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Ipertesto Neoplasie

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   Scheda a cura di Marco Chilosi  (GYM)      

p57^kip2  **

Importante inibitore del ciclo cellulare (interagisce con la formazione di complessi molecolari tra cicline e cyclin-dependent kinases - cdk) è codificato da un gene incluso tra quelli soggetti a imprinting  genomico di tipo materno. 

La proteina p57^KIP2  è correlata strutturalmente ad altri inibitori delle cdk, in particolare p21^CIP1 e p27^KIP1 ,  ed agisce bloccando il ciclo in G1. 

Una prova diretta dell'importanza dell'inibitore nella differenziazione è data da topi privi di questo gene, che presentano alterazioni della proliferazione cellulare e della differenziazione (analoghi a quelli osservati nella sindrome Beckwith-Wiedemann, una malattia legata da anomalie del gene p57^KIP2 ).

Diversamente da altri inibitori di cdk p57^KIP2   ha una distribuzione ristretta nei tessuti umani (p21waf1 è infatti inducibile da p53 mentre p27kip1 è espressa in moltissimi tessuti nella componente cellulare quiescente).

Distribuzione nei tessuti normali

intensa espressione nucleare di p57^kipnelle cellule stromali della decidua. L'epitelio CK8/18+ non esprime  .p57^kip2

Le mole diploidi (complete) originano da errori di concepimento, con la formazione di zigoti il cui genoma è di derivazione esclusivamente paterna. I geni soggetti ad imprinting materno quindi non sono espressi. Le mole diploidi sono caratterizzate da ipo-espressione di p57kip2 , particolarmente evidente nel citotrofoblasto, mentre gli aborti triploidi e le mole parziali sono caratterizzati da normale espressione in tutte le componenti trofoblastiche.

Il citotrofoblasto non esprime p57^kip2 a livello nucleare come nel villo normale .Doppia colorazione p57^kip2 (perossidasi), citocheratina 8/18 (immunocolorazione in rosso/ alk-phosph) 

   I villi della mola diploide NON esprimono p57^kip2 a livello nucleare

Il trofoblasto extravilloso nella mola diploide esprime in percentuali significativamente minori p57^kip2 a livello nucleare (10-30% delle cellule)

p57^kip2 / CK8/18              

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Lab Invest 1998 Mar;78(3):269-76

Differential expression of p57kip2, a maternally imprinted cdk inhibitor, in normal human placenta and gestational trophoblastic disease.

Chilosi M, Piazzola E, Lestani M, Benedetti A, Guasparri I, Granchelli G, Aldovini D, Leonardi E, Pizzolo G, Doglioni C, Menestrina F, Mariuzzi GM.
Istituto di Anatomia Patologica, University of Verona, Italy.
    Evidence has recently been provided to support a role for genomic imprinting in the regulation of embryonic implantation and development and placental growth, as well as in the pathogenesis of proliferative trophoblastic diseases. The cyclin-dependent kinase inhibitor p57KIP2 has recently been recognized as a maternally imprinted gene. We investigated p57KIP2 expression in first-trimester normal placentas from interrupted pregnancy, spontaneous abortions, and different types of proliferative trophoblastic diseases using single- and double-marker immunohistochemical techniques. In normal placenta, nuclear p57KIP2 expression was observed at high frequency (up to 100%) in extravillous trophoblast, cytotrophoblast, and implantation-site interstitial trophoblast, but was absent in syncytiotrophoblast. p57KIP2 was also expressed in the stromal cells of maternal decidua, which was one of the few adult tissues retaining p57KIP2 expression (most other adult tissues investigated were negative). p57KIP2 expression was either absent or low in all cases of diploid/tetraploid complete moles (20 cases) and in three cases of gestational choriocarcinoma. On the other hand, all spontaneous abortions (12 cases) and triploid partial moles (19 cases) showed p57KIP2 levels comparable to those observed in normal placenta. These findings are in line with the hypothesis that deregulation of genomic imprinting, particularly the loss of cell-cycle inhibitors such as p57KIP2, is involved in the abnormal development of androgenetic trophoblastic proliferations. In addition, this simple immunohistochemical analysis could provide a useful diagnostic marker in difficult cases.

Adv Clin Path 1998 Jan;2(1):15-24

Genomic imprinting in human biology and pathology.
Chilosi M, Lestani M, Piazzola E, Guasparri I I, Mariuzzi GM.
Department of Anatomical Pathology, University of Verona, Verona, 37134, Italy.
    Evidence has been recently provided on the relevant role of genomic imprinting in the regulation of implantation, embryonic development, placental growth, and also in development of proliferative trophoblastic diseases and human carcinogenesis. Among the various imprinted genes the cyclin-dependent-kinase inhibitor p57KIP2 (maternally imprinted) is particularly interesting since it can function as a tumor suppressor gene. In this review we describe the different roles of genomic imprinting in human diseases, with particular emphasis on the role of p57KIP2 in molar pregnancy and in tumorigenesis.

I dati sull'espressione di p57 e la sua applicazione nella patologia  del trofoblasto sono stati confermati in studi successivi da altri gruppi:

Am J Surg Pathol 2001 Oct;25(10):1225-30

Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2.
Castrillon DH, Sun D, Weremowicz S, Fisher RA, Crum CP, Genest DR.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. dcastrillon@partners.org
    The p57KIP2 protein is a cell cycle inhibitor and tumor suppressor encoded by a strongly paternally imprinted gene. We explored the utility of p57KIP2 as a diagnostic marker in hydatidiform mole, a disease likely the result of abnormal dosage and consequent misexpression of imprinted genes. Using a monoclonal antibody on paraffin-embedded, formalin-fixed tissue sections, the authors evaluated p57KIP2 expression in normal placenta and in 149 gestations including 59 complete hydatidiform moles, 39 PHMs, and 51 spontaneous losses with hydropic changes. p57KIP2 was strongly expressed in cytotrophoblast and villous mesenchyme in normal placenta, all cases of partial hydatidiform moles (39 of 39) and all spontaneous losses with hydropic changes (51 of 51). In contrast, p57KIP2 expression in cytotrophoblast and villous mesenchyme was absent or markedly decreased in 58 of 59 complete hydatidiform moles. In all gestations p57KIP2 was strongly expressed in decidua and in intervillous trophoblast islands, which served as internal positive controls for p57KIP2 immunostaining. p57KIP2 immunohistochemistry can reliably identify most cases of complete hydatidiform mole irrespective of gestational age and is thus a useful diagnostic adjunct, complementary to ploidy analysis, in the diagnosis of hydatidiform mole.

 

Histopathology. 2003 Jul;43(1):17-25. 

p57kip2 is useful in the classification and differential diagnosis of complete and partial hydatidiform moles. 

Jun SY, Ro JY, Kim KR. 

Department of Pathology, University of Ulsan College of Medicine, Asan Medical Centre, Seoul, Korea.

    AIMS: To determine the utility of p57kip2 in the diagnosis of hydatidiform mole. p57kip2 protein is a cyclin-dependent kinase inhibitor (CDKI) and is strongly paternally imprinted, being expressed from the maternal allele. It has been hypothesized that complete mole (CHM) with only the paternal genome would display reduced or nearly absent expression of p57kip2 compared to partial mole (PHM) having both paternal and maternal genomes. METHODS AND RESULTS: The immunohistochemical expression of p57kip2 protein was investigated using paraffin-embedded tissue sections in histologically unequivocal cases of CHM (n = 51), PHM (n = 7), invasive mole (n = 1), and hydropic miscarriage (n = 2), as well as in histologically undetermined cases (n = 9). In the histologically unequivocal complete and invasive moles, expression of p57kip2 was absent except for one case in which villous cytotrophoblast covering the villous stroma was positive (51/52) as well as villous stromal cells (51/52). In contrast, it was strongly and continuously expressed in both villous cytotrophoblast and stromal cells in all cases of PHM and hydropic miscarriage. Among the nine histologically undetermined cases, five cases showing p57kip2 immunopositivity and hyperploid DNA were classified as PHMs, two cases showing p57kip2 immunonegativity and hyperploidy as CHMs, and two cases with p57kip2 immunopositivity and diploid DNA as hydropic miscarriage and diploid PHM, respectively, upon review of the histopathological findings. Intermediate trophoblast forming trophoblastic columns or anchoring villi and extravillous trophoblast at the implantation site showed variable expression of p57kip2 in all gestational conditions. Maternal decidua showed diffuse and strong p57kip2 expression, whereas syncytiotrophoblast was completely negative in all cases regardless of the diagnosis. CONCLUSIONS: In summary, p57kip2 immunostaining results correlated well with morphological features of molar pregnancies and were helpful in determining histologically equivocal cases. PMID: 12823708 [PubMed - in process]