RESUMO
Tp53 mutations are common in human prostate cancer (CaP), occurring with a frequency of â¼30% and â¼70% in localized and metastatic disease, respectively. In vitro studies have determined several common mutations of Tp53 that have specific gain-of-function properties in addition to loss of function, including the ability to promote castration-resistant (CR) growth of CaP cells in some contexts. To date, a lack of suitable mouse models has prohibited investigation of the role played by Tp53 mutations in mediating CaP progression in vivo. Here, we describe the effects of conditional expression of a mutant Tp53 (Tp53(R270H); equivalent to the human hotspot mutant R273H) in the prostate epithelium of mice. Heterozygous "Tp53(LSL-R270H/+)" [129S4(Trp53(tm3Tyj))] and "Nkx3.1-Cre" [129S(Nkx3-1(tm3(cre)Mms))] mice with prostate-specific expression of the Tp53(R270H) mutation (p53(R270H/+) Nkx3.1-Cre mice) were bred onto an FVB/N background via speed congenesis to produce strain FVB.129S4(Trp53(tm3Tyj/wt)); FVB.129S(Nkx3-1(tm3(cre)Mms/wt)) and littermate genotype negative control mice. These mutant mice had significantly increased incidences of prostatic intraepithelial neoplasia (PIN) lesions, and these appeared earlier, compared with the Nkx3.1 haploinsufficient (Nkx3.1-Cre het) littermate mice, which did not express the Tp53 mutation. PIN lesions in these mice showed consistent progression and some developed into invasive adenocarcinoma with a high grade, sarcomatoid or epithelial-mesenchymal transition (EMT) phenotype. PIN lesions were similar to those seen in PTEN conditional knockout mice, with evidence of AKT activation concomitant with neoplastic proliferation. However, the invasive tumor phenotype is rarely seen in previously described mouse models of prostatic neoplasia. These data indicate that the Tp53(R270H) mutation plays a role in CaP initiation. This finding has not previously been reported. Further characterization of this model, particularly in a setting of androgen deprivation, should allow further insight into the mechanisms by which the Tp53(R270H) mutation mediates CaP progression.
Assuntos
Substituição de Aminoácidos/genética , Progressão da Doença , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteína Supressora de Tumor p53/genética , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Heterozigoto , Proteínas de Homeodomínio/metabolismo , Humanos , Imunofenotipagem , Integrases/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Especificidade de Órgãos , Neoplasia Prostática Intraepitelial/enzimologia , Neoplasia Prostática Intraepitelial/patologia , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Androgênicos/metabolismo , Reprodutibilidade dos Testes , Fatores de Transcrição/metabolismoRESUMO
Malignant melanoma (MM) is a life-threatening disease characterized by a highly aggressive biologic behavior in both humans and dogs. Despite improvements in diagnosis and patient care, most deaths from MM are due to metastases that are resistant to conventional treatment modalities. To ultimately reduce the mortality associated with metastatic disease, it is necessary to better define the fundamental molecular mechanisms of malignant tumor progression. The progression of disease is a consequence of the complex interactions between malignantly transformed cells and host factors. Characterization of the stages of tumor progression and the changes occurring in highly malignant cells is important for the development of effective treatment regimens. The dys-regulated molecular mechanisms of transformed melanocytes are presently being characterized. In this review, we summarize the current understanding of the molecular phases in the progression of MM, which include genetic instability, dysregulated proliferation of melanocytes, increased invasion and metastasis, and angiogenesis.
Assuntos
Doenças do Cão/patologia , Melanoma/veterinária , Neoplasias Cutâneas/veterinária , Animais , Ciclo Celular/genética , Divisão Celular/genética , Progressão da Doença , Doenças do Cão/genética , Doenças do Cão/imunologia , Cães , Predisposição Genética para Doença/genética , Melanócitos/citologia , Melanócitos/imunologia , Melanócitos/patologia , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Neovascularização Patológica/veterinária , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologiaRESUMO
In veterinary medicine, our understanding of the biology and regulation of melanocytic function is mostly based on information realized from human and murine studies. Improved understanding of the biology of melanocytes is needed to develop more effective treatment regimens for malignant melanoma and other melanocytic disorders. In vertebrates, melanocytes are well known for their role in skin pigmentation, hair and feather coloration, and for their ability to produce and distribute melanin to surrounding keratinocytes. Enzymes involved in melanin synthesis are present exclusively in melanosomes. The type of melanin synthesized by melanocytes in mammals is regulated at a genetic, biochemical and environmental level. These regulatory factors affect not only the phenotypic appearance, but also the photoprotective properties of melanin. This review addresses the biology of melanocytes, melanin synthesis and the photoprotective properties of melanin.
