The occurrence of cancer in vertebrates: a mini review.

Neoplasia is a multilevel condition caused by irregularities over the genome, which can lead to a fatal result. To fully understand this phenomenon, an evolutionary challenge has risen during the last decades, away from human limits, driving the scientific quest into the wild life. The study of wild vertebrate populations in their natural habitats has shown that cancer is rather prominent. Thus, the diversity of vertebrates reported with some form of neoplasia is quite scattered through a variety of habitats. However, some species constitute exceptions by exhibiting cancer-protective features, driven by certain loci in their DNA. It is obvious that from an evolutionary standpoint, the incidence of cancer in different taxa is nowadays studied by seeking for patterns and their roots. The main purpose of the evolutionary approach is no other than to answer a fundamental question: Could cancer be ultimately regarded as another evolutionary force conducive to the formation or shaping-up of species?

Introduction

Cancer is a multidimensional phenomenon in which a single cell or a group of cells are being involved in abnormal/non-adjustable growth. The resulting mass lesions are capable of following two different paths: they can remain benign or invade other parts of the body, as metastatic tumors. Cancer is a consequence of the organism’s multicellularity and a prime example of multilevel selection [1], i.e. cancer is a complex phenomenon driven by different types of selective forces. In order to gain a more holistic view of the disease, it is necessary to approach it by different angles and disciplines. Τo understand the disease, most research has focused on molecular and cellular processes in specific types of neoplasia [2]. So far, major lines of investigation, among others, include the pathology of the disease, its developmental stages, functional mechanisms of cancer cells and the polyclonality of tumors in an effort to formulate effective cure treatments. Over the last two decades, the prospect of studying cancer by exploring the relationship of the evolutionary process and the environment has emerged [ [3] and references therein]. Although the idea of considering cancer as an evolutionary phenomenon is not entirely new, little attention has been paid to the applications and assumptions of evolutionary biology for understanding neoplastic development [3]. More or less, the origin and progression of cancer are highly connected with the evolutionary concepts and the environment itself [1]. As a consequence, a growing number of scientists try to clarify what is going on about the appearance of cancer in higher taxa. However, understanding the complexity of the disease as a whole, dictates a multidisciplinary approach that may give new insights and prospects. As a result, it seems that much more attention has to be put on the wild populations and their natural habitat, of which very few items are known so far.

The evolutionary viewpoint of neoplastic existence above species level approximates the process across geological eras. Such an approach includes, among others, the figuring out of the total number of species in which neoplasia has been reported. The main purpose remains to be the acknowledgment of diversity from individual to population level and the ecological stress put on them. Some questions that arise considering the above are: How many different species have been recorded with neoplasia? At what extent does Darwinian evolution shape the phenology of cancer in studied taxa? Are there any organisms that possess cancer-protective mechanisms? Moreover, a complex task like this requires seeking for footprints and elements hidden in the past. In order to do so, it is crucial to run through the fossil record and the provided data aiming to answer fundamental questions about the origin of cancer itself in the evolutionary time. One of the most important queries that has to be answered concerns the origin of neoplasia, the circumstances under which this happened and the taxa involved.

Neoplasia in vertebrates

In this section an overall recording of reported incidence of neoplasia in vertebrate species is attempted based on the scientific journal articles. This approach excludes domesticated animals and model organisms, which are used for all kinds of research experiments. Our focus is mainly restricted on species that live in their natural environment or protected areas.

Cancer appears to be no exception to most animal species and definitely it is not a “privilege” for some. On the contrary, incidents of neoplasia have been reported in a plethora of species from several habitats (Table 1), covering a large number of vertebrate families (Table 2). The diversity of organisms, which have been reported with neoplasia, is spread in many different habitats, each of them applying differential and particular pressure on species performance.

Table 1

Vertebrate taxa bearing neoplastic incidents, categorized according to their habitat

Habitat	Families (species)
Terrestrial	71 (204)
Aquatic	42 (87)
Semi-aquatic	7 (11)
Sum	120 (302)

Table 2

Classification of vertebrate species that have been reported with neoplasia

Class	Order	Family	Species	Common name
Mammalia	Artiodactyla	Monodontidae	Delphinapterus leucas	Beluga whale	[1, 4–8]
			Monodon monoceros	Narwhal	[4, 6]
		Physeteridae	Physeter macrocephalus	Sperm whale	[4, 6]
		Phocoenidae	Phocoena spinipinnis	Burmeister’s porpoise	[4, 6]
			Phocoena phocoena	Harbor porpoise	[4, 6, 7]
			Neophocaena phocaenoides	Finless porpoise	[4]
			Mirounga angustirostris	Northern elephant seal	[4, 7]
			Mirounga leonina	Southern elephant seal	[4]
		Balaenopteridae	Balaenoptera physalis	Fin whale	[4, 7]
			Balaenoptera borealis	Sei whale	[4]
			Balaenoptera musculus	Blue whale	[4, 7]
			Megaptera novaeangliae	Humpback whale	[4]
		Balaenidae	Balaena mysticetus	Bowhead whale	[4]
		Ziphiidae	Mesoplodon densirostris	Blainsvilles beaked whale	[4]
		Kogiidae	Kogia breviceps	Pygmy sperm whale	[4]
Mammalia	Artiodactyla	Delphinidae	Delphinus delphis	Common dolphin	[4, 7]
			Lagenorhynchus obscurus	Dusky dolphin	[4, 6]
			Lagenorhynchus acutus	Atlantic white-sided dolphin	[4, 6]
			Lagenorhynchus obliquidens	Pacific white-sided dolphin	[4, 7]
			Tursiops truncatus	Bottlenose dolphin	[4, 6–8]
			Stenella coeruleoalba	Striped dolphin	[4]
			Stenella attenuata	Pantropical spotted dolphin	[4, 7]
			Stenella frontalis	Atlantic spotted dolphin	[4]
			Globicephala melaena	Pilot whale	[4]
			Globicephala macrorhyncus	Short finned pilot whale	[7]
		Iniidae	Inia geoffrensis	Amazon river dolphin	[4, 7]
			Orcinus orca	Killer whale	[4, 6, 7]
		Hippopotamidae	Hippopotamus amphibius	Hippopotamus	[34]
			Choeropsis liberiensis	Pygmy hippopotamus	[34]
		Giraffidae	Giraffa camelopardalis	Giraffe	[8]
Mammalia	Artiodactyla	Cervidae	Odocoileus virginianus	White-tailed deer	[8, 35]
			Dama dama	Fallow deer	[8]
			Capreolus capreolus	Roe deer	[7, 8]
			Elaphurus davidianus	Pere David’s deer	[7]
		Bovidae	Bubalus arnee	Wild water buffalo	[8]
			Capra nubiana	Nubian ibex	[7]
			Ovis canadensis	Bighorn sheep	[8]
		Camelidae	Camelus dromedaries	Arabian camel	[7]
			Lama glama	Llama	[36]
	Perissodactyla	Equidae	Equus zebra	Zebra	[8]
	Carnivora	Otariidae	Zalophus californianus	Sea lion	[4–8]
			Eumetopias jubatus	Steller sea lion	[4]
			Callorhinus ursinus	Fur seal	[4]
			Arctocephalus pusillus	Brown fur seal	[4]
			Arctocephalus australis	South American fur seal	[4]
Mammalia	Carnivora	Phocidae	Halichoerus grypus	Gray seal	[4]
			Phoca vitulina geronimensis	Harbor seal	[4]
			Phoca hispida	Ringed seal	[4]
			Pagophilus groenlandicus	Harp seal	[4]
		Obodenidae	Odobenus rosmarus	Walrus	[4]
		Ursidae	Ursus maritimus	Bear	[4]
			Helarctos malayanus	Sun bear	[37]
		Canidae	Canis lupus	Wolf	[6, 8]
			Canis lupus baileyi	Mexican gray wolf	[8, 38]
			Canis latrans	Coyote	[7, 8, 39]
			Vulpes vulpes	Red fox	[7]
			Urocyon littoralis	Island fox	[5–8]
		Felidae	Panthera leo	Lion	[7, 40–42]
			Panthera tigris	Tiger	[7, 40–42]
			Panthera pardus	Leopard	[40–42]
Mammalia	Carnivora	Felidae	Panthera pardus japonensis	Chinese-leopard	[41]
			Panthera pardus nimr	Arabian leopard	[43]
			Panthera onca	Jaguar	[8, 40, 42]
			Panthera uncia	Snow leopard	[5, 7, 41, 42]
			Puma concolor	Cougar	[40, 41]
			Acinonyx jubatus	Cheetah	[40, 44]
			Lynx rufus	Bobcat	[40, 42, 45]
			Felis canadensis	Canada lynx	[40]
		Mustelidae	Enhydra lutris	Sea otter	[4]
		Procyonidae	Procyon lotor	Raccoon	[8]
		Herpestidae	Herpestes javanicus	Javan mongoose	[46]
			Suricata suricatta	Meerkat	[7]
		Tupaiidae	Tupaia belangeri	Northern Treeshrew	[47]
		Viverridae	Arctictis binturong	Binturong (Bearcat)	[7]
	Eulipotyphla	Erinaceidae	Atelerix albiventris	Four-toed hedgehog	[7, 37]
Mammalia	Primates	Hominidae	Homo sapiens sapiens	Human
			Pan troglodytes	Common chimpanzee	[11, 48]
			Pan paniscus	Bonobo	[11, 48]
			Pongo pygmaeus	Bornean orangutan	[13, 47, 48]
			Gorilla gorilla	Gorilla	[36, 48]
			Gorilla beringei	Eastern gorilla	[4]
		Cercopithecidae	Chlorocebus aethiops sobaeus	Green monkey	[14]
			Cercocebus atys	Sooty mangabey	[47]
			Trachypithecus obscurus	Dusky leaf monkey	[47]
			Macaca mulatta	Macaque	[48–50]
			Macaca fascicularis	Long-tailed macaque	[47, 50]
			Macaca fuscata	Japanese macaque	[47]
			Macaca arctoides	Stump-tailed macaque	[47]
			Macaca maura	Moor macaque	[47]
			Macaca sinica	Toque macaque	[47]
Mammalia	Primates	Cercopithecidae	Papio spp.	Baboon	[12, 47, 51]
			Papio hamadryas	Hamandryas baboon	[47, 48, 52]
		Atelidae	Ateles paniscus	Black spider monkey	[47]
		Galagidae	Otolemur garnetti	Northern greater galago	[25]
		Cebidae	Saimiri sciureus	Common squirrel monkey	[47, 50]
			Sapajus apella	Tufted capuchin	[47]
		Callitrichidae	Callithrix jacchus	Common marmoset	[47]
			Saguinus fuscicollis	Brown-mantled tamarin	[47, 48]
			Saguinus oedipus	Cotton-top tamarin	[13]
			Saguinus fuscicollis ssp. leucogenys	Andean Saddle-back Tamarin	[47]
		Lemuridae	Lemur catta	Ring-tailed lemur	[53]
		Aotidae	Aotus trivirgatus	Three-striped night monkey	[53]
		Hylobatidae	Hylobater lar	Lar gibbon	[13]
		Daubentoniidae	Daubentonia madagascariensis	Aye–Aye	[53]
	Dasyuromorphia	Dasyuridae	Dasyuroides byrnei	Kowari	[37]
Mammalia	Dasyuromorphia	Dasyuridae	Dasyurus viverrinus	Eastern quoll	[37]
			Dasyurus maculatus	Tiger quoll	[37]
			Dasyurus hallucatus	Northern quoll	[37]
			Sarcophilus harisii	Tasmanian devil	[6–8, 15, 17]
	Monotremata	Trachyglossidae	Tachyglossus aculeatus	Short-beaked echidna	[54]
	Peramelemorphia	Peramelidae	Perameles bougainville	W. barred bandicoot	[5, 6, 8]
	Didelphimorphia	Didelphidae	Didelphis virginiana	Virginia opossum	[7]
			Monodelphis domestica	Gray short-tailed opossum	[15, 25]
	Diprotodontia	Phascolarctidae	Phascolarctos cinereus	Koala	[8, 55]
	Proboscidea	Elephantidae	Elephas maximus	Asian elephant	[7, 25]
			Loxodonta africana	African elephant	[1, 7, 25]
	Perissodactyla	Rhinoceratoidae	Diceros bicornis	Black rhinoceros	[7, 8]
			Ceratotherium simum	White rhinoceros	[8]
		Tapiridae	Tapirus sp.	Tapir	[8]
	Sirenia	Trichechidae	Tricherus manatus	Manatee	[4, 6, 8]
Mammalia	Rodentia	Sciuridae	Marmota monax	Groundhog	[6, 7]
			Spermophilus richardsonii	Richardson’s ground squirrel	[37]
		Echimyidae	Myocastor coypus	Coypu	[7]
	Lagomorpha	Leporidae	Sylvilagus spp	Cottontail rabbit	[7]
			Lepus townsendii	White-tailed jackrabbit	[7]
	Chiroptera	Pteropodidae	Rousettus aegyptiacus	Egyptian fruit bat	[56, 57]
		Vespertilionidae	Antrozous pallidus	Pallid bat	[57]
		Phyllostomidae	Carollia perspicillata	Seba’s short bat	[57]
Aves	Galliformes	Phasianidae	Tympanuchus cupido attwateri	Attwater’s prairie chicken	[6]
			Lophura rufa	Vieilott’s fireback pheasant	[58]
			Phasianus colchicus	Common pheasant	[8]
	Psittaciformes	Psittacidae	Amazona amazonica	Orange-winged parrot	[18]
			Ara ararauna	Blue-yellow macaw	[18]
			Ara chloropterus	Red-green macaw	[18]
Aves	Psittaciformes	Psittacidae	Psittacus erithacus	Grey parrot	[18]
			Agapornis sp.	Lovebird	[18]
			Aratinga solstitialis	Sun conure	[18]
			Aratinga nenday	Nanday conure	[18]
			Forpus coelestris	Pacific parrotlet	[18]
			Brotogeris pyrrhoptera	Grey-cheeked parakeet	[18]
		Cacatuidae	Nymphicus hollandicus	Cockatiel	[18]
			Cacatua moluccensis	Moluccan cockatoo	[18]
		Psittaculidae	Trichoglossus moluccanus	Rainbow lorikeet	[18]
			Melopsittacus undulatus	Budgerigar	[18, 59]
			Eclectus roratus	Eclectus parrot	[18]
			Psittacula krameri	Rose-ringed parakeet	[60]
	Passeriformes	Estrildidae	Erythrura gouldiae	Lady gouldian finch	[18]
		Cardinalidae	Cardinalis cardinalis	Northern cardinal	[18]
Aves	Anseriformes	Anatidae	Anas castanea	Chestnut teal	[18]
			Alopochen aegyptiaca	Egyptian goose	[18]
	Strigiformes	Strigidae	Ninox strenua	Powerful owl	[18]
			Megascops sp.	Screech owl	[18]
			Bubo virginianus	Great horned owl	[18, 61]
			Bubo scandiacus	Snowy owl	[18]
			Strix varia	Barred owl	[18]
	Falconiformes	Falconidae	Falco peregrinus	Peregrine falcon	[18]
			Falco sparverinus	American kestrel	[18]
	Sphenischiformes	Sphenischidae	Spheniscus demersus	African penguin	[62]
			Spheniscus humboldti	Humboldt penguin	[18]
	Procellariiformes	Procellariidae	Fulmarus glacialis	Northern fulmar	[8]
	Rheiformes	Rheidae	Rhea americana araneipes	Greater rhea	[63]
	Phoenicopterifromes	Phoenicopteridae	Phoenicopterus ruber	American flamingo	[64]
Reptilia	Testudines	Cheloniidae	Chelonia mydas	Green sea turtle	[6, 8]
			Dermochelys coriacea	Leatherback sea turtle	[6]
			Lepidochelys kempii	Kemp’s ridley sea turtle	[6]
			Eretmochelys imbricata	Hawksbill sea turtle	[6]
			Caretta caretta	Loggerhead sea turtle	[19]
		Geoemydidae	Cuora flavomarginata	Chinese box turtle	[65]
			Melanochelys trijuga	Indian black turtle	[20]
		Testudinidae	Testudo hermanni	Hermann’s tortoise	[19]
			Geochelone platynota	Burmese star tortoise	[19]
		Emydidae	Pseudemys concinna	River cooter	[20]
		Trionychidae	Apalone spinifera spinifera	Spiny soft shell turtle	[20]
			Apalone ferox	Florida shoftshell turtle	[19]
		Pelomedusidae	Pelusios subniger	African mud turtle	[20]
		Chelidae	Chelodina longicollis	Common snake-necked turtle	[20]
			Chelodina oblonga	Northern snake-necked turtle	[20]
Reptilia	Squamata	Scincidae	Corucia zebrata	Solomon island skink	[20]
			Eugongylus albofasciolatus	Solomon island ground skink	[20]
			Eumeces fasciatus	Five-lined skink	[20]
			Plestiodon laticeps	Broad-headed skink	[20]
			Tiliqua rugosa	Shingleback skink	[20]
		Cordylidae	Cordylus warreni	Warren’s girdle lizard	[20]
		Anguidae	Pseudopus apodus	European legless lizard	[20]
		Shinisauridae	Shinisaurus crocodilurus	Crocodile lizard	[20]
		Eublepharidae	Eublepharis macularius	Leopard gkeko	[20]
		Helodermatidae	Heloderma horridum	Mexican beaded lizard	[20]
			Heloderma suspectum	Gila monster	[20]
		Agamidae	Pogona vitticeps	Bearded dragon	[21]
			Hydrosaurus amboinensis	East Indian water lizard	[19]
		Iguanidae	Iguana iguana	Green iguana	[19, 20]
			Ctenosaura pectinata	Mexican spiny-tailed iguana	[20]
Reptilia	Squamata	Varanidae	Varanus exanthematicus	Savannah monitor	[19]
			Varanus timorensis	Spotted tree monitor	[13]
		Viperidae	Vipera xanthina	Ottoman viper	[66]
			Macrovipera lebetina	Lebetine viper	[20]
			Bitis gabonica	Gaboon viper	[66]
			Bitis nasicornis	Rhinoceros viper	[20]
			Bitis gabonica rhinoceros	West African gaboon viper	[20]
			Bothrops alternatus	Urutu	[66]
			Sistrurus miliarius miliarius	Pygmy rattlesnake	[20]
			Crotalus horridus	Timber rattlesnake	[66]
			Crotalus adamanteus	Eastern diamondback rattlesnake	[20]
			Crotalus lepidus	Rock rattlesnake	[20]
			Crotalus atrox	Western diamondback rattlesnake	[66]
			Crotalus scutulatus	Mojave rattlesnake	[66]
			Crotalus simus	Yucatan neotropical rattlesnake	[66]
Reptilia	Squamata	Viperidae	Antheris sp.	Bush viper	[66]
			Bothriechis lateralis	Side-striped viper	[66]
			Agkistrodon piscivorus	Cottonmouth	[20, 66]
			Agkistrodon contortrix laticinctus	Broad-banded copperhead	[66]
			Agkistrodon contortrix	Copperhead	[66]
		Colubridae	Pantherophis guttacus	Corn snake	[20, 21, 66]
			Elaphe (Pantherophis) obsoleta	Black rat snake	[20, 66]
			Pantherophis bairdi	Baird’s ratsnake	[20]
			Pituophis melanoleucus	Pine snake	[20, 66]
			Pituophis deppei	Mexican bull snake	[20]
			Pituophis catenifer sayi	Bull snake	[20]
			Coluber constrictor	Black racer	[20, 66]
			Lampropeltis elapsoides	Scarlet kingsnake	[20, 66]
			Lampropeltis calligaster	Yellow-bellied kingsnake	[66]
Reptilia	Squamata	Colubridae	Lampropeltis getula	Kingsnake	[19–21]
			Heterodon kennerlyi	Mexican hognose snake	[66]
			Heterodon platirhinos	Eastern hognose snake	[20]
			Drymarchon couperi	Eastern indigo snake	[66]
			Thamnophis sauritus	Ribbon snake	[21]
			Thamnophis radix	Plains garter snake	[20]
			Thamnophis sirtalis	Common garter snake	[21]
			Clelia clelia	Mussurana	[20]
			Gonyosoma oxycephalum	Arboreal ratsnake	[20]
			Natrix natrix	Grass snake	[21]
		Boidae	Boa constrictor	Common boa	[21]
			Corallus hortulanus	Amazon tree boa	[66]
			Eunectes murinus	Common anaconda	[19]
			Eunectes notaeus	Yellow anaconda	[20]
Reptilia	Squamata	Boidae	Epicrates cenchria	Rainbow boa	[20]
			Epicrates chrysogaster	Turks island boa	[20]
			Candoia bibroni	Pacific tree boa	[20]
			Lichanura trivirgata	Rosy boa	[20]
			Chilabothrus subflavus	Jamaican boa	[21]
		Elapidae	Pseudechis australis	King brown snake	[66]
			Aspidelaps scutatus	Shield-nosed cobra	[66]
			Dendroaspis polylepis	Black mamba	[66]
			Naja haje	Egyptian cobra	[66]
			Naja melanoleuca	Forest cobra	[20]
			Naja nivea	Cape cobra	[20]
		Pythonidae	Morelia spilota	Carpet python	[21, 66]
			Python regius	Ball python	[20]
			Bothrochilus albertisii	D’albertis python	[20]
Reptilia	Squamata	Pythonidae	Aspidites melanocephalus	Black-headed python	[21]
		Loxocemidae	Loxocemus bicolor	Mexican python	[20]
		Lamprophiidae	Boaedon fuliginosus	African house snake	[21]
	Crocodilia	Crocodilidae	Crocodylus porosus	Saltwater crocodile	[67]
			Crocodylus niloticus	Nile crocodile	[67]
			Crocodylus acutus	American crocodile	[67]
			Crocodylus siamensis	Siamese crocodile	[67]
		Alligatoridae	Alligator mississippiensis	American alligator	[67]
Amphibia	Anura	Ranidae	Rana pipiens	Northern leopard frog	[6]
		Hylidae	Trachycephalus resinifictrix	Golden-eye tree frog	[6, 68]
	Caudata	Salamandridae	Triturus cristatus	N. crested newt	[32]
Actinopterygii	Salmoniformes	Salmonidae	Salmo salar	Salmon	[6, 8]
			Salvelinus fontinalis	Brook trout	[69]
			Salvelinus namaycush	Lake trout	[69]
Actinopterygii	Salmoniformes	Salmonidae	Oncorhynchus tshawytscha	Chinook salmon	[69]
			Oncorhynchus keta	Chum salmon	[69]
			Oncorhynchus masou	Masu salmon	[69]
	Pleuronectiformes	Pleuronectidae	Parophrys vetulus	English sole	[6]
	Anguilliformes	Anguillidae	Anguilla japonica	Japanese eel	[6]
	Gadiformes	Gadidae	Melanogrammus aeglefinus	Haddock	[69]
	Scorpaeniformes	Sebastidae	Sebastolobus alascanus	Shortspine thornyhead	[69]
	Perciformes	Percidae	Sander vitreus	Walleye	[6]
		Sciaenidae	Micropogonias furnieri	Whitemouth croaker	[69]
		Labridae	Tautogolabrus adspersus	Cunner	[69]
		Sparidae	Sparus aurata	Gilthead seabream	[69]
			Acanthopagrus bifasciatus	Twobar seabream	[69]
		Cichlidae	Pterophyllum scalare	Freshwater angelfish	[69]
			Cichla monoculus	Peacock bass	[69]
Actinopterygii	Siluriformes	Ictaluridae	Ictalurus punctatus	Channel catfish	[6, 69]
			Ameiurus melas	Black bullhead	[69]
			Ameiurus nebulosus	Brown bullhead	[69]
	Cypriniformes	Catostomidae	Catostomus commersonii	White sucker	[6]
	Cyprinodontiformes	Cyprinodontidae	Cyprinodon variegatus	Sheepshead minnow	[69]
			Cyprinus caprio caprio	Common carp	[69]
		Poeciliidae	Xiphophorus variatus	Variatus platy	[70]
Chondrichthyes	Lamniformes	Odontaspididae	Carcharias taurus	Tiger shark	[69–71]
		Lamnidae	Carcharodon carcharias	White shark	[10]
	Carcharhiniformes	Carcharhinidae	Prionace glauca	Blue shark	[69–72]
			Carcharhinus leucas	Bull shark	[70]
			Carcharhinus limbatus	Blacktip shark	[70, 71]
			Carcharhinus brachyurus	Cooper shark	[10]
		Sphyrnidae	Sphyrna tiburo	Bonnethead	[71]
Chondrichthyes	Lamniformes	Triakidae	Mustelus canis	Dusky smooth-hound	[70]
		Scyliorhinidae	Scyliorhinus canicula	Lesser spotted shark	[69, 70]
	Orectolobiformes	Hemiscylliidae	Chiloscyllium plagiosum	Whitespotted bamboo shark	[9]
		Ginglymostomatidae	Ginglymostoma cirratum	Nurse shark	[70, 71]
			Nebrius ferrugineus	Tawny nurse shark	[70]
		Stegostomatidae	Stegostoma fasciatum	Zebra shark	[7, 70]
	Squaliformes	Squalidae	Squalus acanthias	Spiny dogfish	[71]
	Rajifomes	Rajidae	Raja clavata	Thornback ray	[69, 70, 72]
			Raja batis	Common skate	[70]
	Myliobatiformes	Urotrygonidae	Urobatis halleri	Round stingray	[72]
		Potamotrygonidae	Potamotrygon motoro	Ocellate river stringray	[71]

Aquatic habitats

Despite the fact that neoplastic incidents have been reported in about 40 distinct species of marine mammals, classified in more than 10 families (Table 2), the frequency in these taxa seems to be low [4]. Most of the marine mammals follow the general pattern of marine vertebrates. However, dolphins (family: Delphinidae) are those mammals in which neoplasia has been reported with greater frequency compared to other marine families [4]. Special reference has to be made in the case of beluga whale (Delphinapterus leucas) and its populations which are found at St. Lawrence River in Canada [1, 4–8]. In populations of this area, the incidence of cancer is approaching or even exceeding that of humans [7] while its rate is going up to 37% [4]. Exploring further the aquatic habitats, our attention moves forward to the class of Chondrichthyes, which includes a large group of the most effective ocean predators, i.e. sharks. Sharks, such as the great white (Carcharodon carcharias), exhibit low incidence of neoplasia [9, 10].

Terrestrial habitats

Moving from the aquatic environment to land, animal diversity is spreading in a variety of habitats while there is no specific pattern considering the presence of neoplasia. In primates, two of the most known groups, chimpanzees and baboons, exhibit a lot of similarities about the appearance of neoplasia [11, 12]. In the past, it was thought that cancer was unusual in great apes, but, nowadays, it is becoming more and more of a conventional occurrence [see also 11]. The appearance of neoplasia is largely related to the older age classes in both hominid and non-hominid primates [see also 11, 12]. So, the older a chimpanzee is, the more likely is to develop a neoplastic event. Moreover, an interesting fact is that female individuals appear to be more vulnerable to cancer than the males [11]. This situation is similar in non-hominid primates, such as Old World monkeys [12-14].

A special case in the terrestrial habitat is the Tasmanian devil (Sarcophilus harrisii) [6–8, 15–17], the largest carnivorous marsupial. The Tasmanian devil is autochthonous in Tasmania and the observed tumors were identified as a particular type of contagious cancer, which is known as DFTD (Devil Facial Tumor Disease) [6–8, 15–17]. DFTD generally affects facial tissues, jaws and neck, and causes significant deformation of their soft parts [6]. The disease is transmitted through biting during social interactions and in most cases leads to death within six months from the first appearance of symptoms [17].

Across the diverse class of birds, neoplasia is reported in 34 species sorted in 13 families (Table 2). Neoplasia is more common in Psittaciformes, followed by Galliformes, Strigiformes and Falconiformes [18]. The dominant presence in the order of Psittaciformes may be the outcome of the observed longevity among the species comprising this order [18]. It is noteworthy that all families have different types of neoplasia but, as a pattern, lymphoma is more common followed by carcinoma and adenocarcinoma [18].

The reported neoplasia in reptiles (class: Reptilia) is unusual to rare compared to that for mammalian and avian classes [19]. In turtles (order: Testudines), the frequency of reported neoplasia and metastasis, in both terrestrial and aquatic species, appears to be rare [19, 20]. In lizards we have no sound evidence that the frequency of neoplastic events is considerable in wild populations. On the other hand, the percentage of reports in captive populations has increased over the recent years from 0.7% to 5.9% [20]. Snakes are mostly reported with liver and skin cancer [20, 21] but no specific pattern has been identified so far.

How back in time does neoplasia go?—Fossil record

Cancer is present in many species throughout the animal kingdom, spreading out in several families of six vertebrate classes. Nevertheless, the following question arises. How old are these incidents of neoplasia and under which conditions did they appear? Extended evidence is related to dinosaurs, which had been dominating our planet for about 185 million years.

The fossil record reveals that neoplastic incidents have been recorded in several dinosaur species of the Mesozoic Era [22, 23]; most of the evidences refer to tumors observed in bones. At first, cancerous tumors were considered to be rare as, initially, their appearance was restricted to the Hadrosauridae [22]. Such an example was the presence of an ameloblastoma neoplasm in the lower jaw of a specimen referred as Telmatosaurus transsylvanicus in the early Cretaceous [23]. A more extensive and meticulous study of the fossil record has led to the identification of more neoplastic types in different taxa. The first presence of neoplasia, apart from the Hadrosaurid family, was found in a dinosaur fossil record classified in the Titanosaurs, in Brazil [22]. Furthermore, metastatic cancer and cases of osteoma have been found in the fossil record of Mosasaurs, a group of large marine reptiles, of the Jurassic period [24]. Because of the intense neoplasia presence in the Hadrosaurid group, compared with other taxa, this possible pattern may indicate a genetic propensity or, alternatively, reflect specific environmental stress affecting this target group [24].

The whole data set, the different disciplines and the large complexity of the evolutionary nature of cancer contribute to one aspect, which is answering a basic question that mostly precedes the rest: Could cancer eventually be considered as another evolutionary phenomenon that contributes to the formation or shaping-up of species?

Molecular tolerance, durability and resistance

Assuming that every healthy cell has similar endogenous risk to bypass the control/repair mechanisms and paths, and therefore, accumulate mutations in its DNA, the animals of larger body mass/size and longevity, such as elephants and whales [4, 7], should have a higher risk of cancer than smaller ones [25]. However, the data so far tend to reach to a threshold, a phenomenon called Peto’s paradox, supporting that the incidence of cancer at the species level is not related to the number of body cells or lifespan [1, 2, 26, 27]. This trend is confirmed by the fact that there have been only few cases of cancer in whales, while at the same time, carcinogenesis has been very often reported in many other smaller mammals [7]. Therefore, a major question in cancer biology arises: How much and in what ways do animals protect themselves from such pathogeny?

A gene, known as TP53, is found in many animal genomes and in most malignant cases is either damaged or inactive [25]. Under normal conditions, the gene encodes a tumor suppressor protein [25, 28] that senses when DNA is damaged or a cell is under stress [25]. In such occasions, the produced protein either slows the cell growth (while the damage is still under repair) or triggers cell death if the stress exceeds a tolerable threshold [25]. Large animals, such as elephants, may potentially reduce cancer risk by having extra copies of TP53 [8, 25] or other genes that encode tumor suppressor proteins [25, 29]. In the African elephant (Loxodonta africana) genome, it has been confirmed that there is a set of a single TP53 gene and 19 retrogenes (TP53RTG), a number much higher than that of related species in the Proboscidea order, extinct or not. Elephant cells have an increased response to DNA-damage which is mediated by a hyperactive TP53 signaling pathway, depending on the number of copies of retrogenes [25].

Spontaneous neoplasia is apparently different, both by cause and pathogenicity, in different mammalian species [7]. Some mammals, however, possess very special phenotypes which are equipped with important traits for survival [28]. Major examples are two phylogenetically distant species of mole rats, the blind Spalax spp. and the naked Heterocephalus glaber [1, 25, 28, 30]. The blind mole rat (Spalax spp.) has been found to show an extraordinary tolerance to hypoxia, cancer-resistance and longevity despite its small body size [28, 30]. It is remarkable that Spalax is the only genus in which no malignant neoplasia has been detected in thousands of individuals examined in the past 40 years of research [28]. Moreover, with only very few exceptions, Spalax spp. displays a remarkable tolerance to chemically induced carcinogenesis in vivo, while its fibroblasts inhibit cancer growth in vitro [28, 30]. The naked mole rat H. glaber, similar to Spalax spp., shows adaptations to hypoxic stress and an in vitro ability to inhibit cancer cell growth [30].

The interpretation of these special phenotypic traits is hidden in certain regions of the genome. Genome sequencing of Spalax spp. and genome-transcriptome analysis have revealed interesting genomic features, which are potentially the basis of some of the observed adaptive traits [30]. Some of them include high rates of DNA editing (repair mechanism), reduced chromosomal rearrangements, adaptation to hypoxic/hypercapnic conditions by positive selection of respiratory proteins and reduced sensitivity to hypercapnia-induced acid pain [30].

Contrary to mammals, in which spontaneous neoplasia is present in many families, in wild amphibian populations it is extremely rare [31, 32] (Table 2). Amphibians, also, appear to be resistant to chemically induced malignant neoplasms [31]. A particular difference between amphibians and mammals may be the requirement of mammalian cells to enter the cell cycle before programmed cell death by apoptosis. On the other hand, amphibian cells have the ability to undergo apoptosis immediately in response to antigens that induce or, even, promote carcinogenesis. This feature could serve as a cytoprotective mechanism reducing the sensitivity or availability of cells that could be stimulated and become malignant [31]. More protective mechanisms and traits may be hidden in this group of taxa, like an important antimicrobial peptide family called dermaseptin that needs additional research. Dermaseptin-PH, which is a specific peptide derived from the skin secretion of a frog (Pithecopus hypochondrialis) specimen, exhibits a wide range of antimicrobial and anticancer activities [33]. However, any antimicrobial peptide is not necessarily an anticancer agent.

Conclusions

The necessity of understanding evolutionary mechanisms as driving forces matched with cancer as a potential result of natural selection, have triggered many scientists to search beyond humans clarifying the importance of vertebrate populations in this quest. A variety of vertebrate species have been reported over the years with neoplasia and despite the fact that the total number of recorded incidents seems to be low (Table 1), it is very important to focus on the following fact: the crushing majority of studied cases revealed some form of cancer, which became lethal while cases in which neoplasia has not been identified are only exceptions. Looking into the evolutionary perspective of cancer, much more attention should be focused on the past. The Mesozoic Era offers a plethora of neoplastic incidents, which may have a catalytic contribution to this endeavor. The rich fossil record contains important evidence for possible evolutionary paths and traits and many more are expected in the future if such a study is prioritized. Therefore, data from the fossil record should be utilized to unravel the conditions and/or pressures of the geo-chronological period, which may attribute to cancer its potential impacts on the formation and shaping-up of species.

The collected data tend to define cancer as a common phenomenon through the animal kingdom. However, there are cases in which specific taxa possess features capable of defending this pathogeny. Both mole rats cited above, Spalax spp. and Heterocephalus glaber [1, 25, 28, 30], show some remarkable tolerance and resistance to cancer due to specific genes in their genomes. Moreover, the low incidence of cancer in amphibians [31, 32] and the presence of some peptides with interesting properties [33] point out new research insights. These cases, among others, indicate the prospects for investigating the tumor suppressive mechanisms and cancer-resistant phenology in phylogenetically distal taxa. Their potential relationship with conserved elements in human genome and their significance in biomedical procedures should be addressed as holistically as possible.

Despite the growing interest of the scientific community towards the ecological and evolutionary background of neoplasia in wild populations, the list of relevant literature remains limited [6, 8]. To acquire safer and clearer ascertainments, it is essential to intensify these efforts since the benefits of studying wild population dynamics in their own habitats are multiple. This is expected to provide crucial evidence and answers to the very primary queries on the evolutionary nature of cancer while its effects on individual and population level disclose the onset of neoplastic phenomena through time, as major factors in the survival and shaping up of species.