Expression and Significance of p53, Rb, p21/waf-1, p16/ink-4a, and PTEN Tumor Suppressors in Canine Melanoma

Koenig, Amanda; Bianco, S. R.; Fosmire, Susan; Wojcieszyn, John; Modiano, Jaime F.

doi:10.1354/vp.39-4-458

Cited by 99 publications

(123 citation statements)

References 65 publications

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“…Although most studies indicate that loss of nuclear expression of Rb protein may be responsible for malignant transformation, no studies have so far attempted to correlate its aberrant cytoplasmic expression with prognosis. Thus, cytoplasmic localisation of Rb protein may be a novel mechanism of inactivation of the Rb protein as reported by Koenig et al 2002. In the present study, an attempt has been made to determine the localisation of the Rb protein and to delineate its prognostic significance.…”

Section: Discussionmentioning

confidence: 79%

Aberrant cytoplasmic accumulation of retinoblastoma protein in basal cells may lead to increased survival in malignant canine mammary tumours

Gautam¹,

Sood²,

Gupta³

2014

Vet. Med. - Czech

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ABSTRACT:The retinoblastoma susceptibility gene RB-1 is a tumour suppressor gene that encodes a protein (Rb) that regulates the transition from the G1 phase to the S phase of the cell cycle. Inactivation of the Rb gene has been shown in a variety of human tumours, including breast, ovarian, hepatic, prostatic, and endometrial carcinomas. Although Rb protein is normally expressed in the nuclei of healthy cells, during carcinogenesis there is a partial or complete loss of nuclear expression. Recently, some reports have indicated aberrant cytoplasmic expression of Rb protein. However, little is known about its cytoplasmic expression and significance as a prognostic marker in canine mammary tumours (CMT). The present study was performed on 36 malignant CMT cases in order to assess the mutational status and prognostic significance of Rb in primary malignant CMT. We report an almost complete loss of nuclear expression of Rb protein with corresponding gain of aberrant cytoplasmic expression in basal/myoepithelial cells in CMT. Strikingly, our analysis reveals a significant positive correlation between survival time and cytoplasmic expression of Rb protein in basal cells. Moreover, cytoplasmic expression of Rb protein in basal cells was also correlated with tumour grade and stage.

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Section: Discussionmentioning

confidence: 79%

Aberrant cytoplasmic accumulation of retinoblastoma protein in basal cells may lead to increased survival in malignant canine mammary tumours

Gautam¹,

Sood²,

Gupta³

2014

Vet. Med. - Czech

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“…The observation that various pathways required for intrinsic apoptosis are frequently inactivated in canine melanoma 9 led us to consider the possibility of promoting extrinsic apoptosis in these cells using FasL overexpression. The use of FasL was previously shown to be safe by one of our groups in rodents bearing prostatic cancer xenografts; 21 moreover, as noted above, Fas expression by the tumors would not be absolutely required for the treatment to be effective.…”

Section: Discussionmentioning

confidence: 99%

“…27 Based on previous data indicating that various molecules that promote apoptosis using the intrinsic pathways are commonly inactivated in canine melanoma, 9 we examined the capacity to promote apoptosis of these cells by overexpression of FasL as a means to activate the extrinsic pathways.…”

Section: Induction Of Apoptosis Of Canine Melanoma Cells By Faslmentioning

confidence: 99%

“…[6][7][8] Previous data indicate that various pathways that promote intrinsic apoptosis are commonly inactivated in canine melanoma. 9 Consequently, proapoptotic genes that can activate the cell death program irrespective of the genetic make-up of the tumor would be needed to develop a feasible treatment protocol that will re-establish the capacity of tumor cells to undergo apoptosis. In addition, recent data suggest that vigorous inflammatory responses at the site of a primary tumor might promote an antitumor response that can prevent growth of distant metastases.…”

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confidence: 99%

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Enhancing antimelanoma immune responses through apoptosis

et al. 2003

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We examined the feasibility of using tumor apoptosis at accessible sites to enhance antimelanoma immune responses in a model of spontaneous canine melanoma. We show that priming peripheral blood mononuclear cells with apoptotic melanoma cells significantly enhanced autologous and allogeneic lymphokine-activated killing of tumor cells. Since various pathways required for intrinsic apoptosis are often inactivated in melanoma, we used Fas ligand (FasL) overexpression to promote extrinsic apoptosis. FasL induced apoptosis in five of six cell lines. Each of the susceptible lines, but not the resistant one, expressed Fas mRNA. In addition, direct intratumoral administration of FasL DNA to tumor-bearing dogs was safe, with no adverse events reported over 7 days of observation. A reduction of tumor burden was seen in three of five dogs treated. The reduction of tumor volume was correlated with Fas expression by the tumors, although one dog with a Fas-negative tumor survived for 82 weeks after treatment. Our data show that overexpression of FasL is suitable to promote apoptosis of Fas + melanomas, and support the notion that priming immune responder cells with apoptotic tumor cells may enhance antitumor responses. The results also suggest that intratumoral administration of FasL offers a safe route for therapeutic gene delivery.

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“…Deletions and mutations of PTEN are widely reported in several human malignancies (Worby & Dixon 2014) and in canine osteosarcoma (Levine et al 2002), melanoma (Koenig et al 2002), hemangiosarcoma (Dickerson et al 2005), and mammary tumors (Ressel et al 2009), suggesting that PTEN is associated with tumor development and growth in veterinary oncology.…”

Section: Introductionmentioning

confidence: 99%

Over-expression of PTEN on proliferation and apoptosis in canine mammary tumors cells

Tong

Zhang

Sun

et al. 2016

Animal Cells and Systems

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Phosphatase and tensin homolog (PTEN) is an important tumor-suppressor gene which constitutes an important PI3K/Akt pathway by regulating the signaling of multiple biological processes, including apoptosis, metabolism, cell proliferation, and cell growth has been gaining increasing attention. However, the role of PTEN in regulating apoptosis of canine mammary tumors cells still needs further investigation. In this experiment, the effect of PTEN on proliferation and apoptosis in canine mammary tumors (CMT) cells was analyzed. As a result, gene and protein expression levels of apoptosis-related genes were detected. Eukaryotic expression vector pcDNA3.1+-PTEN were successfully constructed and stably transferred into canine CMT cells after geneticin (G418) selection. After pcDNA3.1+-PTEN transfection, compared with control group, the cells proliferation was inhibited and the cell apoptosis was increased in CMT cells. The expression of p-Akt was decreased and the apoptosis-related genes, such as caspase-3, caspase-9, and Bax, were increased. These data serve to demonstrate the function of PTEN on apoptosis and gene regulatory in PI3K/Akt pathway in CMT cells. Collectively, our data link the tumorsuppressor activities of PTEN to the machinery controlling cell cycle through the modulation of signaling molecules whose signal target is the functional inactivation of the apoptosis gene product. ARTICLE HISTORY

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Expression and Significance of p53, Rb, p21/waf-1, p16/ink-4a, and PTEN Tumor Suppressors in Canine Melanoma

Cited by 99 publications

References 65 publications

Aberrant cytoplasmic accumulation of retinoblastoma protein in basal cells may lead to increased survival in malignant canine mammary tumours

Aberrant cytoplasmic accumulation of retinoblastoma protein in basal cells may lead to increased survival in malignant canine mammary tumours

Enhancing antimelanoma immune responses through apoptosis

Over-expression of PTEN on proliferation and apoptosis in canine mammary tumors cells

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