Tumor venéreo transmissível canino: expressão dos genes MDR-1, TP53 e da família Bcl-2 e suas implicações no comportamento biológico e terapêutico

Luis Mauricio Montoya Floréz, Haline Ballestero Fêo, Noeme Sousa Rocha

Resumen


O tumor venéreo transmissível (TVT) é uma neoplasia de células redondas de aspecto plasmocitóide ou linfocitóide. O tumor  apresenta várias particularidades que tem sido objeto de numerosas investigações e apesar disso, ainda existem lacunas que necessitam de maiores estudos. Por exemplo, nos últimos anos, tem-se evidenciado um aumento progressivo de tumores que apresentam elevados porcentuais de agressividade e variável resposta à quimioterapia, inclusive resistência. Desta forma, atualmente há interesses científicos com relação a compreender
melhor estas diferenças, permitindo predizer uma possível  evolução clínica entre cães acometidos pelo tumor e buscando cada vez mais uma conduta terapêutica adequada e  individualizada. Assim, a revisão de literatura, centra-se em apresentar possíveis implicações da expressão dos genes MDR-1 (glicoproteína-p), TP53, BCL-2, BAX, quanto à resistência à quimioterapia, e/ou comportamento biológico do TVT.

Tumor venéreo transmisible canino: expresión de los genes MDR-1, TP53 y de la familia Bcl-2 y sus implicaciones en el comportamiento biológico y terapéutico

El tumor venéreo transmisible (TVT) es una neoplasia de células redondas de aspecto plasmocitoide o linfocitoide. El tumor presenta varias particularidades que han sido objeto de numerosas investigaciones y a pesar de eso, aún existen algunos vacíos en su conocimiento que requieren mayores estudios. Por ejemplo, en los últimos años, se ha evidenciado un aumento progresivo de tumores que presentan elevados porcentajes de agresividad y una respuesta variable a la quimioterapia, inclusive alguna resistencia. En este sentido, actualmente hay intereses científicos con relación a comprender mejor estas diferencias, permitiendo predecir una posible evolución clínica entre perros
afectados por el tumor y buscando cada vez más una conducta terapéutica adecuada e individualizada. Así, la revisión de literatura, se centra en presentar posibles implicaciones de la expresión de los genes MDR-1 (glicoproteína-p), TP53, BCL-2, BAX, en cuanto a la resistencia a la quimioterapia, y/o el  comportamiento biológico del TVT.

Canine transmissible venereal tumor: expression of MDR-1, and TP53 and BCL-2 family genes and its implic ations in biological and therapeutic behavior

Transmissible venereal tumor (TVT) is a neoplasm of round cells with plasmocytoid or lymphocytoid appearance. The tumor presents several particularities, which have been the subject of numerous studies; however there still have investigations that need to be done. For example, a progressive increase of highly
aggressive tumors with varying response to chemotherapy -including resistance- has been evidenced in recent years. There is scientific interest to understand these differences, allowing predicting possible clinical outcomes in affected dogs and increasingly searching adequate and individualized therapy. This
review focuses on presenting possible implications of the expression of MDR-1 (P-glycoprotein), TP53, BCL-2, and BAX genes, regarding resistance to chemotherapy and/or the biologic behavior of TVT.


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Referencias


Adorno M, Cordenonsi M, Montagner M, Wong C,

Hann B, et al. A Mutant-p53/Smad complex opposes

p63 to empower TGFbeta-induced metastasis. Cell

; 137(1): 87– 98.

Amaral AS, Ferreira I, Colodel MM, fávero Dm,

rocha ns. DNA damage in canine transmissible

venereal tumor. Rev Lus Ciên Med Vet 2011; 4: 1– 5.

Amaral AS, Gaspar LF, Bassini-Silva S, Rocha NS.

Cytological diagnostic of transmissible venereal

tumor in the Botucatu region, Brazil (descriptive

study: 1994-2003). Rev Port Ciên Vet 2004; 99(551):

–171.

Amaral AS, Bassani-Silva S, Ferreira I, Fonseca

LS, Andrade FH, et al. Cytomorphological

characterization of transmissible canine venereal

tumor. Rev Port Ciên Vet 2007; 103: 563–564.

Andrade SMF. Antineoplasicos. In: Andrade SMF.

Manual de terapêutica veterinária. 3ª ed. São Paulo:

ROCA, 2008. p. 206–209.

Athanasius EC, Kene RO, Anyanwu HC. Comparative

efficacy of surgery, vincristine sulphate and combined

therapy of levamisole and Bacille Calmette Guerin

vaccine in the treatment of transmissible venereal

tumour-infected dogs. Comp Clin Pathol 2013;

p.1–5.

Attardi LD, Jacks T. The role of p53 in tumour

suppression: lessons from mouse models. Cell Mol

Life Sci 1999; 55(1): 48–63.

Bergman PJ, Ogilve GK, Powers BE.

Monoclonalantibody C219 immunochemistry against

P-glycoprotein: sequential analysis and predictive

ability in dogs with lymphoma. J Vet Inter Med 1996;

(6): 354–359.

Binkhathlan Z, Lavasanifar A. P-glycoprotein

inhibition as a therapeutic approach for overcoming

multidrug resistance in cancer: Current status and

future perspectives. Curr Cancer Drug Targets 2013;

(3): 326–346.

Cadwel C, Zambetti GP. Effects of wild-types p53

tumour suppressor activity and mutant p53 gain-of

function on cell grown. Gene 2001; 277(1-2): 15–30.

Cory S, Adams JM. The Bcl2 family: regulators of

the cellular life-or-death switch. Nat Rev Cancer

; 2(9): 647–656.

Czabotar PE, Lessene G, Strasser A, Adams MJ.

Control of apoptosis by the BCL‑2 protein family:

implications for physiology and therapy. Nat Rev

Mol Cell Biol 2014; 15(1): 49–63.

Chao DT, Korsmeyer SJ. BCL-2 family: regulators

of cell death - Review. Annu Rev Immunol 1998;

:395–419.

Choi YK, Kim CJ. Sequence analysis of canine

LINE-1 elements and p53 in canine transmissible

venereal tumor. J Vet Sci 2002; 3(4): 285–292.

Das U, Das AK. Review of canine transmissible

venereal sarcoma. Vet Res Commun 2000; 24(8):

–556.

Delfino AB. O envolvimento de genes e proteínas

na regulação da apoptose – carcinogênese. Rev Bras

Cancerol 1997; 43(3): 173–186.

Erünal-Maral N, Findik M, Asalan S. Use of

exfoliative cytology for diagnosis of transmissible

venereal tumour and controlling the recovery period

in the bitch. Dtsch Tierärztl Wochenschr 2000;

(5): 175–180.

Fett-Conte A, Salles AB. A importância do gene p53

na carcinogênes humana. Rev Bras Hematol Hemoter

; 24(2): 85–89.

Ferreira AJ, Jaggy A, Varejão AP, Ferreira

ML, Correia, JM, et al. Brain and ocular metastases

from a transmisible venereal tumour in a dog. J Small

Anim Pract 2000; 41(4): 165–168.

Frenzel A, Grespi F, Chmelewskij W, Villunger

A. Bcl2 family proteins in carcinogénesis and the

treatment of cancer. Apoptosis 2009; 14(4): 584–596.

Ganguly B, Das U, Das K. Canine transmissible

venereal tumour: a review. Vet Comp Onc 2013;

(4): 1–12.

Gaspar LF. Caracterização citomorfológica do tumor

venéreo transmissível canino correlacionada com

danos citogenéticos, taxa de proliferação e resposta

clínica à quimioterapia. Tese de doutorado, Faculdade

de Medicina Veterinária e Zootecnia, Universidade

Estadual Paulista, Botucatu, 2005. 143 p.

Gaspar LF, Amaral AS, Bassani-Silva S, Rocha

NS. Imunorreatividade à glicoproteína-p nos

diferentes tipos citomorfológicos de tumor venéreo

transmissível canino. Vet em Foco 2009; 6(2): 140–

Gaspar LF, Ferreira I, Colodel MM, Brandão

CV, Rocha NS. Spontaneus canine transmissible

venereal tumor: cell morphology and influence on

p-glycoprotein expression. Turk J Vet Anim Sci

; 34(5): 447–454.

Harris C, Hollstein M. Clinical implications of the

p53 tumor-suppressor gene. N Engl J Med 1993;

(18): 1318–1327.

Heinlein C, Krepulat F, Lohler J, Speidel D, Deppert

W, et al. Mutant p53(R270H) gain of function

phenotype in a mouse model for oncogene-induced

mammary carcinogenesis. Int J Cancer 2008; 122(8),

-1709.

Hodges LM, Markova SM, Chinn LW, Gow JM,

Kroetz DL, et al. Very important pharmacogene

summary: ABCB1 (MDR1, Pglycoprotein).

Pharmacogenet. Genomics 2011; 21(3): 152–161.

Kunakornsawat S, Yippaditr W, Jamjan N, Bootcah R,

Netramai S, et al. Surgical correction of transmissible

venereal tumor with vincristineresistance using

episiotomy and vulvo vagino plasty in female and

subtotal penile amputation and scrotal ablation in

male dogs. In Proceeding of 48th Kasetsart University

Annual Conference: Veterinary Medicine. 2010; Feb

-5, Bangkok, Thailand, 191–200.

Kanayan N, Okuda N, Toyama N, Oikawa T, Inokuma

H, et al. Detection of the anti-P53 antibodies in dogs

with tumors. J Vet Med Sci 2002; 64(11): 973–979.

Kirchoff N, Nohr B. Spinal metastasis of a canine

transmissible venereal tumor. Kleintierpraxis 1994;

(11): 797–798.

Kirkin V, Joof S, Zorning M. The role of Bcl-2

family members in tumorigenesis. Biochem Bioph

Act 2003; 16(44): 229–249.

Lacroix M, Toillon RA, Leclercq, G. p53 and breast

cancer, an update. Endocr Relat Cancer 2006; 13(2):

–325.

Lee JJ, Hughes CS, Fine RL, Page RL. P-glycoprotein

expression in canine lymphoma. Cancer 1996; 77(9):

–1898.

Macleod RJ. MDR-1, Bcl-xL, H. pylori, and Wnt/bcatenin

signalling in the adult stomach: how much

is too much?. Laboratory Investigation 2012; 92(12):

–1673.

Marchal T, Chabanne L, Kaplanski C, Rigal D,

Magnol JP. Immunophenotype of the canine

transmissible venereal tumour. Vet Immunol

Immunop 1997; 57(1-2):1–11.

Maia RC, Rumjanek VM. Mecanismos moleculares

de resistência a múltiplas drogas. In: Ferreira CG,

Rocha JC. Oncologia molecular. São Paulo: Atheneu;

p. 113–122.

Mealey KL, Barhoumi R, Rogers K, Kochevar DT.

Doxorubicin induced expression of P-glycoprotein

in a canine osteosarcoma cell line. Cancer Let 1998;

(2): 187–192.

Menendez D, Inga A, Resnick MA. The biological

impact of the human master regulator p53 can be

altered by mutations that change the spectrum and

expression of its target genes. Mol Cell Biol 2006;

(6): 2297–308.

Mendelsohn J, Howley I, Thompson G. The molecular

basis of cancer. 3rd ed. Saunders, 2008.

Mihara M, Erster S, Zaika A, Petrenko O, Chittenden

T, et al. p53 has a direct apoptogenic role at the

mitochondria. Mol. Cell., v.11, p. 577–590, 2003.

Mochida Y, Taguchi K, Taniguchi S, Tsuneyoshi

M, Kuwano H, et al. The role of P-glycoprotein

in intestinal tumorigenesis: disruption of mdr1 a

suppresses polyp formation in Apc (Min/+) mice.

Carcinogenesis 2003; 24(7): 1219–1224.

Montoya FL, Pedraza FJ, Grandi F, Rocha N.

Cytologic subtypes of canine transmissible venereal

tumor. Vet Clin Pathol 2012; 41(1): 4–5.

Montoya FL, Pedraza FJ, Monteiro S, Brandão

CV, Rocha NS. Cytological and clinical staging

of transmissible venereal tumour at the Veterinary

Hospital of Botucatu. Rev Vet Zoot 2014; in press.

Mozos E, Méndez A, Gómez-Villamandos JC,

Martín de las mulas J, Pérez J. lmmunohistochemical

characterization of canine transmissible venereal

tumor. Vet Path 1996; 33(3): 257–263.

Moro JV, Tinucci-Costa M, Silveira AC, Gerardi

DG, Alessi AC. Reactivity of p53 protein in canine

transmissible venereal tumor. Arq Bras Med Vet

Zootec 2010; 62(2): 318–323.

Muller PA, Caswell PT, Doyle B, Iwanicki M, Tan

E, et al. Mutant p53 drives invasion by promoting

integrin recycling. Cell 2009; 139(7): 1327–1341.

Muller PA, Vousden KH, Norman JC. p53 and its

mutants in tumor cell migration and invasion. J Cell

Biol 2011; 192(2): 209–218.

Murchison PE, Wedge DC, Alexandrov LB, Fu B,

Martincorena I, et al. Transmissable Dog Cancer

Genome Reveals the Origin and History of an Ancient

Cell Lineage. Science 2014; 343( 6169): 437–440.

Nielsen SW, Kennedy PC. Tumors of the genital

systems. In: Moulton JE. Tumors in domestic animals.

ª ed. Los Angeles: London; 2000. p. 479–517.

Oliveira DK, Quessada AM, Medeiros SM, Lima CF,

Dos Santos LS, et al. Transmissible Venereal Tumor

Treated with Autohemotherapy. Acta Scientiae

Veterinariae 2013; 41:1107.

Ozaki T, Nakagawara A. p53: The Attractive Tumor

Suppressor in the Cancer Research Field. J Biomed

Biotechnol 2011; [acesso: 14 fevereiro de 2014]. http://

www.hindawi.com/journals/bmri/2011/603925/

Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the

p53 Tumor Suppressor Gene: Important Milestones

at the Various Steps of Tumorigenesis. Genes Cancer

; 2(4): 466–474.

Rogers KS. Transmissible venereal tumour. Compend

Contin Educ Pract Vet 1997; 19(9): 1036–1045.

Rogers KS, Walker MA, Dillon HB. Transmissible

venereal tumor: a retrospective study of 29 cases. J

Am Anim Hosp Assoc 1998; 34(6): 463– 470.

Said RA, Silva LF, Albuquerque A, Sousa- Neta,

EM, Lavinsky MO. Efficacy and side effects of

vincristine sulfate treatment on canine transmissible

venereal tumor. In Proceeding of the 34th World

Small Animal Veterinary Association, Sao Paulo,

[acesso: 10 de Fevereiro de 2014]. http:/

/s.plx? CID =WSAVA2009&Category=&PID =5379

&0=Generic

Santos FG, Vasconcelos AC, Nunes JE, Cassali GD,

Paixão TA, Moro L. O tumor venéreo transmissível

canino - aspectos gerais e abordagens moleculares

(revisão de literatura). Bioscience J 2005; 21(3): 41–

Servín SA, Martínez S, Alarcon EC, Fajardo R.

TP53 Polymorphisms allow for genetic sub-grouping

of the canine transmissible venereal tumor. J Vet Sci

; 10(4): 353– 355.

Siddle HV, Kaufman J. A tale of two tumours:

Comparison of the immune escape strategies of

contagious cancers. Mol Immunol 2013; 55(2): 190–

Soto CV. Caracterización del efecto anticanceroso

e identificación de dianas moleculares de principios

activos procedentes de serrata marcescens. Tesis

de doctoral, Universidad de Barcelona, Barcelona,

España, 2007. 252 p.

Soussi T, Beroud C. “Assessing TP53 status in human

tumours to evaluate clinical outcome. Nat Rev Can

; 1(3): 233–240.

Sousa J, Saito V, Nardi B, Rodaski S, Guerios S,

Bacila M. Características e incidência do tumor

venéreo transmissível (TVT) em cães e eficiência

da quimioterapia e outros tratamentos. Arch Vet Sci

Curitiba 2000; 5: 41– 48.

Stockmann D, Ferrari H, Andrade A, Cardoso T,

Luvizotto M. Detection of the tumour suppressor

gene TP53 and expression of p53, Bcl-2 and p63

proteins in canine transmissible venereal tumor. Vet

Comp Oncol 2011a; 9(4): 1– 9.

Stockmann D, Ferrari H, Andrade A, Lopes A,

Cardoso T, Luvizotto M. Canine Transmissible

Venereal Tumors: Aspects Related to Programmed

Cell Death. Braz J Vet Pathol 2011b; 4(1): 67– 75.

Sudjaidee P, Theewasutrakul P, Techarungchaikul

S, Ponglowhapanl S, Chatdarong K. Treatment of

canine transmissible venereal tumor using vincristine

sulfate combined with l-asparaginase in clinical

vincristine-resistant cases: a case report. Thai J Vet

Med 2012; 42(1): 117– 122.

Suzuki K, Matsubara H. Recent Advances in p53

Research and Cancer Treatment. J Biomed Biotechnol

; 2-7.

Szakács G, Paterson J, Ludwig J, Booth-genthe C,

Gottesman MM. Targeting multidrug resistance in

cancer. Nat rev 2006; 5(3): 219– 234.

Thomas H, Coley H. Overcoming multidrug

resistance in cancer: An update on the clinical strategy

of inhibiting p -glycoprotein. Canc Cont 2003; 10(2):

– 165.

Tomita Y, Marchenko N, Erster S, Nemajerova A,

Dehner A, et al. WT p53, but not tumor-derived

mutants, bind to Bcl2 via the DNA binding domain

and induce mitochondrial permeabilization. J Biol

Chem 2006; 281(13): 8600–8606.

Tsujimura S, Tanaka Y. Treatment strategy based on

targeting P-glycoprotein on peripheral lymphocytes

in patients with systemic autoimmune disease. Clin

Exp Nephrol 2012; 16(1): 102–108.

Varaschin M, Wouters V, Soares T, Tokura V, Dias

M. Tumor venéreo transmissível canino na região

de Alfenas, Minas Gerais: formas de apresentação

clínicopatológicas. Rev Clín Vet 2001; 32: 40– 48.

Vázquez M, Martínez S, Alarcón C, lagunes L,

Fajardo R. The T963C mutation of TP53 gene does

not participate in the clonal origin of canine TVT. Vet

Res Commun 2008; 32(2): 187–191.

Walerych D, Napoli M, Collavin L, Del Sal G. The

rebel angel: mutant p53 as the driving oncogene in

breast cancer. Carcinogenesis 2012; 33(11): 2007–

Wang L, Song Y, Zheng W, Jiang L, Ma L. The

association between polymorphisms in the MDR1

gene and risk of cancer: a systematic review and

pooled analysis of 52 case–control studies. Cancer

Cell International 2013; 13(1): 46 .

Warr JR, Bamford A, Quinn DM. The preferential

induction of apoptosis in multidrug resistant B cells

by 5-fluouracil. Cancer Lett 2002; 175: 39−44.

Zhou H, Chen J, Meagher J, Yang C, Aguilar A,

et al. Design of Bcl-2 and Bcl-xL Inhibitors with

Subnanomolar Binding Affinities Based upon a New

Scaffold. J Med Chem 2012; 55(10): 4664−4682.

Vazquez A, Bond EE, Levine AJ, Bond GL. The

genetics of the p53 pathway, apoptosis and cancer

therapy Nature 2008; 7: 979–987.




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