Mollusca: Disseminated Neoplasia in Bivalves and the p53 Protein Family

  • Annette F. Muttray
  • Katerina Vassilenko


Insights into the common mechanisms that likely exist in invertebrate and in vertebrate cancers will lead to a more coherent understanding of the fundamental processes that are altered during tumorigenesis and of tumor immunity. Invertebrates possess an innate immune system, primarily consisting of cellular and humoral defenses. In mollusks, hemocytes provide the first line of defense against foreign particles or organisms but lose their functionality when transformed into neoplastic cells. Neoplasia, or abnormal growth and proliferation of cells, has been described in many invertebrate species ranging from sponges to mollusks and arthropods. Occurrence of neoplasia in invertebrates appears to be by far not as common or as diverse in nature as it is in vertebrates, but some invertebrates even display cancers with metastatic potential, notably the bivalve mollusks. This chapter will focus on a cancer of the hemocytes in marine bivalves called disseminated neoplasia. Disseminated neoplasia in bivalves can be induced by a retrotransposon, appears to have contributing environmental factors, and is one of only four known cases of a transmissible cancers, not only between members of the same species but also between members of closely related species. This chapter will describe how disseminated neoplasia and the components of the innate immune system are linked by one of the central nodes in a wide signaling network that integrates DNA stability, apoptosis, and cell growth: the p53 tumor suppressor family.


Mollusks Bivalves Mussels Clams Cockles Disseminated neoplasia p53 p63 p73 Mortalin MDM2 RAS Apoptosis Cell cycle Retrovirus Retrotransposon Bivalve leukemia Cancer Tumor Transmissible tumor Horizontal transmission Hemocytes Hemolymph Mytilus ssp.  Mya arenaria Crassostrea ssp. Cerastoderma edule Environmental contamination Biotoxins Innate immunity Interferon Interleukine 



The authors would like to extend their gratitude to Charles Walker, Antonio Villalba, and Patricia Keen for their thorough review of this chapter and for their thoughtful contributions.


  1. AboElkhair M, Siah A, Clark KF, McKenna P, Pariseau J, Greenwood SJ, Berthe F, Cepica A (2009a) Reverse transcriptase activity associated with haemic neoplasia in the soft-shell clam Mya arenaria. Dis Aquat Org 84:57–63PubMedGoogle Scholar
  2. AboElkhair M, Synard S, Siah A, Pariseau J, Davidson J, Johnson G, Greenwood SJ, Casey JW, Berthe F, Cepica A (2009b) Reverse transcriptase activity in tissues of the soft shell clam Mya arenaria affected with haemic neoplasia. J Invertebr Pathol 102:133–140PubMedGoogle Scholar
  3. AboElkhair M, Iwamoto T, Clark KF, McKenna P, Siah A, Greenwood SJ, Berthe F, Casey JW, Cepica A (2012) Lack of detection of a putative retrovirus associated with haemic neoplasia in the soft shell clam Mya arenaria. J Invertebr Pathol 109:97–104PubMedGoogle Scholar
  4. Aguilera F (2017) Neoplasia in mollusks: what does it tell us about cancer in humans? – a review. J Genet Disord 1:07Google Scholar
  5. Alderman DJ, van Banning P, Perz-Colomer A (1977) Two European oyster (Ostrea edulis) mortalities associated with an abnormal haemocytic condition. Aquaculture 10:335–340Google Scholar
  6. Anand SK, Tikoo SK (2013) Viruses as modulators of mitochondrial functions. Adv Virol 2013:17Google Scholar
  7. Arriagada G, Metzger MJ, Muttray AF, Sherry J, Reinisch C, Street C, Lipkind WI, Goff SP (2014) Activation of transcription and retrotransposition of a novel retroelement, Steamer, in neoplastic hemocytes of the mollusk Mya arenaria. Proc Natl Acad Sci U S A 111:14175–14180Google Scholar
  8. Balint E, Reisman D (1996) Increased rate of transcription contributes to elevated expression of the mutant p53 gene in Burkitt's lymphoma cells. Cancer Res 56:1648–1653PubMedGoogle Scholar
  9. Baptiste N, Friedlander P, Chen X, Prives C (2002) The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells. Oncogene 21:9–21PubMedGoogle Scholar
  10. Barber BJ (2004) Neoplastic diseases of commercially important marine bivalves. Aquat Living Resour 17:449–466Google Scholar
  11. Belyi VA, Ak P, Markert E, Wang H, Hu W, Puzio-Kuter A, Levine AJ (2010) The origins and evolution of the p53 family of genes. Cold Spring Harb Perspect Biol 2:a001198PubMedGoogle Scholar
  12. Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689PubMedGoogle Scholar
  13. Böttger S, Jerszyk E, Low B, Walker C (2008) Genotoxic stress-induced expression of p53 and apoptosis in leukemic clam hemocytes with cytoplasmically sequestered p53. Cancer Res 68:777–782PubMedGoogle Scholar
  14. Böttger S, Amarosa EJ, Geoghegan P, Walker C (2013) Chronic natural occurrence of disseminated neoplasia in select populations of the soft-shell clam, Mya arenaria, in New England. Northeast Nat 20:430–440Google Scholar
  15. Bourdon J-C (2007) p53 and its isoforms in cancer. Br J Cancer 97:277–282PubMedPubMedCentralGoogle Scholar
  16. Bower SM (2010) Synopsis of infectious diseases and parasites of commercially exploited shellfish. Accessed November 2017. (Nanaimo, BC, Fisheries and Oceans Canada)
  17. Brousseau DJ, Baglivo JA (1991) Field and laboratory comparisons of mortality in normal and neoplastic Mya arenaria. J Invertebr Pathol 57:59–65PubMedGoogle Scholar
  18. Burns TF, El-Deiry WS (1999) The p53 pathway and apoptosis. J Cell Physiol 181:231–239PubMedGoogle Scholar
  19. Calabro V, Mansueto G, Parisi T, Vivo M, Calogero RA, La Mantia G (2002) The human MDM2 oncoprotein increases the transcriptional activity and the protein level of the p53 homolog p63. J Biol Chem 277:2674–2681PubMedGoogle Scholar
  20. Carballal MJ, Iglesias D, Díaz S, Villalba A (2013) Disseminated neoplasia in clams Venerupis aurea from Galicia (NW Spain): histopathology, ultrastructure and ploidy of the neoplastic cells, and comparison of diagnostic procedures. J Invertebr Pathol 112:16–19PubMedGoogle Scholar
  21. Carballal MJ, Barber BJ, Iglesias D, Villalba A (2015) Neoplastic diseases of marine bivalves. J Invertebr Pathol 131:83–106Google Scholar
  22. Carballal MJ, Iglesias D, Darriba S, Cao A, Mariño JC, Ramilo A, No E, Villalba A (2016) Parasites and pathological conditions of the lagoon cockle Cerastoderma glaucum from Galicia (NW Spain) and its resistance to Marteilia cochillia. Dis Aquat Org 122:137–152PubMedGoogle Scholar
  23. Carella F, De Vico G, Landini G (2017) Nuclear morphometry and ploidy of normal and neoplastic haemocytes in mussels. PLoS One 12:e0173219PubMedPubMedCentralGoogle Scholar
  24. Cetin-Atalay R, Ozturk M (2000) p53 mutations as fingerprints of environmental carcinogens. Pure Appl Chem 72:995–999Google Scholar
  25. Chillemi G, Kehrloesser S, Bernassola F, Desideri A, Dötsch V, Levine AJ, Melino G (2017) Structural evolution and dynamics of the p53 proteins. Cold Spring Harb Perspect Med April 7:a028308Google Scholar
  26. Christensen DJ, Farley A, Kern FG (1974) Epizootic neoplasms in the clam Macoma balthica (L.) from Chesapeake Bay. J Natl Cancer Inst 52:1739–1749PubMedGoogle Scholar
  27. Ciocan CM, Moore JD, Rotchell JM (2006) The role of ras gene in the development of haemic neoplasia in Mytilus trossulus. Mar Environ Res Pollut Resp Mar Org (PRIMO 13) 62:S147–S150Google Scholar
  28. Coffill CR, Lee AP, Siau JW, Chee SM, Joseph TL, Tan YS, Madhumalar A, Tay B-H, Brenner S, Verma CS et al (2016) The p53–Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans. Genes Dev 30:281–292PubMedPubMedCentralGoogle Scholar
  29. Collins CM, Mulcahy MF (2013) Cell-free transmission of a haemic neoplasm in the cockle Cerastoderma edule. Dis Aquat Org 54:61–67Google Scholar
  30. Copper HL, Mackay CM, Banfield WG (1964) Chromosome studies of a contagious reticulum cell sarcoma of the Syrian hamster. J Natl Cancer Inst 33:691–706PubMedGoogle Scholar
  31. Cox RL, Stephens RE, Reinisch CL (2003) p63/73 homologues in surf clam: novel signaling motifs and implications for control of expression. Gene 320:49–58PubMedGoogle Scholar
  32. Cremonte F, Vázquez N, Silva MR (2011) Gonad atrophy caused by disseminated neoplasia in Mytilus chilensis cultured in the Beagle Channel, Tierra Del Fuego Province, Argentina. J Shellfish Res 30:845–849Google Scholar
  33. De Tomaso AW, Nyholm SV, Palmeri KJ, Ishizuka KJ, Ludington WB, Mitchel K, Weissman IL (2005) Isolation and characterization of a protochordate histocompatibility locus. Nature 438:454–459PubMedPubMedCentralGoogle Scholar
  34. DeLeo AB, Jay G, Appella E, Dubois GC, Law LW, Old LJ (1979) Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci U S A 76:2420–2424PubMedPubMedCentralGoogle Scholar
  35. Díaz S, Cao A, Villalba A, Carballal MJ (2010) Expression of the mutant protein p53, hsp70 and hsp90 chaperons in the haemolymph of cockles, Cerastoderma edule affected by disseminated neoplasia. Dis Aquat Org 90:219–226Google Scholar
  36. Díaz S, Renault T, Carballal MJ, Villalba A (2011) Disseminated neoplasia in cockles Cerastoderma edule: ultrastructural characterisation of neoplastic cells and effects of disseminated neoplasia on haemolymph cell parameters. Dis Aquat Org 96:157–167Google Scholar
  37. el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B (1992) Definition of a consensus binding site for p53. Nat Genet 1:45–49PubMedGoogle Scholar
  38. Elston RA, Kent ML, Drum AS (1988a) Progression, lethality and remission of hemic neoplasia in the bay mussel Mytilus edulis. Dis Aquat Org 4:135–142Google Scholar
  39. Elston RA, Kent ML, Drum AS (1988b) Transmission of hemic neoplasia in the bay mussel, Mytilus edulis, using whole cells and cell homogenate. Dev Comp Immunol 12:719–727PubMedGoogle Scholar
  40. Elston RA, Moore JD, Brooks K (1992) Disseminated neoplasia in bivalve molluscs. Rev Aquat Sci 6:405–466Google Scholar
  41. Everett H, McFadden G (1999) Apoptosis: an innate immune response to virus infection. Trends Microbiol 7:160–165PubMedGoogle Scholar
  42. Farley CA (1969) Probable neoplastic disease of the hematopoietic system in oysters, Crassostrea virginica and Crassostrea gigas. Natl Cancer Inst Monogr 31:541–555Google Scholar
  43. Ford SE, Barber RD, Marks E (1997) Disseminated neoplasia in juvenile eastern oysters Crassostrea virginica, and its relationship to the reproductive cycle. Dis Aquat Org 28:73–77Google Scholar
  44. Gestl EE, Boettger SA (2012) Cytoplasmic sequestration of the tumor suppressor p53 by a heat shock protein 70 family member, mortalin, in human colorectal adenocarcinoma cell lines. Biochem Biophys Res Commun 423:411–416PubMedGoogle Scholar
  45. Gosling E (2003) Bivalve molluscs: biology, ecology and culture. Fishing News Books, a division of Blackwell Publishing, Oxford, UKGoogle Scholar
  46. Greenblatt M, Bennett W, Hollstein M, Harris C (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–4878PubMedGoogle Scholar
  47. Greiss S, Schumacher B, Grandien K, Rothblatt J, Gartner A (2008) Transcriptional profiling in C. elegans suggests DNA damage dependent apoptosis as an ancient function of the p53 family. BMC Genomics 9:334PubMedPubMedCentralGoogle Scholar
  48. Harms K, Nozell S, Chen X (2004) The common and distinct target genes of the p53 family transcription factors. Cell Mol Life Sci 61:822–842PubMedGoogle Scholar
  49. Hofseth L, Hussain S, Harris CC (2004) p53: 25 years after its discovery. Trends Pharmacol Sci 25:117–181Google Scholar
  50. Holbrook LAC, Butler RA, Cashon RE, Van Beneden RJ (2009) Soft-shell clam (Mya arenaria) p53: a structural and functional comparison to human p53. Gene 433:81–87PubMedGoogle Scholar
  51. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53PubMedGoogle Scholar
  52. House ML, Kim CH, Reno PW (1998) Soft shell clams Mya arenaria with disseminated neoplasia demonstrate reverse transcriptase activity. Dis Aquat Org 34:187–192PubMedGoogle Scholar
  53. Jessen-Eller K, Kreiling JA, Begley GS, Steele ME, Walker CW, Stephens RE, Reinisch CL (2002) A new invertebrate member of the p53 gene family is developmentally expressed and responds to polychlorinated biphenyls. Environ Health Perspect 110:377–385PubMedPubMedCentralGoogle Scholar
  54. Joerger AC, Fersht AR (2016) The p53 pathway: origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem 85:375–404PubMedGoogle Scholar
  55. Johannesen J, Pie A, Karlsen AE, Larsen ZM, Jensen A, Vissing H, Kristiansen OP, Pociot F, Nerup J (2004) Is mortalin a candidate gene for T1DM. Autoimmunity 37:423–430PubMedGoogle Scholar
  56. Kaul SC, Deocaris CC, Wadhwa R (2007) Three faces of mortalin: a housekeeper, guardian and killer. Exp Gerontol 42:263–274PubMedGoogle Scholar
  57. Kelley ML, Winge P, Heaney JD, Stephens RE, Farell JH, Van Beneden RJ, Reinisch CL, Lesser MP, Walker CW (2001) Expression of homologues for p53 and p73 in the softshell clam (Mya arenaria), a naturally-occurring model for human cancer. Oncogene 20:748–758PubMedGoogle Scholar
  58. Kelley ML, Walker CW, Beneden RJV (2008) Accession number FJ041332, direct submission to Genbank, submitted (13-AUG-2008) School of Marine Sciences. University of Maine, OronoGoogle Scholar
  59. Kent ML, Wilkinson MT, Drum AS, Elston RA (1991) Failure of transmission of hemic neoplasia of bay mussels, Mytilus trossulus, to other bivalve species. J Invertebr Pathol 57:435–436PubMedGoogle Scholar
  60. Kouidou S, Agidou T, Kyrkou A, Andreou A, Katopodi T, Georgioua E, Krikelis D, Dimitriadou A, Spanos P, Tsilikas C et al (2005) Non-CpG cytosine methylation of p53 exon 5 in non-small cell lung carcinoma. Lung Cancer 50:299–307PubMedGoogle Scholar
  61. Kouidou S, Malousi A, Maglaveras N (2006) Methylation and repeats in silent and nonsense mutations of p53. Mutat Res 599:167–177PubMedGoogle Scholar
  62. Landsberg JH (1996) Neoplasia and biotoxins in bivalves: is there a connection? J Shellfish Res 15:203–230Google Scholar
  63. Lane DP, Crawford LV (1979) T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263PubMedGoogle Scholar
  64. Lane DP, Cheok CF, Brown C, Madhumalar A, Ghadessy FJ, Verma C (2010a) Mdm2 and p53 are highly conserved from placozoans to man. Cell Cycle 9:540–547PubMedGoogle Scholar
  65. Lane DP, Cheok CF, Brown CJ, Madhumalar A, Ghadessy FJ, Verma C (2010b) The Mdm2 and p53 genes are conserved in the Arachnids. Cell Cycle 9:748–754PubMedGoogle Scholar
  66. Levin TC, King N (2013) Evidence for sex and recombination in the choanoflagellate Salpingoeca rosetta. Curr Biol 23:2176–2180PubMedPubMedCentralGoogle Scholar
  67. Levrero M, De Laurenzi V, Costanzo A, Gong J, Wang J, Melino G (2000) The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci 113:1661–1670PubMedGoogle Scholar
  68. Linzer DI, Levine AJ (1979) Characterization of a 54K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52PubMedGoogle Scholar
  69. Lu W, Pochampally R, Chen L, Traidej M, Wang Y, Chen J (2000) Nuclear exclusion of p53 in a subset of tumors requires MDM2 function. Oncogene 19:232–240PubMedGoogle Scholar
  70. Lu W-J, Amatruda JF, Abrams JM (2009) p53 ancestry: gazing through an evolutionary lens. Nat Rev Cancer 9:758–762PubMedGoogle Scholar
  71. Manso CF, Díaz S, Carballal MJ, Villalba A, Romalde JL (2012) Detection of reverse transcriptase activity in golden carpet shell clams (Venerupis aurea) with disseminated neoplasia. Bull Eur Assoc Fish Pathol 32:56–63Google Scholar
  72. Marin MC, Kaelin WGJ (2000) p63 and p73: old members of a new family. Biochim Biophys Acta 1470:M93–M100PubMedGoogle Scholar
  73. Marine J-C, Jochemsen AG (2005) Mdmx as an essential regulator of p53 activity. Biochem Biophys Res Commun 331:750–760PubMedGoogle Scholar
  74. Metzger MJ, Reinisch C, Sherry J, Goff SP (2015) Horizontal transmission of clonal cancer cells causes leukemia in soft-shell clams. Cell 161:255–263PubMedPubMedCentralGoogle Scholar
  75. Metzger M, Villalba A, Carballal M, Iglesias D, Sherry J, Reinisch C, Muttray A, Baldwin S, Goff S (2016) Widespread transmission of independent cancer lineages within multiple bivalve species. Nature 534:705–709PubMedPubMedCentralGoogle Scholar
  76. Miciak J, Bunz F (2016) Long story short: p53 mediates innate immunity. Biochim Biophys Acta 1865:220–227PubMedPubMedCentralGoogle Scholar
  77. Miosky D, Smolowitz R, Reinisch C (1989) Leukemia cell specific protein of the bivalve mollusc Mya arenaria. J Invertebr Pathol 53:32–40PubMedGoogle Scholar
  78. Mix MC (1983) Haemic neoplasia of bay mussels, Mytilus edulis L., from Oregon: Occurence, prevalence, seasonality and histopathological progression. J Fish Dis 6:239–248Google Scholar
  79. Moll UM, Slade N (2004) p63 and p73: roles in development and tumor formation. Mol Cancer Res 2:371–386PubMedGoogle Scholar
  80. Moll UM, Zaika A (2001) Nuclear and mitochondrial apoptotic pathways of p53. FEBS Lett 493:65–69PubMedGoogle Scholar
  81. Moll UM, Ostermeyer AG, Haladay R, Winkfield B, Frazier M, Zambetti G (1996) Cytoplasmic sequestration of wild-type p53 protein impairs the G1 checkpoint after DNA damage. Mol Cell Biol 16:1126–1137PubMedPubMedCentralGoogle Scholar
  82. Momand J, Villegas A, Belyi VA (2011) The evolution of MDM2 family genes. Gene 486:23–30PubMedPubMedCentralGoogle Scholar
  83. Murgia C, Pritchard JK, Kim SY, Fassati A, Weiss RA (2006) Clonal origin and evolution of a transmissible cancer. Cell 126:477–487PubMedPubMedCentralGoogle Scholar
  84. Muttray AF, Cox RL, St-Jean SD, van Poppelen P, Reinisch CL (2005) Identification and phylogenetic comparison of p53 in two distinct mussel species (Mytilus). Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 140:237–250Google Scholar
  85. Muttray AF, Cox RL, Reinisch CL, Baldwin SA (2007) Identification of DeltaN isoform and polyadenylation site choice variants in molluscan p63/p73-like homologues. Mar Biotechnol 9:217–230PubMedGoogle Scholar
  86. Muttray AF, Schulte PM, Baldwin SA (2008) Invertebrate p53-like mRNA isoforms are differentially expressed in mussel haemic neoplasia. Mar Environ Res 66:412–421PubMedGoogle Scholar
  87. Muttray AF, O'Toole TF, Morrill W, Van Beneden RJ, Baldwin SA (2010) An invertebrate mdm homolog interacts with p53 and is differentially expressed together with p53 and ras in neoplastic Mytilus trossulus haemocytes. Comp Biochem Physiol Part B 156:298–308Google Scholar
  88. Muttray A, Reinisch C, Miller J, Ernst W, Gillis P, Losier M, Sherry J (2012) Haemocytic leukemia in Prince Edward Island (PEI) soft shell clam (Mya arenaria): spatial distribution in agriculturally impacted estuaries. Sci Total Environ 424:130–142PubMedGoogle Scholar
  89. Nedelcu AM, Tan C (2007) Early diversification and complex evolutionary history of the p53 tumor suppressor gene family. Dev Genes Evol 217:801–806PubMedGoogle Scholar
  90. Noda T (2011) The maternal genes Ci-p53/p73-a and Ci-p53/p73-b regulate zygotic ZicL expression and notochord differentiation in Ciona intestinalis embryos. Dev Biol 360:216–229PubMedGoogle Scholar
  91. Noël D, Pipe RK, Elston RA, Bachere E, Mialhe E (1994) Antigenic characterization of haemocyte subpopulations in the mussel Mytilus edulis by means of monoclonal antibodies. Mar Biol 119:549–556Google Scholar
  92. Nzoughet JK, Hamilton JTG, Botting CH, Douglas A, Devine L, Nelson J, Elliott CT (2009) Proteomics identification of azaspiracid toxin biomarkers in blue mussels, Mytilus edulis. Mol Cell Proteomics MCP 8:1811–1822PubMedGoogle Scholar
  93. O'Brate A, Giannakakou P (2003) The importance of p53 location: nuclear or cytoplasmic zip code? Drug Resist Updat 6:313–322PubMedGoogle Scholar
  94. Oprandy JJ, Chang PW (1983) 5-bromodeoxyuridine induction of hematopoietic neoplasia and retrovirus activation in the soft-shell clam, Mya arenaria. J Invertebr Pathol 42:196–206PubMedGoogle Scholar
  95. Oprandy JJ, Chang PW, Pronovost AD, Cooper KR, Brown RS, Yates VJ (1981) Isolation of a viral agent causing hematopoietic neoplasia in the soft-shell clam, Mya arenaria. J Invertebr Pathol 38:45–51Google Scholar
  96. Ou HD, Löhr F, Vogel V, Mäntele W, Dötsch V (2007) Structural evolution of C-terminal domains in the p53 family. EMBO J 26:3463–3473PubMedPubMedCentralGoogle Scholar
  97. Owens L, Malham S (2015) Review of the RNA interference pathway in molluscs including some possibilities for use in bivalves in aquaculture. J Mar Sci Eng 3:87Google Scholar
  98. Pankow S, Bamberger C (2007) The p53 tumor suppressor-like protein nvp63 mediates selective germ cell death in the sea anemone Nematostella vectensis. PLoS One 2:e782PubMedPubMedCentralGoogle Scholar
  99. Pavletich NP, Chambers KA, Pabo CO (1993) The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. Genes Dev 7:2556–2564PubMedGoogle Scholar
  100. Pearse AM, Swift K (2006) Allograft theory: transmission of devil facial-tumour disease. Nature 439:549PubMedGoogle Scholar
  101. Poder M, Auffret M (1986) Sarcomatous lesion in the cockle Cerastoderma edule: I. Morphology and population survey in Brittany, France. Aquaculture 58:1–8Google Scholar
  102. Potts M-S (1996) Effects of hematopoietic neoplasia on reproduction and population size distribution in the softshell clam. J Shellfish Res 15:519Google Scholar
  103. Reinisch CL, Charles AM, Troutner J (1983) Unique antigens on neoplastic cells of the soft shell clam Mya arenaria. Dev Comp Immunol 7:33–39PubMedGoogle Scholar
  104. Rhodes LD, Van Beneden RJ (1997) Isolation of the cDNA and characterization of mRNA expression of ribosomal protein S19 from the soft-shell clam, Mya arenaria. Gene 197:295–304PubMedGoogle Scholar
  105. Robert J (2010) Comparative study of tumorigenesis and tumor immunity in invertebrates and nonmammalian vertebrates. Dev Comp Immunol 34:915–925PubMedPubMedCentralGoogle Scholar
  106. Romalde JL, Luz Vilarino M, Beaz R, Rodriguez JM, Diaz S, Villalba A, Carballal MJ (2007) Evidence of retroviral etiology for disseminated neoplasia in cockles (Cerastoderma edule). J Invertebr Pathol 94:95–101PubMedGoogle Scholar
  107. Rowley AF, Powell A (2007) Invertebrate immune systems–specific, quasi-specific, or nonspecific? J Immunol 179:7209–7214PubMedGoogle Scholar
  108. Ruiz P, Díaz S, Orbea A, Carballal MJ, Villalba A, Cajaraville MP (2013) Biomarkers and transcription levels of cancer-related genes in cockles Cerastoderma edule from Galicia (NW Spain) with disseminated neoplasia. Aquat Toxicol 136-137:101–111PubMedGoogle Scholar
  109. Ruiz M, Darriba S, Rodríguez R, Lopez C (2015) Marteilia sp. and other parasites and pathological conditions in Solen marginatus populations along the Galician coast (NW Spain). Dis Aquat Org 112:177–184PubMedGoogle Scholar
  110. Sacht G, Brigelius-Flohe R, Kiess M, Sztajer H, Flohe L (1999) ATP-sensitive association of mortalin with the IL-1 receptor type I. Biofactors 9:49–60PubMedGoogle Scholar
  111. Seton-Rogers S (2016) Tumour metabolism: adapting to harsh conditions. Nature Review Cancer 16:616–617Google Scholar
  112. Shabalina S, Ogurtsov A, Spiridonov N (2006) A periodic pattern of mRNA secondary structure created by the genetic code. Nucleic Acids Res 34:2428–2437PubMedPubMedCentralGoogle Scholar
  113. Shadfan M, Lopez-Pajares V, Yuan Z-M (2012) MDM2 and MDMX: alone and together in regulation of p53. Translat Cancer Res 1:88–89Google Scholar
  114. Shieh S-Y, Ikeda M, Taya Y, Prives C (1997) DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91:325–334PubMedGoogle Scholar
  115. Siah A, Delaporte M, Pariseau J, McKenna P, Berthe FCJ (2008) Patterns of p53, p73 and mortalin gene expression associated with haemocyte polyploidy in the soft-shell clam, Mya arenaria. J Invertebr Pathol 98:148–152PubMedGoogle Scholar
  116. Siah A, McKenna P, Danger JM, Johnson G, Berthe FCJ (2011) Induction of transposase and polyprotein RNA levels in disseminated neoplastic hemocytes of soft-shell clams: Mya arenaria. Dev Comp Immunol 35:151–154PubMedGoogle Scholar
  117. Siddlea HV, Kreissb A, Tovarb C, Yuena CK, Chengc Y, Belovc K, Swiftd K, Pearsed A-M, Hamedee R, Jonese ME et al (2013) Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer. PNAS 110:5103–5108Google Scholar
  118. Smolarz K, Renault T, Wolowicz M (2005) Histology, cytogenetics and cytofluorymetry in diagnosis of neoplasia in Macoma balthica (Bivalvia, L.) from the southern Baltic Sea. Caryologia 58:212–219Google Scholar
  119. Smolowitz RM, Miosky D, Reinisch CL (1989) Ontogeny of leukemic cells of the soft shell clam. J Invertebr Pathol 53:41–51PubMedGoogle Scholar
  120. Spadafora C (2004) Endogenous reverse transcriptase: a mediator of cell proliferation and differentiation. Cytogenet Genome Res 105:346–350PubMedGoogle Scholar
  121. Stephens RE, Walker CW, Reinisch CL (2001) Multiple protein differences distinguish clam leukemia cells from normal hemocytes: evidence for the involvement of p53 homologues. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 129:329–338Google Scholar
  122. Stifanic M, Micic M, Ramšak A, Blaškovic S, Ruso A, Zahn RK, Batel R (2009) p63 in Mytilus galloprovincialis and p53 family members in the phylum Mollusca. Comp Biochem Physiol B: Biochem Mol Biol 154:264–273Google Scholar
  123. St-Jean SD, Stephens RE, Courtenay SC, Reinisch CL (2005) Detecting p53 family proteins in leukemia cells of Mytilus edulis from Pictou Harbour, Nova Scotia. Can J Fish Aquat Sci 62:2055–2066Google Scholar
  124. Suh EK, Yang A, Kettenbach A, Bamberger C, Michaelis AH, Zhu Z, Elvin JA, Bronson RT, Crum CP, McKeon F (2006) p63 protects the female germ line during meiotic arrest. Nature 444:624–628PubMedGoogle Scholar
  125. Sunila I (2003) Disseminated sarcoma in the soft shell clam (Mya arenaria) – physiological and molecular aspects. AAC Spec. Publ. 6:56–59Google Scholar
  126. Taraska NG, Böttger AS (2013) Selective initiation and transmission of disseminated neoplasia in the soft shell clam Mya arenaria dependent on natural disease prevalence and animal size. J Invertebr Pathol 112:94–101PubMedGoogle Scholar
  127. Thanos CD, Bowie JU (1999) p53 family members p63 and p73 are SAM domain-containing proteins. Protein Sci 8:1708–1710PubMedPubMedCentralGoogle Scholar
  128. Vassilenko E, Baldwin SA (2013) p53 sequence polymorphisms in late-stage leukemic Mytilus edulis are homologous with M. trossulus p53. Mar Biol 160:1751–1760Google Scholar
  129. Vassilenko EI, Baldwin SA (2014) Using flow cytometry to detect haemic neoplasia in mussels (Mytilus trossulus) from the Pacific Coast of Southern British Columbia, Canada. J Invertebr Pathol 117:68–72PubMedGoogle Scholar
  130. Vassilenko EI, Muttray AF, Schulte PM, Baldwin SA (2010) Variations in p53-like cDNA sequence are correlated with mussel haemic neoplasia: a potential molecular-level tool for biomonitoring. Mutat Res 701:145–152PubMedGoogle Scholar
  131. Vázquez N, Cremonte F (2017) Review of parasites and pathologies of the main bivalve species of commercial interest of Argentina and Uruguay, Southwestern Atlantic Coast. Arch Parasitol 1:2Google Scholar
  132. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310PubMedGoogle Scholar
  133. von der Chevallerie K, Rolfes S, Schierwater B (2014) Inhibitors of the p53–Mdm2 interaction increase programmed cell death and produce abnormal phenotypes in the placozoon Trichoplax adhaerens (FE Schulze). Dev Genes Evol 224:79–85PubMedGoogle Scholar
  134. Voskoboynik A, Newman AM, Corey DM, Sahoo D, Pushkarev D, Neff NF, Passarelli B, Koh W, Ishizuka KJ, Palmeri KJ et al (2013) Identification of a colonial chordate histocompatibility gene. Science 341:384–387PubMedPubMedCentralGoogle Scholar
  135. Wadhwa R, Yaguchi T, Hasan MK, Mitsui Y, Reddel RR, Kaul SC (2002) Hsp70 family member, mot-2/mthsp70/GRP75, binds to the cytoplasmic sequestration domain of the p53 protein. Exp Cell Res 274:246PubMedGoogle Scholar
  136. Walker C, Bottger S, Low B (2006) Mortalin-based cytoplasmic sequestration of p53 in a nonmammalian cancer model. Am J Pathol 168:1526–1530PubMedPubMedCentralGoogle Scholar
  137. Walker C, Bottger SA, Mulkern J, Jerszyk E, Litvaitis M, Lesser M (2009) Mass culture and characterization of tumor cells from a naturally occurring invertebrate cancer model: applications for human and animal disease and environmental health. Biol Bull 216:23–39PubMedGoogle Scholar
  138. Walker CL, Van Benedeny RJ, Muttray AF, Bottger SA, Kelley ML, Tucker AE, Kelley Thomas W (2011) p53 superfamily proteins in marine bivalve cancer and stress biology. Adv Mar Biol 59:1–36PubMedGoogle Scholar
  139. Walker C, Low B, Böttger SA (2012) Mortalin in invertebrates and the induction of apoptosis by wild-type p53 following defeat of mortalin-based cytoplasmic sequestration in cancerous clam hemocytes. In: Kaul S, Wadhwa R (eds) Mortalin biology: life, stress and death. Springer, Dordrecht, pp 97–113Google Scholar
  140. Wolowicz M, Smolarz K, Sokolowski A (2005) Neoplasia in estuarine bivalves: effect of feeding behaviour and pollution in the Gulf of Gdansk (Baltic Sea, Poland). Springer, BerlinGoogle Scholar
  141. Yoon M-K, Ha J-H, Lee M-S, Chi S-W (2015) Structure and apoptotic function of p73. BMB Rep 48:81–90PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Annette F. Muttray
    • 1
  • Katerina Vassilenko
    • 2
  1. 1.Environmental Resource Management (ERM)VancouverCanada
  2. 2.Coastal Ocean Research Institute, OceanWiseVancouverCanada

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