Precancerous Lesions and Conditions of the Prostate

Montironi, Rodolfo; Mazzucchelli, Roberta; Scarpelli, Marina

doi:10.1111/j.1749-6632.2002.tb04108.x

Cited by 54 publications

(8 citation statements)

References 68 publications

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“…They play fundamental roles in several processes, including tissue remodelling, inflammation, wound healing, fibrosis, cell migration, and metastasis, among others (Ellerbroek and Stack 1999). MMPs are synthesized as pro-enzymes and are activated upon proteolytic cleavage in the extracellular space (Montironi et al 2002). MMP-2, also known as gelatinase A, can degrade collagens, gelatin, elastin, fibronectin, laminins, and is possibly involved in the activation of other MMPs, such as MMP-9 and MMP-13 (Fridman et al 2009).…”

Section: Resultsmentioning

confidence: 99%

“…MMPs exist in the matrix as pro-enzymes and are activated upon proteolytic cleavage. Unlike other MMPs, the activation of MMP-2 occurs at the cell surface (Montironi et al 2002), a feature which confers to this enzyme a central role in cell migration. It requires the binding of membrane type 1 MMPs (MT1-MMPs) with the tissue inhibitor of metalloproteinase type 2 (TIMP2) (Lehti et al 1998; Nagase et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, it is well established that such lesions represent a common precursor site for overt neoplasia (Clark et al 1984; Foulds 1975; Hruban et al 2000; Hytiroglou et al 2007; Montironi et al 2002; Noffsinger 2009; Schreer and Lüttges 2005; Su et al 1997), thus implying that gaining insights into their biology and pathogenesis bears direct relevance to our understanding of the natural history of neoplastic disease.…”

Section: Introductionmentioning

confidence: 99%

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The growth pattern of transplanted normal and nodular hepatocytes

Doratiotto

Krause

Serra

et al. 2011

Histochem Cell Biol

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Overt neoplasia is often the end result of a long biological process beginning with the appearance of focal lesions of altered tissue morphology. While the putative clonal nature of focal lesions has often been emphasized, increasing attention is being devoted to the possible role of an altered growth pattern in the evolution of carcinogenesis. Here we compare the growth patterns of normal and nodular hepatocytes in a transplantation system that allows their selective clonal proliferation in vivo. Rats were pre-treated with retrorsine, which blocks the growth of resident hepatocytes, and were then transplanted with hepatocytes isolated from either normal liver or hepatocyte nodules. Both cell types were able to proliferate extensively in the recipient liver, as expected. However, their growth pattern was remarkably different. Clusters of normal hepatocytes integrated in the host liver, displaying a normal histology; however, transplanted nodular hepatocytes formed new hepatocyte nodules, with altered morphology and sharp demarcation from surrounding host liver. Both the expression and distribution of proteins involved in cell polarity, cell communication, and cell adhesion, including connexin 32, E-cadherin, and matrix metalloproteinase-2, were altered in clusters of nodular hepatocytes. Furthermore, we were able to show that down-regulation of connexin 32 and E-cadherin in nodular hepatocyte clusters was independent of growth rate. These results support the concept that a dominant pathway towards neoplastic disease in several organs involves defect(s) in tissue pattern formation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The growth pattern of transplanted normal and nodular hepatocytes

Doratiotto

Krause

Serra

et al. 2011

Histochem Cell Biol

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“…In addition, using in situ hybridization, we recently found greater SENP1 mRNA levels in precancerous prostatic intraepithelial neoplasia (PIN) compared with adjacent normal prostate epithelia (10). Transformation of the normal prostate epithelia to carcinoma is preceded by the development of this well characterized PIN state (11). The presence of elevated SENP1 levels in this precursor state posed the question as to whether SENP1 induction is not associated merely with the carcinoma but instead could directly contribute to prostate carcinogenesis.…”

mentioning

confidence: 99%

SENP1 Induces Prostatic Intraepithelial Neoplasia through Multiple Mechanisms

Bawa-Khalfe

Cheng

Lin

et al. 2010

Journal of Biological Chemistry

101

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SUMOylation has been shown to modulate DNA replication/ repair, cell cycle progression, signal transduction, and the hypoxic response. SUMO (small ubiquitin-like modifier)-specific proteases regulate SUMOylation, but how changes in the expression of these proteases contribute to physiological and/or pathophysiological events remains undefined. Here, we show that SENP1 (sentrin/SUMO-specific protease 1) is highly expressed in human prostate cancer specimens and correlates with hypoxia-inducing factor 1␣ (HIF1␣) expression. Mechanistic studies in a mouse model indicate that androgen-driven expression of murine SENP1 leads to HIF1␣ stabilization, enhanced vascular endothelial growth factor production, and angiogenesis. Further pathological assessment of the mouse indicates that SENP1 overexpression induces transformation of the normal prostate gland and gradually facilitates the onset of high-grade prostatic intraepithelial neoplasia. Consistent with cell culture studies, SENP1 enhances prostate epithelial cell proliferation via modulating the androgen receptor and cyclin D 1 . These results demonstrate that deSUMOylation plays a critical role in prostate pathogenesis through induction of HIF1␣-dependent angiogenesis and enhanced cell proliferation.SUMO (small ubiquitin-like modifier) modification of protein substrates is a dynamic process that modulates the target protein's expression, function, and/or subcellular location (1, 2). SUMOylation is regulated by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes and reversed by a family of sentrin/SUMO-specific proteases (3-5). These enzymes are critical for maintaining a balance between the level of SUMOylated and unmodified cellular substrates and hence play an important role in mediating normal cellular physiology.Several large-scale gene expression studies report changes in the levels of SUMO E1, E2, and SENP1 (sentrin/SUMO-specific protease 1) in various cancers, suggesting an imbalance in the SUMO system (6 -9). SENP1 mRNA levels are elevated in thyroid oncocytic adenocarcinoma (6) and human prostate cancer (PCa) 3 (10). In addition, using in situ hybridization, we recently found greater SENP1 mRNA levels in precancerous prostatic intraepithelial neoplasia (PIN) compared with adjacent normal prostate epithelia (10). Transformation of the normal prostate epithelia to carcinoma is preceded by the development of this well characterized PIN state (11). The presence of elevated SENP1 levels in this precursor state posed the question as to whether SENP1 induction is not associated merely with the carcinoma but instead could directly contribute to prostate carcinogenesis.Recently, we demonstrated that SENP1 enhances the stability of hypoxia-inducing factor 1␣ (HIF1␣) and, consequently, HIF1␣-mediated transcription; in the absence of SENP1, HIF1␣ is actively SUMOylated and subsequently degraded under hypoxic conditions (12). In prostate carcinogenesis, hypoxic tissue environments emerge due to rapidly proliferating cancer cells, and HIF1␣ is post...

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“…também observou uma menor intensidade de marcação e uma menor porcentagem de células positivas para este receptor em ácinos prostáticos em meio a prostatite em relação a ácinos normais ou hiperplásicos, em próstata canina.Já na PIN, o que chamou a atenção foi a heterogenidade em relação à expressão do AR, em que uma mesma lesão apresentava núcleos exibindo marcação discreta, moderada ou intensa, sendo em geral de menor intensidade em relação aos núcleos de ácinos normais ou hiperplásicos.Não há relatos na literatura em relação a este receptor na PIN canina. Já em humanos, as células de PIN apresentam marcação nuclear para o AR(HARPER et al, 1998;MAZZUCCHELLI;SCARPELLI, 2002).A menor expressão de AR nas PINs observadas neste estudo pode ser devido à origem a partir de células basais malignas presentes entre as células basais, visto que uma parte destas não apresenta marcação para este receptor. Estas células proliferariam, diferenciar-se-iam parcialmente ou totalmente, e uma parte delas poderia passar a expressar o AR.…”

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Caracterização da próstata canina quanto a aspectos envolvidos na evolução para o carcinoma prostático

Terazaki¹

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Precancerous Lesions and Conditions of the Prostate

Cited by 54 publications

References 68 publications

The growth pattern of transplanted normal and nodular hepatocytes

The growth pattern of transplanted normal and nodular hepatocytes

SENP1 Induces Prostatic Intraepithelial Neoplasia through Multiple Mechanisms

Caracterização da próstata canina quanto a aspectos envolvidos na evolução para o carcinoma prostático

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