Human tumor growth is inhibited by a vaccinia virus carrying the E2 gene of bovine papillomavirus

Valadéz-Graham, Viviana; Sutter, Gerd; José, Marco V.; García‐Carrancá, Alejandro; Erfle, Volker; Mendoza, Norma Moreno; Merchant, Hugo; Rosales, Ricardo

doi:10.1002/(sici)1097-0142(20000401)88:7<1650::aid-cncr20>3.0.co;2-l

Cited by 30 publications

(17 citation statements)

References 43 publications

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“…We did not carry out a systematic analysis of molecular markers of senescence, because in contrast to the situation with fibroblasts, such markers have not been clearly defined for keratinocytes. Although the E2 protein can induce apoptosis in other systems (27,33), we did not detect apoptosis in our experiments (unpublished results). Furthermore, E2-induced senescence was inhibited by constitutive expression of the HPV16 E6 and E7 genes and did not occur in HPV-negative cells (refs.…”

Section: Senescent Cells Exhibit a Number Of Features That Distinguismentioning

confidence: 48%

Rapid induction of senescence in human cervical carcinoma cells

Goodwin

Yang

Lee

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

178

181

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Expression of the bovine papillomavirus E2 regulatory protein in human cervical carcinoma cell lines repressed expression of the resident human papillomavirus E6 and E7 oncogenes and within a few days caused essentially all of the cells to synchronously display numerous phenotypic markers characteristic of cells undergoing replicative senescence. This process was accompanied by marked but in some cases transient alterations in the expression of cell cycle regulatory proteins and by decreased telomerase activity. We propose that the human papillomavirus E6 and E7 proteins actively prevent senescence from occurring in cervical carcinoma cells, and that once viral oncogene expression is extinguished, the senescence program is rapidly executed. Activation of endogenous senescence pathways in cancer cells may represent an alternative approach to treat human cancers. Cancer is thought to be caused by the stepwise accumulation of genetic changes, resulting in progressive phenotypic abnormality. Infection of cervical keratinocytes with a highrisk human papillomavirus (HPV) such as HPV18 is the initiating event in the great majority of cervical carcinomas (1). The HPV E6 and E7 proteins are continuously expressed in cervical carcinoma cells and seem to play a role in tumor development and in maintenance of the malignant phenotype (1). The role of the E6 and E7 proteins in the progression from normal keratinocytes to transformed cells has been studied in cell culture. Normal human keratinocytes can undergo a limited number of cell divisions in vitro and then stop proliferating, a phenomenon referred to as replicative senescence (2-4). Telomere length progressively shortens during cell passage (5, 6), and it has been proposed that once the length of one or more telomeres falls below a critical threshold, an active genetic program is mobilized that culminates in senescence (7,8). Cultured keratinocytes can escape senescence and become immortalized by inactivation of the retinoblastoma tumor suppressor pathway and activation of telomerase, the enzyme responsible for maintaining telomere length (9, 10). Expression of the HPV E6 and E7 proteins also can immortalize keratinocytes (11,12), an activity that is consistent with the known biochemical activities of these proteins. The E7 protein neutralizes the retinoblastoma tumor suppressor pathway, and the E6 protein stimulates telomerase activity in keratinocytes (1,6,13). Although the mechanistic basis for this effect on telomerase activity is not known, this activity seems crucial for immortalization because E6 mutants defective for telomerase activation are immortalization-defective (10). In addition, host-cell mutations are required for HPVimmortalized keratinocytes to become tumorigenic and to acquire other malignant characteristics, such as metastatic potential (9, 14 -20). The E6 and E7 proteins facilitate the acquisition of these mutations by causing accelerated degradation of p53 and p105 Rb , respectively, resulting in abrogation of DNA damage checkpoint control, elevat...

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Section: Senescent Cells Exhibit a Number Of Features That Distinguismentioning

confidence: 48%

Rapid induction of senescence in human cervical carcinoma cells

Goodwin

Yang

Lee

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

178

181

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“…The growth of human tumors was effectively controlled by immunization with the recombinant vaccinia virus Ankara (MVA) expressing HPV E2 (MVA-E2). This vaccine showed potential to be used as a therapeutic vaccine ( 95 ). The viral vector-based MVA-E2 therapeutic vaccine inhibited HPV growth in high-grade lesions (CIN2 and CIN3) ( 96 ).…”

Section: Hpv Diseasementioning

confidence: 99%

Advances in Designing and Developing Vaccines, Drugs and Therapeutic Approaches to Counter Human Papilloma Virus

Dadar

Chakraborty²,

Dhama

et al. 2018

Front. Immunol.

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Human papillomavirus (HPV) is a viral infection with skin-to-skin based transmission mode. HPV annually caused over 500,000 cancer cases including cervical, anogenital and oropharyngeal cancer among others. HPV vaccination has become a public-health concern, worldwide, to prevent the cases of HPV infections including precancerous lesions, cervical cancers, and genital warts especially in adolescent female and male population by launching national programs with international alliances. Currently, available prophylactic and therapeutic vaccines are expensive to be used in developing countries for vaccination programs. The recent progress in immunotherapy, biotechnology, recombinant DNA technology and molecular biology along with alternative and complementary medicinal systems have paved novel ways and valuable opportunities to design and develop effective prophylactic and therapeutic vaccines, drugs and treatment approach to counter HPV effectively. Exploration and more researches on such advances could result in the gradual reduction in the incidences of HPV cases across the world. The present review presents a current global scenario and futuristic prospects of the advanced prophylactic and therapeutic approaches against HPV along with recent patents coverage of the progress and advances in drugs, vaccines and therapeutic regimens to effectively combat HPV infections and its cancerous conditions.

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“…Subsequently, several virus stocks were characterized in detail by verifying the expression of the E2 gene. The E2 RNA was detected by reverse transcription/polymerase chain reaction, and the E2 protein was detected by Western blotting of cell lysates from BS-C-1-and HeLa-infected cells [51].…”

Section: Construction Of Vaccinia Recombinantsmentioning

confidence: 99%

“…For all these reasons, we have used the MVA strain to construct a new recombinant virus carrying the E2 gene of bovine papillomavirus. This recombinant virus, named MVA E2, directed the expression of the E2 protein in infected cells, and was able to arrest human tumor growth in nude mice [51].…”

Section: Introductionmentioning

confidence: 99%

A recombinant vaccinia virus containing the papilloma E2 protein promotes tumor regression by stimulating macrophage antibody-dependent cytotoxicity

Rosales

Valadéz-Graham²,

Rosas

et al. 2000

Cancer Immunol Immunother

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Human papillomavirus infection is associated with cervical cancer. The E6 and E7 papillomavirus proteins are normally required for the maintenance of the malignant phenotype. Expression of these proteins in infected cells is negatively regulated by the binding of the papilloma E2 protein to the long terminal control region of the papilloma virus genome. The E2 protein can also promote cell arrest and apoptosis in HeLa cells. Therefore, it is clear that this protein has the potential of inhibiting the malignant phenotype. Because, anticancer vaccines based in vaccinia viruses have recently been shown to be an effective way to treat and to eradicate tumors, a recombinant vaccinia virus expressing the E2 gene of bovine papilloma virus (Modified Vaccinia Ankara, MVA E2) was created, to explore further the antitumor potential of the E2 protein. A series of rabbits, containing the VX2 transplantable papilloma carcinoma, were treated with MVA E2. An impressive tumor regression, up to a complete disappearance of tumor, was observed in most animals (80%). In contrast, very little or no regression was detected if the normal vaccinia virus was used. Lymphocytes isolated from MVA E2-treated rabbits did not show cytotoxic activity against tumor cells. However, in these animals a humoral immune response against tumor cells was observed. These antitumor antibodies were capable of activating macrophages to destroy tumor cells efficiently. These data indicate that injecting the MVA E2 recombinant vaccinia virus directly into the tumor results in a robust and long-lasting tumor regression. Data also suggest that antitumor antibodies are responsible, at least in part, for eliminating tumors by activating macrophage antibody-dependent cytotoxicity.

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Human tumor growth is inhibited by a vaccinia virus carrying the E2 gene of bovine papillomavirus

Cited by 30 publications

References 43 publications

Rapid induction of senescence in human cervical carcinoma cells

Rapid induction of senescence in human cervical carcinoma cells

Advances in Designing and Developing Vaccines, Drugs and Therapeutic Approaches to Counter Human Papilloma Virus

A recombinant vaccinia virus containing the papilloma E2 protein promotes tumor regression by stimulating macrophage antibody-dependent cytotoxicity

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