bien que les modifications du g6nome soient les m6mes. Cette diff6rence semble due au "turnover"
plus rapide des cellules 6pith61iales de la muqueuses. D'autres exp6riences montrent qu'en outre les cellules du colon seraient plus r6ceptives
la D.M.H. que celles du foie ou du rein.
* Les tumeurs induites
Leur nature d6pend du protocole exp6rimental : mode d'administration, fr6quence des doses, voie d'administration, hge de l'animal, 6tat physiologi- que (gestation), sexe (les femelles sont moins sen- sibles que les mfiles).
On peut noter que, contrairement aux carci- nomes, les ad6nomes peuvent atteindre une grande taille sans devenir malins [13].
Or chez l'homme, la plupart des cancers du colon r6sulte de la d6g6n6rescence d'ad6nomes b6nins au d6part.
Autre comparaison significative entre l'homme et l'animal [13] : ~ haute dose de D . M . H . , c'est le cancer du colon gauche qui pr6domine, alors qu'~t faible dose c'est celui du colon droit. Chez l'homme, dans les zones h forte incidence de can- cer, c'est celui du colon gauche qui pr6domine, alors que c'est celui du colon droit dans les zones
faible incidence.
L'utilisation de l'animal de laboratoire et la d6couverte de substances canc6rig~nes efficaces et sp6cifiques ont donc permis de mettre en place des protocoles exp6rimentaux complexes et subs- tantiels. Ces exp6riences ont d6j~ beaucoup fait progresser la connaissance du cancer colo-rectal, nous verrons h pr6sent quelques r6sultats fonda- mentaux.
C . Q u e l q u e s r 6 s u l t a t s d e s 6 t u d e s e x p 6 r i m e n t a l e s s u r les c a n c e r s c o l o - r e c t a u x .
1) I m m u n i t ~ et t u m e u r s
La majorit6 des 6tudes cit6es [13], montrent que les propri6t6s antig6niques du cancer du colon, ainsi que les d6fenses immunitaires de l'h6te diri- g6es contre ces tumeurs sont tr6s semblables chez l'homme et l'animal.
Acta Endoscopica Volume 17 N" 2 - 1987 69
On a pu p r o u v e r que les antigOnes du colon chez le rat sont capables d'induire une rOponse immunitaire protectrice.
Mais ceci ne p r o u v e pas q u ' u n e m a n i p u l a t i o n du syst~me i m m u n i t a i r e pourrait protOger c o n t r e le dOveloppement du cancer ou ~tre bOnOfique ~ un animal dOjh cancOreux.
On sait aussi que le B . C . G . , i m m u n o s t i m u l a n t non spOcifique, est un agent anti-tumoral, mais il s'est av6r6 sans effet sur les cancers expOrimentaux
la D . M . H . [13]
2) Le facteur gOnOtique
On connait bien le facteur de p o l y p o s e familiale humaine. Le ph6nomOne de r6sistance & tel ou tel canc6rig~ne p o u r r a i t 6tre transmis c o m m e un fac- teur a u t o s o m a l d o m i n a n t , c o m m e l'est la transmis- sion des polyposes. L e mOcanisme de la r6sistance pourrait 6tre soit l'absence d ' u n e n z y m e requis p o u r l'activation m6tabolique d'un procancOrigOne ( D . M . H . ) , soit la r6sistance sp6cifique de la m u q u e u s e au cancOrigOne [13].
C o m m e l'a m o n t r 6 l'6tude du mOcanisme d'action de la D . M . H . , on sait que le point d'induction du c a n c e r est une modification gOnique par plusieurs facteurs d6clenchants, ici la D . M . H . .
Ainsi, une des d6couvertes les plus i m p o r t a n t e s prOsentOe au CongrOs de la M a r t i n i q u e , dObut 1986, est l'existence d'oncog~nes endogOnes ou exogOnes (virus) d o n t l'expression serait ~ l'origine des modifications cancOreuses: on les appelle gOnes du cancer.
3) Effet d'une substance iatrogOne sur les cancers expOrimentaux : la Warfarine
La warfarine est c o n n u e p o u r ses effet anti- coagulants, mais elle rdduit aussi chez le rat le n o m b r e des cancers colo-rectaux induits par l ' a z o x y m e t h a n e [15].
Les auteurs m o n t r e n t qu'il n'y a pas de relation entre Faction anti-coagulante et l'action anti-tumo- rale, la dose n ' a y a n t aucune incidence sur la rOduction des t u m e u r s [15].
La w a r f a r i n e n'a pas non plus d ' e f f e t global sur la prolifOration cellulaire, mais une action sur 'TunitO" adOnocarcinome au stade de la transfor- mation maligne o u avant. C o m m e le n o m b r e de micro-adOnomes diminue avec la w a r f a r i n e , elle agit au stade prd-adOnomateux. L ' e f f e t spOcifique de la warfarine est la prOvention de modifications nOoplasiques dans des cellules qui ont subi les c h a n g e m e n t s fonctionnels m o r p h o l o g i q u e m e n t indOtectables des p r e m i e r s stades de la cancOrogO- n~se, les auteurs p e n s e n t , mais n ' o n t pu le dOmon- trer, que son action est cytotoxique.
4) ROle du p H focal
On sait q u e les populations humaines ~ selles de p H alcalin ont un plus grand risque de c a n c e r du colon que les autres. Cette o b s e r v a t i o n a a m e n 6
des expOriences de variation du p H dans le c a d r e de la canc6rog6nOse expOrimentale [16]. O n utilise du lactulose et du sulfate de sodium p o u r acidifier le contenu colique et les selles. Les rOsultats con- firment le role p r o t e c t e u r d ' u n p H acide dans le cancOrogOn~se ~ la D . M . H . . Ces rOsultats ont 6t6 rapprochOs du g r a n d risque de cancer du colon associ6 h une faible c o n s o m m a t i o n de fibres vOtgO- tales et une f o r t e c o n s o m m a t i o n de graisse et de protOines animales.
Les deux substances choisies acidifient le colon d ' u n e maniOre tr~s diffOrente, mais le lactulose fait intervenir la p o p u l a t i o n microbienne. O n ne con- nait pas e n c o r e le mOcanisme de "protection", mais on 6met l'hypotOse d ' u n e relation e n t r e l'appari- tion des t u m e u r s et une modification des sels biliaires par des e n z y m e s bactOriens dans un envi- r o n n e m e n t ofa le p H j o u e r a i t un grand r61e.
5) ROle des bactOries et des virus dans l'Otiologie du cancer colo-rectal chez l'animal
I1 ne s'agit pas ici s e u l e m e n t d'expOrimentations mais aussi d ' o b s e r v a t i o n s fortuites, parfois sur un grand n o m b r e d ' a n i m a u x .
Bact~ries
Nous avons dOj~ vu ~ plusieurs reprises le role suppos6 de la flore b a c t 6 r i e n n e et de ses e n z y m e s dans la t r a n s f o r m a t i o n de processus procarcino- gOnes alimentaires o u biliaires. Plus le r6gime c o m p o r t e de graisses animales et aussi de pro- t6ines, plus le risque de cancer du colon aug- mente. On a m o n t r 6 [13] que la c o n s o m m a t i o n de graisse a u g m e n t a i t la p r o d u c t i o n de bile, modifiOe par la flore colique en acides biliaires secondaires et en stOrols ( c o p r o s t a n a n e et coprostanol), eux mOmes m6tabolisOs p a r la flore (surtout clostridia species qui m6tabolise le n o y a u st6roidien) en sub- stances canc6rigOnes, c o m m e les p h 6 n a n t r ~ n e s [13].
D ' a u t r e part, u n e n o u r r i t u r e riche en protOines animales a u g m e n t e r a i t le taux focal d ' e n z y m e s bac- tOriens : nitrorOductase, azorOductase bOta-glucuro- nidase. Ces e n z y m e s p o u r r a i e n t synthOtiser des carcinog~nes e n d o g ~ n e s en rOduisant les composOs azotOs en amines a r o m a t i q u e s [13].
On a aussi c h e r c h 6 & modifier la flore bactO- rienne p o u r m i e u x c e r n e r son r61e lors de la canc6rogOnOse. P a r e x e m p l e , la D . M . H . induit des tumeurs du c o n d u i t auditif, du rein et de l'intestin chez des rats n o r m a u x . Chez des rats "germ-flee", on ne r e t r o u v e q u e 20 % de cancers du colon (contre 93 % ) et ce sont les seules t u m e u r s qui apparaissent [14]. Ceci est ~ r a p p r o c h e r de l'utili- sation d ' a n t i b i o t i q u e s dans la cancOrogOnOse h la D . M . H . [17] qui dOprimant la flore intestinale, limite aussi les cas d e t u m e u r s . E n r e v a n c h e , si on utilise l'azoxymOthane, p a r instillation intra-rectale, c'est chez les rats "germ-free" ou moins contaminOs (par clostridium p e r f r i n g e n s ) que les auteurs trou-
70 V o l u m e 1 7 - N ~ 2 - 1 9 8 7 A c t a E n d o s c o p i c a
v e n t le plus de cancers du c o l o n [14]. Cette diff6- r e n c e reste e n c o r e inexpliqu6e, mais il est impor- tant de r e m a r q u e r q u e c o n t r a i r e m e n t ~ la D . M . H . , l'action de l ' a z o x y m 6 t h a n e est intra-lumi- nale.
A c6t6 de la canc6rog6n~se exp6rimentale, on a pu aussi n o t e r la pr6sence de bact6ries dans des modifications hyperplasiques o u dysplasiques de l'intestin chez le rat, le p o r c , l'agneau, le hamster, le furet et le cheval [18]. Plus pr6cis6ment, les a d 6 n o m e s 6taient associ6s fa des bact6ries de type C a m p y l o b a c t e r . O n a p u 6tudier 17 cas chez le rat, apparus en 17 ans au cours d'6tudes de toxi- cit6 [18]. Les 16sions o b t e n u e s sont d6crites c o m m e des a d 6 n o c a r c i n o m e s , car les modifications du colon sont n6oplasiques. U n e situation similaire semble exister chez l ' h o m m e . O n observait plu- sieurs types de 16sions colo-rectales, mais t o u s l e s rats pr6sentaient une i n f l a m m a t i o n des ganglions lympathiques locaux. O n a r e t r o u v 6 des bact6ries c a m p y l o b a c t e r - l i k e dans les d6bris celluaires de la lumi6re (leucocytes, cellules 6pith61iales d6g6n6- r6es) et au p61e apical des cellules normales, dans les couches sub-6pith61iales, dans les m6tastases, dans les foyers d'invasion, dans la cellule surtout proximit6 des c h r o m o s o m e s .
C e t t e derni/~re o b s e r v a t i o n pourrait m o n t r e r l'interaction de la bact6rie avec le mat6riel g6n6ti- q u e de la cellule, on sait q u ' u n e modification g6n6tique est h l'origine de la cellule canc6reuse ; ceci expliquerait aussi l'6tiologie virale possible des cancers colo-rectaux.
Les virus
P o u r des raisons t e c h n i q u e s , les interactions e n t r e virus et c a n c e r ont 6t6 peu 6tudi6es chez l'animal. C e p e n d a n t , des 6tudes ont montr6 une interaction possible e n t r e un carcinog~ne alimen- taire -de la foug6re aigle- un virus papilloma et la cellule isol6e [19]. F a u t e de p o u v o i r r6aliser une e x p 6 r i m e n t a t i o n sur le b6tail, cette 6tude s'est c a n t o n n 6 e h une o b s e r v a t i o n minutieuse et d6tail- 16e.
A u d6part, on a constat6 u n e localisation pr6- cise du cancer du t u b e digestif sup6rieur, li6e ~ la r6partition de la foug6re aigle q u ' o n sait contenir un canc6rig~ne p o u r le t u b e digestif (exp6riences chez le rat, la souris et le c o b a y e [19]). Par ailleurs, on a r e t r o u v 6 des virus papilloma au niveau des tumeurs.
C e t t e o b s e r v a t i o n ne c o n c e r n e pas l e cancer colo-rectal, mais nous interesse parce que la fou- g~re grand aigle est canc6rig~ne p o u r le colon de l'animal de l a b o r a t o i r e et p a r c e qu'elle o u v r e la voie de la r e c h e r c h e actuelle.
E n effet, grglce aux progr~s de la biochimie mol6culaire, surtout dans le d o m a i n e des virus oncog6nes, on est arriv6 h p r o u v e r dans certains cas (par e x e m p l e le c a n c e r du col ut6rin) une origine virale h la t u m e u r , en r e t r o u v a n t le mat6-
riel g6n6tique viral associ6 ~ celui de la cellule tumorale. Esp6rons que des d 6 c o u v e r t e s sembla- bles p o u r r o n t 6tre faites au niveau du cancer colo- rectal.
Mais h ce niveau de la r e c h e r c h e , l'exp6rimenta- tion animale c~de le pas aux cultures cellulaires, plus aptes ~ m o n t r e r les m6canismes intimes de l'induction du cancer.
D I S C U S S I O N
Dans cette masse d ' i n f o r m a t i o n , q u e l q u e peu disparate, force est de constater q u e l'6tat actuel des r e c h e r c h e s en pathologie animale n ' a p p o r t e que p e u d'6claircissements mais e n c o u r a g e plut6t les o r i e n t a t i o n s choisies en m 6 d e c i n e humaine.
A u j o u r d ' h u i , on peut envisager c o m m e causes du c a n c e r colorectal humain [20] :
- une sensibilit6 individuelle g6n6tique
- l'ingestion de substances canc6rig6nes
- l'ingestion de substances n o n canc6rig~nes mais qui p e u v e n t le d e v e n i r sous l'action d ' e n z y m e s bact6riens ou d ' a u t r e s r6actions chimi- ques dans l'organisme
- des substances physiologiques c o m m e les st6- roides biliaires qui seraient transform6s en sub- stances canc6rig6nes par des r6actions du m6me type
- l ' i n t e r v e n t i o n de microorganismes, bact6ries ou virus
tous ces facteurs soulignent l ' i m p o r t a n c e du r6gime et des habitudes a l i m e n t a i r e s ; ils sont aussi modul6s par des p a r a m 6 t r e s " e n v i r o n n e m e n - taux" tels que le p H , la vitesse de transit digestif...
P o u r ce qui est de l'aspect g6n6tique, les cas de cancers animaux spontan6s sont t r o p sporadiques p o u r t e n t e r une 6tude sur le terrain ; seule I'exp6- r i m e n t a t i o n p o u r r a a p p o r t e r des renseignements.
E n ce qui c o n c e r n e les autres facteurs, ils sont mis en cause m 6 m e chez les animaux.
L e plus int6ressant, p o u r m i e u x c o m p r e n d r e la p a t h o l o g i e h u m a i n e , serait l'6tude c o m p a r a t i v e 6pid6miologique. P o u r le m o m e n t , un seul cas attire v r a i m e n t n o t r e a t t e n t i o n et son 6tude apro- fondie serait tr6s n6cessaire : il s'agit des cas de cancers li6s h la c o n s o m m a t i o n de la foug6re grand-aigle.
N o u s avons vu qu'elle p r o v o q u a i t des cancers chez le b6tail ; nous savons aussi que la foug6re grand-aigle est canc6rig6ne p o u r l ' h o m m e (cancers colo-rectaux). Elle est c o n s o m m 6 e c o u r a m m e n t [21] au J a p o n , au Canada, en Nouvelle-Z61ande et aux Etats-Unis.
D ' a u t r e part, il existe une coincidence trou- blante e n t r e les zones h haut risque de cancer colo-rectal et les zones o/~ on r e t r o u v e le pt6ri-
A c t a E n d o s c o p i c a V o l u m e 17 IV" 2 - 1 9 8 7 71
disme [22] ex. : l'Ecosse, oh on a, d'apr~s Burkitt, 51, 5 % de risque de c a n c e r colo-rectal chez l ' h o m m e de 35-64 ans et oh l'on o b s e r v e du pt6ri- disme.
L e d e r n i e r 616ment est la p r e u v e , dans certains cas, de l'interaction de la foug~re et d ' u n virus (cf.
plus haut).
Cancer +
Cancer + + / Cancer + + (?)
Cancer + + + ) Procanc~rig~ne J ~ Virus
Cancer + ~-- inconnu oncog~ne ~ Cancer + (?)
r - j
Cancer + + (?)
SCHI~MA DES DIFFI~.RENTES I N T E R A C T I O N S E N T R E F A C T E U R S I ~ T I O L O G I Q U E S M E T T A N T EN J E U PTERIS A Q U I L I N A
Le p r o b l ~ m e est donc tr~s c o m p l e x e : la foug~re grand-aigle r e p r 6 s e n t e h elle seule un canc6rig6ne et semblerait "potentialiser" d'6ventuelles substan- ces procanc6rig~nes p r o p r e s h certaines r6gions.
L e b6tail agirait ici en tant que r6v61ateur de la pr6sence de ces substances. Vient se greffer l'agent d ' u n a u t r e i n d u c t e u r de cancer, m 6 m e iso- 16ment dans certains cas : le virus 9
Sont d o n c n6cessaires m a i n t e n a n t :
U n e m e i l l e u r e connaissance de l ' i n t e r v e n t i o n des virus o n c o g 6 n e s dans ce type de cancers
une 6 t u d e a p p r o f o n d i e d e l'effet cancerig~ne de la foug~re grand-aigle :
isolement de la ou des substances actives . m6canismes d ' a c t i o n
- une 6 t u d e du facteur procanc6rig~ne "inconnu"
dans les pays h h a u t e incidence de c a n c e r : 9 substance alimentaire : 6tude des r6gimes et habitudes alimentaires
9 facteurs digestifs incluant le r61e de la micro- flore.
R ~ F ~ R E N C E S
1. A L L E Y M . R . , J O H N S T O N E A . C . , J O L L Y R . D . - - Small intestinal carcinoma in cattle. N Z Vet. J, 1983, 31, 147-149.
2 . V I T O V E C J. - - Carcinomas of the Intestine in Cattle and Pigs. Zbl Vet. Med A, 1977, 24, 413-421.
3 . G E O R G S S O N G . , V I G F U S S O N H . - - Carcinoma of the small intestine of sheep in I c e l a n d : a pathological and epizootiological study. Acta Vet. Scand, 1973, 14, 392-409.
4 . C R E S P E A U F . - - A p r o p o s d'un cas de polypose intesti- nale de la vache : Recueil de m~decine v~t(rinaire, 1974, 150, 687-689.
5. H E L F E R D O N H., K O L L E R LD. - - Intestinal polyps with coccidial forms in a lamb. Cornell Vet., 1976, 66, 369- 371.
6. E C K E R L I N R. H. - - Ileal Polypoid Leiomyoma in a Dog9 Javma, 1975, 1677, 70-71.
7. SELLER R. J. - - Colorectal polyps of the Dog : A clinico- pathologic Study of 17 Cases Javma, 1979, 174, 72-73.
8. R I D G W A Y J. J. - - Intestinal polyps in a D o g : Modern veterinary practice, 1973, 54, 59.
9. LE C A I N A. - - Coprostase chez le chien par polype rec- tal : L'animal de compagnie, 1977, 3, 311-313.
10. C H A F F E E V . W . , F O R T N E Y W., H R I B R E N I K T., W E I R I C H W. E. - - Rectal polyp in an English Bulldog (a case report). Vet Med., 1976, 71, 169-170.
1i. S I L V E R B E R G S . G . - - Carcinoma Arising in Adenoma- tous Polyps of the rectum in a Dog. Dis. Col. and Rect., 1971, 14, 191-194.
12. P A T N A I K A 9 K., H U R V I T Z A. I., J O H N S O N G. F. - - Canine intestinal adenocarcinoma and carcinoid. Vet. Pa- thol., 1980, 17, 149-163.
13. L A M O N T J . T . , O ' G O R M A N N T . A . - - Exp6rimental colon cancer. Gastroenterology, 1978, 75, 1157-1169.
14. B A N D A R U S . R . , N A R I S A W A T., W R I G H T P., V U K U S I C H D., W E I S B U R G E R J. H., W Y N D E R E. L.
- - Colon carcinogenesis with azoxymethane and dimethyl-
hydrazine in Germ-free rats. Cancer Reseach, 1975, 35, 287-290.
15. G O E T I N G N., T R O T T E R G . A . , C O O K E T., KIR- K H A M N., T A Y L O R I. - - Effect of the warfarin on cell kinetics, epithelial morphology and tumour incidence in induced colorectal cancer in the rat. GUT, 1985, 26, 807- 815.
16. S A M E L S O N S . L . , NELSON R . L . , N Y H U S L 9 M. - - Protective role of f~ecal pH in experimental colon carcino- genesis. Journal o f the Royal Society of Medecine, 1985, 78, 230-233.
17. G O L D I N B. R., G R O B A C H S. L. - - Effect of antibiotics on incidence of rat intestinal tumors induced by 1,2-Dime- thylhydrazine Dihydrochloride. INCI, 1981, 67, 877-880.
18. V A N D E R B E R G H E J., V E R H E Y D E N A., L A U - WERS A., G E B O E S K . - - Spontaneous adenocarcinoma of the ascending colon in Wistar rats : The intracytoplasmic presence of a campylobacter-like bacterium. J. Comp.
Path., 1985, 95, 45-55.
19. J A R R E T W. F . H . , M c N E I L P. E., G R I M S H A W T. R., S E L M A N I. E., M c l N T Y R E W. I. M. - - High incidence area of cattle cancer with a possible interaction between an environmental carcinogen and a papilloma virus. Nature, 1978, 274, 215-217.
20. C A R O L Y N A., L I G E M A N M. D., G A R N E R F. M.
Comparative study of intestinal carcinomas of animals and man. J. Nat. Cancer Inst., 1972, 48, 325-346.
21. P A M U K C U A . M . , V A L C I N E R S., B R Y A N G . T . - - Inhibition of carcinogenic effect of Bracken F e r n (Pteri- dium Aquilinum) by various chemicals. Cancer, 1977, 40, 2450-2454.
22. B U R K I q T D. P. - - Epidemiology of cancer of the colon and rectum. Cancer, 1971, 28, 1-13.LIBRE
72 Volume 17 - N ~ 2 - 1987 Acta Endoscopica
This type o f cancer which causes 50 000 deaths each year in United States and over 15 000 in France fully justifies all the interest taken in it at the present time by the public health services in the western countries.
Its prevention and screening involve the detection of polyps that can easily be removed.
Nevertheless the etiology o f this cancer is very little k n o w n and many different hypotheses have been put forward.
The observation o f similar cancer in the animal and especially the experimental study of cancerige- nic products in the animal and the tumors which they induce, will perhaps allow us to k n o w this curse better and maybe control it.
I. I N T E S T I N A L C A N C E R IN T H E C O U R S E O F V E T E R I N A R Y P R A C T I C E .
S P O N T A N E O U S C A N C E R S A . F a r m a n i m a l s : b o v i n e s - s h e e p - p i g s .
Cancer o f the small intestine o f ruminants seems to be the most interesting subject o f study for several reasons :
This cancer which is generally rare concerns a high proportion o f sheep in certain countries (Island : 0,97 % [3], N e w - Z e a l a n d : 1,6 % of older animals [1]).
Now, the highest proportion of human colorectal cancers is observed in New-Zealand [1] where bovines and sheep f o r m the 2 greatest species for meat.
On the other hand, one must keep in mind that because o f there digestive physiology, microbian population is predominant [1] in the rumen and small intestine o f the ruminants and in the colon in humans.
Therefore, the cancer o f the small intestine in ruminants show the most anology with human colo- rectal cancer.
A s a process o f cancer induction, the authors [1]
have thought o f microbial activation o f cancerigenic substances, which also seems to be the case in human cancer at least in part.
Other research has shown :
The precancerigenic character o f nitrosamines present in certain f o o d concentrates such as fish meal [3].
The cancerigenic character o f natural substances.
It has been k n o w n for a long time that the con- sumption o f bracken (pteris aquilina) causes benign or malignant tumors, sometimes colorectal tumors in cattle [4, 19] : tumors o f the bladder in bovines, o f the intestine and bladder in sheep.
The presence o f parasites associated with colorec- tal polyps [5]. But it seems that the parasite finds in the polyp and ideal site f o r multiplication and in
and in no cases, induces the formation o f the polyp, therefore potentially the formation o f a mali- gnant tumor.
The study o f cancer o f the intestine in farm animals is still very superficial. It allows us howe- ver to draw comparisons between small intestine cancer o f ruminants and colorectal cancer o f humans which would prove the role o f bacterial flora associated to precancerigenic f o o d substancies
in the etiology o f these forms o f cancer.
B . D o m e s t i c a n i m a l s
The only species properly studied in veterinary pratice is the dog.
The dog rarely develops colorectal polyps. Some isolated cases have been mentionned especially in the Collie and Airedale races [6, 7]. In most cases, these polyps are benign [8, 9, 10], but they need to be removed because they often lead to coprostasis [9].
The most c o m m o n symptoms of these canine polyps are liquid stools containing blood as with human polyps but it is not always the case [6].
The comparative observation o f many cases has allowed to make a histopathologic classification o f these polyps [7] :
- Hyperplastic polyp
- Papillar adenoma Tubular adenoma Others.
The cases o f cancerous polyps in the dog are even rarer [11].
Sometimes, canine polyps o f a diameter greater than 1 cm degenerate into malignant tumors. These are papiUo-tubular adenoma revealing atypic epithe- lial cells like carcinoma. The development f r o m benign polyp to adenocarcinoma is well k n o w n in animals and certain authors suggest classifications similar to that o f W.H.O. [12].
The observations with ganglionary, pulmonary, hepatic and even intestinal wall metastasis develop- ping f r o m polyps have been described [12].
We k n o w very little about the etiology o f colorec- tal polyps and cancer in dog. We k n o w that the dog develops them much less frequently than man in industrialized western countries in spite o f a rather similar diet.
It has been thought that dog with a much shorter life than man was consequently less affected by possible nutritious cancerigenic substances. But this hypothesis remains debatable since it supposes on the one hand that the cancer is caused by f o o d which is suspected but not proved and on the other hand, the existence o f a sort o f accumulative pro- cess which would not be taken into account in the young animal.
Acta Endoscopica Volume 17 N ~ 2 - 1987 73
Therefore, concerning colorectal polyps and can- cer in the dog, until now their research has only been very descriptive in veterinary pratice and this because we are mainly preoccupied in establishing a histopathological classification of tumors and of surgical techniques of exeresis. More thorough his- tological research is desirable but it remains diffi- cult to see how this can be done at the present time because this canine pathology is not very wides- pread and the treatment would be very expensive.
* Aromatic amines
CH3 CH3
~
NH22',3 dimethyl-4-aminobiphenyl
These components are actively secreted in the bile and are thus found in the target cells.
I I . C O L O R E C T A L C A N C E R A N D A N I M A L E X P E R I M E N T A T I O N
A. The animal experimentation model
The small rodent (rat, mouse, hamster) is the best animal for experimentation because it is cheap, reproduces quickly and can easily be bred in suffi- cient number to allow statistical evaluation. The results are then comparable from one experiment to another. On the other hand, these rodents very rarely show spontaneous cancer of the colon [13]
but cancer induced by certain chemical products like 1,2 dimethylydrazine ( D . M . H . ) are similar to spontaneous colorectal tumors in man.
Thanks to the use of carcinogenic substances and the observation of the effect of different environ- mental factors (conditions, bacterias, virus), the animal model allows to study the development of the cancer from the initial modification of D.N.A.
in the epithelial cell to the development of invading adenocarcinoma. Thanks to many experiments, at the present time it is now possible to know the early modifications of cellular metabolism which would allow us to make a diagnostic test at this stage and to use more specific therapies.
Laboratory animals are the only way to go from the discovery of new therapeutical techniques (immunotherapy, chemotherapy etc...) to the appli- cation in human cancer.
* Hydrazine derivates
CH3 - N H - N H - CH3
1,2 dimethyl hydrazine Laqueur, in 1963, isolated cycasine, cancerigenic of the cycas circinalis plants (Guam islands). It is a hydrosoluble glucoside o f methyl oxymethanol [13].
Druckey's, in 1967, discovered that 1,2 D M H was very close in structure to cycasine [13]. D M H is the most effective and specific cancerigenic sub- stance for the colon.
Metabolic activation o f these components give an alkylation agent (methyldiazonium) which gives rise to a very reactive carbonium ion, methylating pro- teins and nucleic acids.
* Alkynitrosamides
N methyl - N'nitro - N nitrosoguanidine = MNNG M N N G causes the appearance o f adenomatous polyps and cancers in the distal colon and can be administered by intra-rectal instillation.
B. Cancerigenic substances used in the animal and the mechanism of the experimental carcinogenesis.
i) Cancerigenic substances
They can induce colon cancer but also of other organs : kidney, liver, auditory meatus [13, 14].
They have been classified in 5 groups [13]
* Chloranthenes
~ i l l i l c h l o r a n t h ~ n e
Their structure is similar to that of biliary salts and cholesterol. They can be produced by steroid metabolism and intestinal flora.
*Others
We should mention aflatoxine, metabolite of the Aspergillus flavus fungus. It induces tumors in the colon, in small numbers, in vitamine A deficient rats.
o o
Aflatoxine B1
Much research has also been done on the effects of bracken extracts (pteris aquilina), but the cance- rigenic substance has not been isolated. The cance- rigenic effects o f this bracken are well known in bovine pathology, they are associated to the pteri- dism syndrome [4].
7 4 Volume 17 - N ~ 2 - 1987 Acta Endoscopica
2) Pathogenesis of a major cancerigenic substance : D . M . H .
*Means o f action
Experiences [13] show that D.M.H. and its metabolites can be carried to the epithelial cells of the colon by blood circulation ; most of its metabo- lites are excreted by the kidney and the lung.
Therefore biliary secretion is not necessary for D.M.H. to induce tumors. Its action is not luminal.
In situ, through methylation of A . D . N . , D.M.H.
modifies the genome and thus the phenotype of target cells. It is the key step universally recognized in cancerogenesis : a direct effect on the genes.
There is therefore dedifferentiation, abnormal proli- feration and spreading. Authors [13] have noted that tumors of the colon induced by D.M.H. have a greater incidence than tumors of the liver or the kidney, although the modification of the genome is the same. This difference seems to be due to the more rapid turnover o f epithelial cells in the mucosa. Other experiments have shown in addition that the cells o f the colon seem to be more recep- tive than those of the liver or the kidney, to D.M.H.
*Induced tumors
Their nature depends on the experimental proto- cole: method o f administration, frequency of the doses, way o f administration, age of the animal, physiological state (gestation) and sex (females are
less sensitive than males).
It can be noted that contrarily to carcinoma, adenoma can reach a large size without becoming malignant [13].
But in man most colon cancers result from the the degenerescence o f adenoma which are at the begining benign.
There is another significant comparison between man and animal [13]: with a high dose of D.M.H., cancer o f the left colon is predominant whereas at a low dose, it is in the right colon. In man, in areas with a high incidence of cancer, it is the left colon which predominates whereas it is the right colon in areas with low incidence.
The use of laboratory animal and the discovery of efficient and carcinogenic substances have allo- wed us to set up complex and substantial experi- mental procedures. These experiments have already allowed us to increase our knowlege of colorectal cancer and we will now look at some fundamental results.
C. S o m e results o f e x p e r i m e n t a l research o f colorectal c a n c e r
1) Immunity and tumors
Most of the research quoted [13], shows that the antigenic property o f colon cancer as well as immu- nitary defenses of the host against these tumors are very similar in man and animal. However it has
been proved that the colon antigenes in the rat are capable of inducing a protective immunitary res- ponse. But it is not proved that a manipulation of the immunitary system could protect against the development of cancer or be beneficious to an animal already suffering from cancer.
We also know that B. C.G., a non specific immu- nostimulant is an anti-tumoral agent but it has proved to be without effect on experimental cancer induced by D.M.H. [13].
2) Genetic factor
The factor of familial human polyposis is well known. The resistance phenomenon to different cancerigenic substances could be transmitted as a dominant autosomal factor as with the transmission of polyposis. The mechanism of resistance could be either the absence o f an enzyme required for the metabolic activation o f a procancerigenic substance (D.M.H.) or the specific resistance of the mucosa against the cancerigenic substance [13].
As research has shown about the mean of action of D.M.H., we know that the point by which the cancer is induced is a genetic modification by seve- ral factors, in this case, D . M . H .
One of the most important discoveries of research presented at the Martinique Congress at the beginning of 1986, is the existence of endogenic or exogenic oncogenes (virus) the expression of which would be at the origin of cancerous modifi- cations : those are called cancer genes.
3) The effect of a iatrogenic substance on experimental c a n c e r : Warfarine
Warfarine is known for its anticoagulant effects but it also reduces the number of colorectal cancers in the rat induced by azoxymethane [15]. Authors have shown that there is no relationship between the anti-coagulant action and the anti-tumoral action because the dose has no incidence on the reduction of these tumors [15].
Warfarine has no overall effect either on cell proliferation but an action on the adenocarcinoma
"unit' at the stage o f its malignant transformation or before. As the number of micro-adenoma decreased with warfarine, it acts at the pre-adenomatous stage. The specific effect of warfarine is the preven- tion of neoplastic modifications in cells which have undergone functional changes morphologically inde- tectable at the first stages of cancerogenesis. The authors think but they have not been able to prove it that its action was cytotoxic.
4) The role of the fecal pH
It is known that human populations with alcaline p H stools have a greater risk of colon cancer than the others. This observation has led to experiments on the variation o f p H in the field of experimental cancerogenesis [16]. Lactulose and sodium sulfate are used to acidify the colic content and the stools.
The results confirm the protective role of acid p H in D.M.H. cancerogenesis. These results have been
A c t a E n d o s c o p i c a V o l u m e 17 N " 2 - 1987 75
put in parallel with the high risk of colon cancer associated with a low vegetable fibres diet and a high consumption o f fat and animal proteins.
The two substances chosen acidify the colon in a very different way but lactulose produces a reaction on the microbian population. We do not yet know the "protection" mechanism but an hypothesis has been put forward of a relationship between the appearing of tumors and a modification o f the biliary salts by bacterial enzymes in an environment where p H plays a large role.
5) Role of bacteria and viruses in the etiology of colorectal cancer in the animal
We will not only consider questions of experi- mentation but also fortuitous observations some- times on a great number of animals,
Bacteria
We have already seen several times the supposed role of bacterial flora and its enzymes in the trans- formation of alimentary or biliary procarcinogenic processes. The more animal fat and proteins the diet contains, the more the risk of cancer o f the colon increases. It has been shown [13] that the consumption of fat increases the production o f bile which is modified by the colic flora into secundary biliary acids and sterols (coprostanane and copros- tanol), being themselves metabolized by the flora (especially clostridia species which metabolize the steroid nucleus) into cancerigenic substances, such as phenantrenes [13]. On the other hand, a food rich in animal proteins seem to increase the fecal rate of bacterial enzymes : nitroreductase, azore- ductase, beta-glucuronidase. These enzymes could synthetize endogenous carcinogenes by reducing the nitrogenous compounds into aromatic amines [13].
An attempt has also been made to modify the bacterial flora in order to better appreciate its role in carcinogenesis. For instance, D.M.H. induces tumors of the auditory meatus, of the kidney and of the intestine in normal rats. In germ-free rats, only 20 % of colon cancers (compared to 93 %) were found and these are the only tumors which appeared. This is to be compared to the use of antibiotics in D . M . H . induced carcinogenesis [17]
which reduces the intestinal flora and also limit the number of cases of tumors. On the other hand, if azoxymethane is used by intrarectal instillation, the germ-free rats or those less contaminated (by clos- tridium perfringens) show the greatest number o f the colon according to the authors [14]. This diffe- rence has not been explained yet but it is important to mention that contrarily to D.M.H. the action of azoxymethane is intraluminal.
Parallel to experimental cancerogenesis the pre- sence of bacteria has also been noted in hyperplas- tic or dysplastic modifications of the intestine in the rat, the pig, the lamb, the hamster, the ferret and the horse [18]. More specifically the adenomas were associated to Campylobacter type bacteria. 17
cases have been studied in the rat in the course of 17 years of toxicity research [18]. The lesions obtai- ned were described as adenocarcinoma because the modifications of the colon were neoplastic. A simi- lar situation seems to exist in man. Several types of colorectal lesions were observed but all the rats showed an inflamation o f local lymphatic gan- glions. Campylobacter-like bacteria has been found in the cell remains of the light (leucocytes, degene- rated epithelial cells) and in the apical pole of normal cells, in sub-epithelial layers, in metastases, in invaded loci and in the cell especially near chromosomes.
This last observation could show the interaction of bacteria with the genetic material of the cell. We know that a genetic modification is at the source of the cancerous cell ; this would explain also the possible viral etiology o f colorectal cancers.
Viruses
For technical reasons, the interactions bvetween virus and cancer have been very little studied in the animal. But the studies have shown a possible interaction between an alimentary carcinogene - bracken - a papilloma virus and the isolated cell [19]. Because experimentation has not been able to be carried out on cattle, this research was restricted to careful and detailed observation.
A t the beginning, a specific localization of the cancer of the upper digestive tract, linked to the distribution of bracken which is known to contain a cancerigenous substance for the digestive tract (experiments on rat, mouse and the guinea-pig [19]). In addition the papilloma virus was found at the level of the tumors.
This observation does not concern colorectal can- cer, but it is interesting because bracken is cenceri- genous for the colon of laboratory animals and because it opens the way to present time research.
In fact, thanks to the progress of molecular bio- chemistry, especially in the field of oncogenic viruses, it has now been proved that in certain cases (for example in the uterus cervix) there is a viral origin to the tumor. This was discovered in finding the viral genetic material associated with the one of the tumoral cell. Let us hope that such discoveries may be made at the level of colorectal cancer.
But at this stage o f the research, animal experi- mentation gives way to cellular cultures, more able to show the deeper mechanisms of cancer induc- tion.
DISCUSSION
In this mass of information rather disparate, we have to note that the present state of research in animal pathology does not enlighten us very much
76 Volume 17 - N ~ 2 - 1987 Acta Endoscopica
but does encourage us in the options chosen is human medicine9 Today, we can envisage as causes o f human colorectal cancer [20] :
- an individual genetic sensitivity
- the ingestion o f cancerigenic substances
- the ingestion o f non cancerigenic substances but which can become so under the action o f bacterial enzymes or o f other chemical reactions in the orga- nism
Physiological substances like biliary steroids which might be transformed into cancerigenous substances o f the same type
Intervention o f microorganisms, bacteria or virus
A l l these factors underline the importance o f the diet and o f the alimentary habits. They are also modulated by environmental parameters such as the pH, the speed o f digestive transit..9
A s far as the genetic aspect is concerned, the cases o f spontaneous animal cancers are too spora- dic to attempt a field work ; only experimentation will bring the information 9
A s far as other factors are concerned, they are acting in the same way as with animals9
The most interesting thing in order to understand human pathology would be an epidemiological comparative study. For the moment, just one case has really attracted our attention and its thorough study would be very necessary: it is the case o f cancers linked to the consumption o f bracken9 We have seen that it p r o v o k e d cancer in the cattle, we also know that bracken is cancerigenic for. man (colorectal cancer). It is often used up [21] in Japan, Canada and United States.
On the other hand, there is a worrying coinci- dence between high risk areas for colorectal cancer and the areas where pteridism [22] is found, for example Scotland where according to Burkitt, there is 51,5 % o f colorectal cancer risk for men between 36 and 64, Scotland being a country where pteri- dism is observed.
The other item is the proof, in certain cases, o f the interaction o f bracken and a virus (as mention- ned before).
The problem is therefore very complex : bracken represents in itself a cancerigenic substance and would seem to potentialize other possible procance- rigenous substances which are particular to certain areas. Cattle would there act as a revealer o f the presence o f these substances9 Then there is in addi- tion the agent o f another cancer inducer, even in an isolated way in some cases : the virus.
Cancer +
Cancer + + ~ ' ~ " B r a c ~ e n f e r n - ~
t
C a n c e r + + (?,[ Cancer + + + / Unknown . , ~ ~ , , /
p r 0 c a n c e r i g e n i c / ~ " Oncogenous
Cancer + ~ substance virus --> Cancer + (?)
Cancer + + (?)
D I A G R A M SHOWING THE D I F F E R E N T INTERACTIONS BETWEEN ETIOLOGICAL FACTORS
INVOLVING PTERIS AQUILINA
Therefore we now need to obtain :
- a better knowledge o f the role o f oncogenous viruses in this type o f cancers
- a thorough study o f the cancerigenic effect o f bracken :
the isolation o f the active substance(s) the mechanisms o f action
- a study o f the ~ u n k n o w n ~ procancerigenic factor in countries with high risk o f cancer :
9 alimentary s u b s t a n c e a study o f the diets and f o o d habits
9 Digestive factors including the role o f micro- flora9
Acta Endoscopica Volume 17 N" 2 - 1987 77
